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Abstract Background Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease caused by insufficient functional survival motor neuron protein (SMN). The SMN expression level in the spinal cord is highest during the 2nd trimester of the foetal period. We previously reported the SMN spot analysis in peripheral blood using imaging flow cytometry (IFC) as a biomarker of functional SMN protein expression. In this study, we analysed neonatal cord blood, postnatal peripheral blood, and maternal peripheral blood in presymptomatic five infants whose sibling has type 1 SMA to estimate prenatal and postnatal SMN dynamics before the onset of severe SMA. Results Data from 37 untreated patients with SMA showed that SMN-spot+ cells were significantly correlated with SMA clinical classification and the copy numbers of the SMN2 gene. The range of values for cord blood, converted from each SMN2 copy number statistics, was − 0.7 to + 2.0 standard deviation (SD) (0.1–24.0%) for SMN-spot+ cells in patients with SMA. Subsequent analyses of the peripheral blood of neonates ranged from − 0.8 to + 0.8 SD (0.4–15.2%). The analysis of each maternal blood, converted from carrier statistics, ranged from − 0.2 to + 2.4 SD (1.4–25.2%). A correlation was observed between the cord blood and maternal peripheral blood. Conclusions This study suggests that the status of the motor neuron pool in the spinal cord can be presumed by cord blood SMN-spot+ cells and that SMN protein depletion determines the timing of disease onset. As the SMN spot analysis values tended to decrease with time after birth, they may eventually lead to the development of SMA. Furthermore, a correlation was found between the SMN spot analysis values of neonatal cord blood and maternal blood, which predicts disease severity after birth. In other words, the SMN protein supplied from the mother to the foetus may suppress the development of SMA in the infant at birth, and depletion of the SMN protein may occur after birth, causing the infant to develop SMA. Our findings demonstrated the effectiveness of newborn screening and the potential of maternally mediated treatment strategies by providing a rationale for prompt treatment initiation in SMA.

Abstract This study aimed to identify trends and factors in postpartum depression after the Fukushima nuclear accident among women who participated in the Fukushima Health Management Survey (FHMS). We analyzed the prevalence of depressive symptoms and concerns about radiation exposure using FHMS data from FY2011-FY2018. We also analyzed the characteristics of women who did not have depressive symptoms in the postpartum period but had developed them at 4 years after childbirth and women with depressive symptoms in the postpartum period but had improved at 4 years after childbirth. In this survey, depressive symptoms were evident in 23.1% of women in the postpartum period. Factors significantly associated with developing depressive symptoms at 4 years after childbirth were younger maternal age, not being healthy, lacking maternal confidence, history of mental illness, and not intending to become pregnant again because of radiation effects. Improvement from initial depressive symptoms at 4 years after childbirth was associated with being very healthy, having maternal confidence, no medical history, no history of mental illness, having received sufficient perinatal care, and intending to become pregnant again. Our results suggest the need for comprehensive assessment of depression risks for prevention and thorough continuous professional care for disaster affected women with postpartum depression.

Abstract To determine the efficacy and safety of selective laser trabeculoplasty (SLT) in patients with uveitic glaucoma, we retrospectively evaluated 17 eyes from 13 consecutive uveitic glaucoma cases who were treated with SLT due to inadequate interocular pressure (IOP) control despite glaucoma medical therapy. The mean IOP was significantly decreased from 28.4 ± 6.50 mmHg to 17.3 ± 9.4 mmHg at baseline, and 6 months after SLT, respectively (P

Abstract This study aimed to evaluate whether the subjective global assessment (SGA) could effectively predict energy malnutrition, as assessed by indirect calorimetry, and mortality in hospitalized patients with cirrhosis. Energy malnutrition was defined by a nonprotein respiratory quotient (npRQ)

Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease. Most patients with SMA have a mutation in the survival motor neuron 1 (SMN1) gene on chromosome 5q. With current genetic testing, SMN1 copy number is determined; a diagnosis is reached when the copy number is zero. When the SMN1 copy number is 1, exons and intron/exon boundaries of the allele are examined for single-nucleotide variants (SNVs). Genetically undiagnosed cases of SMA exist when 2 copies of SMN1 exist or when a SNV is in the deep intron. Furthermore, SMN1 is highly homologous to SMN2; therefore, it is expected that many SNVs have not been elucidated. Methods This retrospective observational study conducted in Japan used pre-collected DNA samples from patients with clinically diagnosed SMA. Enrollment period was January 28, 2020 to September 30, 2021. SNV analysis of SMN1 (exon 1–8 and intron 1–7) was conducted by long-range polymerase chain reaction and next-generation sequencing. Results From 336 DNA samples collected from patients, 62 patient samples were included in the SNV analysis. Two patients have been genetically diagnosed (a heterozygous variant in intron 6 with 1 copy of SMN1; a homozygous missense mutation in exon 3 with 2 copies of SMN1). Three SNVs in intron 6, c.834+1506A>G (n = 9), c.834+1751G>A (n = 2), and c.835-367C>A (n = 5) were identified; all were numerically, and c.834+1506A>G and c.835-367C>A were significantly, more frequent in patients with 0 copies versus those with ≥ 1 copy of exon 7 in SMN1. We confirmed 3 hybrid SMN gene types in 5 patients that contained SMN2 gene sequence (aaTgg) flanked by upstream “t” and downstream “G” SMN1 sequence. Conclusions In this study of patients with clinically diagnosed SMA, 2 cases with genetic SMN types were identified that would not have been identified through current genetic testing, which examines SMN1 deletions only. Furthermore, for 1 patient with a homozygous SMN1 missense mutation, SMA was not suspected by the current copy number screening method. This study demonstrated the importance of performing full-length sequencing for clinically diagnosed SMA to complement current screening methods. Trial registration: University Hospital Medical Information Network Clinical Trials Registry (Number: UMIN000040095).

Abstract Background Droplet digital PCR (ddPCR) is a highly sensitive tool for detecting bacterial DNA in bacterial bloodstream infections (BSI). This study aimed to examine the sensitivity and specificity of ddPCR and the association between bacterial DNA load in whole blood and the time-to-positivity (TTP) of blood culture (BC) in patients with Escherichia coli BSI. Methods This prospective study enrolled patients with E. coli BSI confirmed via BC at the Hiroshima University Hospital from June 2023 to August 2024. The E. coli DNA load in whole blood, which was simultaneously obtained from two BC sets, was measured using ddPCR with E. coli specific primer and probe. Whole blood samples from 50 patients with BC positive for pathogens other than E. coli (n = 25) and BC negative (n = 25) were also evaluated using ddPCR. Results A total of 131 patient samples were analyzed in this study. Of the 81 patients with E. coli BSI, ddPCR detected E. coli DNA in 67 (82.7%). The results of ddPCR for E. coli had a sensitivity of 82.7% (95% CI: 73.1–89.4%), specificity 100% (95% CI: 93.0–100%). Patients with positive ddPCR results had significantly shorter TTP than those with negative results (median, 8.8 h vs. 10.7 h, p

Abstract Biliary and pancreatic tract stenosis are hallmark symptoms in pancreaticobiliary diseases, transcending malignancy. Endoscopic techniques are pivotal for biliary/pancreatic drainage; however, challenging scenarios arise when attempting to pass a guidewire (GW) through obstruction. Cholangioscopy-assisted GW placement has proven valuable, but challenges persist in its execution, particularly in maneuvering the GW through cholangioscopy. Therefore, we explored the integration of a 3-Fr microcatheter into cholangioscopy with the aim of enhancing direct visualization and offering a super-selective approach. When GW manipulation under a digital single-operator cholangioscope (D-SOC) guidance was still unsuccessful in a resistant obstruction, the 3-Fr microcatheter was introduced. This technique was performed in 42 individuals for 37 biliary and 5 pancreatic duct drainages, among which there were 19 malignant, 18 benign, and 4 anastomotic obstructions. In all patients, contrast-filled cholangiography in the target area couldn’t be achieved at the pre-microcatheter insertion stage due to obstruction. The technical success rate was 85.7% overall, 89.5% in malignant strictures, 84.2% in benign strictures, and 75.0% in anastomotic obstructions, resulting in a clinical success rate of 78.6%. The use of a 3-Fr microcatheter appears effective for endoscopic drainage performed for obstruction. This technique could pave the way for improved outcomes in patients with pancreaticobiliary diseases.

Accurately identifying neoantigens is crucial for developing effective cancer vaccines and improving tumor immunotherapy. Mass spectrometry-based immunopeptidomics has emerged as a promising approach to identifying human leukocyte antigen (HLA) peptides presented on the surface of cancer cells, but false-positive identifications remain a significant challenge. In this study, liquid chromatography-tandem mass spectrometry-based proteomics and next-generation sequencing were utilized to identify HLA-presenting neoantigenic peptides resulting from non-synonymous single nucleotide variations in tumor tissues from 18 patients with renal cell carcinoma or pancreatic cancer. Machine learning was utilized to evaluate Mascot identifications through the prediction of MS/MS spectral consistency, and four descriptors for each candidate sequence: the max Mascot ion score, predicted HLA binding affinity, aliphatic index and retention time deviation, were selected as important features in filtering out identifications with inadequate fragmentation consistency. This suggests that incorporating rescoring filters based on peptide physicochemical characteristics could enhance the identification rate of MS-based immunopeptidomics compared to the traditional Mascot approach predominantly used for proteomics, indicating the potential for optimizing neoantigen identification pipelines as well as clinical applications.

Abstract The 3′ untranslated region (3′UTR) plays a crucial role in determining mRNA stability, localisation, translation and degradation. Cap analysis of gene expression (CAGE), a method for the detection of capped 5′ ends of mRNAs, additionally reveals a large number of apparently 5′ capped RNAs derived from locations within the body of the transcript, including 3′UTRs. Here, we provide direct evidence that these 3′UTR-derived RNAs are indeed capped and widespread in mammalian cells. By using a combination of AGO2 enhanced individual nucleotide resolution UV crosslinking and immunoprecipitation (eiCLIP) and CAGE following siRNA treatment, we find that these 3′UTR-derived RNAs likely originate from AGO2-binding sites, and most often occur at locations with G-rich motifs bound by the RNA-binding protein UPF1. High-resolution imaging and long-read sequencing analysis validate several 3′UTR-derived RNAs, showcase their variable abundance and show that they may not co-localise with the parental mRNAs. Taken together, we provide new insights into the origin and prevalence of 3′UTR-derived RNAs, show the utility of CAGE-seq for their genome-wide detection and provide a rich dataset for exploring new biology of a poorly understood new class of RNAs. Graphical Abstract Schematic representation of the proposed model where 3′UTR-derived RNAs originate from G-rich regions enriched in AGO2 and UPF1 binding sites.

Background/purpose: Cognitive flexibility is a personality trait, which can influence how effectively a healthcare professional can manage a challenging clinical situation. This study explored the cognitive flexibility of undergraduate dental hygiene students at two universities in Asia to gather baseline information in order to consider whether there was an educational need for pre-clinical students with regards to this personality factor. Materials and methods: Participants were all undergraduate dental hygiene students in the 2022 academic year at Tokyo Medical and Dental University (TMDU; n = 79) and Taipei Medical University (TMU; n = 88). An anonymous questionnaire was distributed, which included questions on demographic information and the Cognitive Flexibility Inventory (CFI). Results: The response rates were 97.5% (TMDU) and 89.8% (TMU). The CFI total scores were 91.77 for TMDU and 95.87 for TMU, and there was no significant difference between the two schools. The Alternatives scores were significantly higher in TMU than TMDU (P = 0.044), but there were no significant differences in the Control scores between the two schools. There were also no significant differences between school years of both universities. Conclusion: The dental hygiene students from both dental schools exhibit moderate cognitive flexibility. The educators in both dental schools may consider whether they should investigate and develop this personality factor further during the undergraduate training of their dental hygiene students.

Abstract The antigen-mediated B cell isolation method, based on the detection of surface IgG (sIgG), has increased the efficiency of therapeutic antibody (Ab) discovery. However, the reduction in sIgG expression on B cells during plasma cell differentiation presents challenges as it enables Ab production from only a small subset of B cells (e.g., memory B cells). The present study aimed to addressed this problem by developing a workflow to isolate human-IgG-secreting hybridoma cells produced by cell fusion, the majority of which express sIgG. We showed that our sIgG-based antigen-coated bead separation method efficiently enriched hybridoma cells expressing antigen-specific Abs with a yield of 83.5% (from the cell fusion pool) and a positive rate of 73.2%. Furthermore, because the separation could be performed after only a short (1–2-day) culture period following cell fusion, diverse hybridoma clones could be obtained, minimizing clonal selection and the incidence of duplicates. Given that the expression of membrane-bound IgG and sIgG are regulated by different splicing mechanisms, we speculate that the cell fusion step potentially attenuated the suppression of human sIgG expression. Overall, our proposed method is expected to markedly improve the efficiency of therapeutic Ab candidate production, which will have important clinical implications.

Abstract Recent studies indicate a potential link between oral health and cognitive function; however, long-term associations remain unclear. This study aimed to identify oral health factors that predict changes in cognitive function among older adults over time. The study included 583 independent older adults (201 male, 382 female) with a mean age of 72.7 years. Cognitive function was assessed using Mini-Mental State Examination (MMSE) at baseline and follow-up over two years, with relative change in MMSE (rMMSE) calculated. Baseline oral health variables included number of remaining teeth, masticatory performance, occlusal force, oral diadochokinesis and tongue pressure. Physical performance and confounding factors were also considered. The relationship between rMMSE and the variables was analyzed using Pearson’s correlation, Mann-Whitney U test, and multiple linear regression analysis. Cognitive function declined in 196 subjects, with rMMSE significantly correlated with oral diadochokinesis. Regression analysis revealed significant associations between cognitive changes and oral diadochokinesis (p = 0.020) and knee extension strength as a physical performance (p = 0.047). Our findings suggest that cognitive decline may be indicated by declines in both physical and oral motor performance. Incorporating oral diadochokinesis testing into health screenings could aid early detection of cognitive decline, improving outcomes and reducing healthcare burdens.

(1) Background: The number of patients with cancer undergoing cancer genome profiling is increasing; however, it remains unclear how accurately they understand the details of the tests and treatments. This study aimed to clarify the awareness of cancer genome profiling tests among patients with cancer who visited cancer genome medical clinics. (2) Methods: A questionnaire survey was conducted on awareness, anxiety, sources of information, and psychological states concerning cancer genome profiling tests. (3) Results: In total, 265 patients with cancer (117 men, 142 women, 6 no response, average age of 58.29 ± 11.9 years) were included in the study, of which 218 (82.3%) were aware of the term “cancer genomic medicine” and 90 (34.0%) were aware of its details. Thus, only a few respondents understood that cancer genome profiling tests facilitate the discovery of secondary findings and of genes associated with hereditary tumors. Regarding their psychological state when visiting the cancer genome clinic, the respondents were anxious about standard treatment and prognosis limits. (4) Conclusions: From the viewpoint of advance care planning, we suggest that medical professionals build a support system that links palliative care and cancer treatment and coordinates genetic counseling at an early stage.

Abstract Background We previously investigated methods for separating mutagenic contaminants from aqueous solutions using cellulose-bearing covalently bound trisulfo-Cu-phthalocyanine (blue cotton and blue rayon). Mutagenic contaminants with three or more fused aromatic rings in their structures were adsorbed onto blue cotton and rayon. Since Cu-phthalocyanine is considered an unsuitable absorption ligand for byproducts of water chlorination, such as 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (Mutagen X or MX), we investigated the development of a new material for the elimination of MX from aqueous solvents. Results We selected green cellulose powder bearing ferrous phthalocyanine (FePh), hereafter referred to as green cellulose or GP, as the candidate material. GP is composed of cationized cellulose (white cellulose, WP) and FePh tetracarboxylic acid. The mutagenicity of MX dissolved in buffer or dimethyl sulfoxide (DMSO) solution significantly decreased after treatment with GP. The effects of GP on the elimination of MX from the solvent were very close to being expired after 70 cycles of repeated adsorption of the same GP, and the capacity of GP for MX removal was estimated to be exhausted after 120 cycles of repeated adsorption based on the extrapolation of the obtained result; thus, the interacting ligands on GP may be saturated after complete MX adsorption. The mutagenicity of MX dissolved in aqueous buffer significantly decreased after treatment at pH7.4 but not at pH 4.0. Since MX is dissociated to be the anionic form at pH 6 or higher, the negative charge of MX in the buffer at pH 7.4 may interact with the positive charge of ferrous ions in GP to create a linkage between MX and GP. After GP adsorbed MX, mutagenicity was extracted with water or acetonitrile and recovered in the eluent. Thus, the reversible interaction between MX and FePh may have caused adsorption of MX onto GP. Conclusion GP could be used as a new eliminator and recovery agent for MX in chlorinated drinking water. Developing new materials for the removal and recovery of agents for the detection of mutagenic contaminant-related chlorination in water is beneficial for environmental health.

The synthesis of cellulose oligomers catalyzed by cellodextrin phosphorylase (CDP) can easily yield microcrystals with functional groups exposed on their surfaces using glucose derivatives with various functional groups at the C1 position as primers. In this study, we examined and compared the effects of primers with various structures on the structural characteristics of the resulting synthetic products. The yield of the synthetic products positively correlated with the CDP activity toward the primer, whereas the degree of polymerization (DP) and molecular weight distribution showed an inverse correlation. However, deviations from these trends were observed, suggesting the influence of varying solubilities and crystallization behaviors due to the introduction of functional groups. The obtained microcrystals exhibited a primarily plate-like shape with a thickness increasing in proportion to the DP, resulting in larger plate-like crystals at higher DP values. These findings provide insights into strategies for controlling the structure of the resulting cellulose oligomers.

Phase angle (PhA) has garnered increasing attention; however, its relationship with cognitive function has not been fully elucidated. This cross-sectional study explores the relationship between PhA using bioelectrical impedance analysis, and cognitive function among older adults with cognitive impairment in Japan, ranging from subjective cognitive decline to Alzheimer's disease. We hypothesized that lower PhA values, correlates with greater cognitive decline. To test this, we analyzed data from 726 cognitively impaired patients, focusing on variables such as PhA, walking speed, and cognitive assessments including the Mini-Mental State Examination. The results show that higher PhA values are significantly associated with improved cognitive performance, and no significant ''gender × PhA'' interaction was detected in the overall sample.

BackgroundA common definition of “subthreshold” is that the diagnostic threshold is not met but the individuals are not asymptomatic. Some symptoms are present, causing significant difficulty in functioning and negatively impacting quality of life. Despite the attention given to subthreshold symptoms and the interventions for subthreshold symptoms being efficient in preventing the transition to psychiatric disease in primary care, reports on specific interventions are insufficient. ObjectiveThis study aimed to verify the effectiveness of internet-delivered cognitive behavioral therapy (ICBT) for subthreshold depression (SD), subthreshold insomnia (SI), and subthreshold panic (SP). Additionally, this study aimed to explore the minimally important change (MIC) of each subthreshold group’s effectiveness outcome. MethodsParticipants aged 18-70 years from internet research monitors were categorized into SD, SI, and SP groups based on screening assessment. They were randomly assigned to intervention or control groups within each subthreshold symptom. The intervention groups worked on 4 weeks of nonguided ICBT (“Mentre”), while the control groups worked on a sham app. The primary outcome was the score change from screening (T1) to 4-week follow-up (T4) using the Center for Epidemiologic Studies Depression Scale (CESD) in the SD group, the Pittsburgh Sleep Quality Index (PSQI) in the SI group, and the Panic and Agoraphobia Scale (PAS) in the SP group. Secondary outcomes were score changes in the Generalized Anxiety Disorder-7 (GAD-7) scale, the Patient Health Questionnaire 9 (PHQ-9), the CESD, the PSQI, and the PAS, except the primary outcome in each group. Secondary outcomes were analyzed using complete-case analysis and repeated-measures ANOVA. Additionally, the MIC in the primary endpoint for each group was also calculated as an exploratory outcome. ResultsThe SD, SP, and SI groups contained 846, 597, and 1106 participants, respectively. In the SD group, the difference in the CESD score change from baseline to follow-up between the intervention and control groups was significant (difference=0.52, 95% CI 1.29-4.66, P

The omentum is a common site of peritoneal metastasis in various cancers, including gastric cancer. It contains immune cell aggregates known as milky spots, which provide a microenvironment for peritoneal immunity by regulating innate and adaptive immune responses. In this study, we investigated gene expression profiles in cells from omental milky spots of patients with gastric cancer (n = 37) by RNA sequencing analysis and classified the patients into four groups (G1-4). Notably, significant differences were observed between the groups in terms of macroscopic type, lymphatic invasion, venous invasion, and pathological stage (pStage). G3, which was enriched in genes related to acquired immunity, showed earlier tumor stages (macroscopic type 0, Ly0, V0, and pStage I) and a better prognosis. In contrast, G4 showed enrichment of genes related to neutrophils and innate immunity; G1 and G2 showed no enrichment of innate or adaptive immune-related genes, suggesting an immune desert microenvironment. Cytometric analysis revealed significantly more T and B cells and fewer neutrophils in G3. Accordingly, the immune microenvironment in omental milky spots may vary depending on the stage of gastric cancer progression. When univariate Cox proportional hazards regression models were used to search for prognostically relevant genes specific to G3, 23 potential prognostic genes were identified as common genes associated with relapse-free survival and overall survival. In addition, the multivariate Cox proportional hazards model using these prognostic genes and clinicopathological information showed that combining the B cell marker CD19 and Ly had a high predictive accuracy for prognosis. Based on this study’s results, it is possible that tumor progression, such as lymphatic and/or venous infiltration of tumor cells, may affect the immune cell composition and proportions in omental milky spots of patients with gastric cancer and analysis of gene expression in omental milky spots may help to predict gastric cancer prognosis.

ObjectiveThis multicenter, randomized, double-blind, placebo-controlled, crossover trial aimed to evaluate whether prolonged noisy galvanic vestibular stimulation improves body balance in patients with vestibulopathy.Materials and methodsThis trial was registered in the Japan Pharmaceutical Information Center Clinical Trials Information registry (jRCT1080224083). Subjects were 20- to 85-year-old patients who had been unsteady for more than one year and whose symptoms had persisted despite more than six months of rehabilitation. Enrolled subjects were randomly assigned to one of two groups; one group received the optimal intensity of noisy galvanic vestibular stimulation first and then the placebo 14 days later, the other was evaluated in the reverse order. The primary outcome was the difference of the mean percent change from the baseline in the velocity of center of pressure during 3 h of stimulation between the noisy galvanic vestibular stimulation and placebo periods. This was analyzed with the mixed effects model.ResultsForty-two subjects were enrolled. The mean percent change in the velocity during stimulation for 3 h was -9.3% (SD 19.9%) for noisy galvanic vestibular stimulation and -12.6% (SD 15.0%) for placebo. No significant effects of noisy galvanic vestibular stimulation over placebo were found for velocity in the least-squares means of the difference [3.1% (95% CI -0.2 to 6.4, p = 0.066)].ConclusionProlonged noisy galvanic vestibular stimulation did not significantly improve body balance in patients with poorly-compensated vestibulopathy.

ABSTRACT Unicentric Castleman's disease (UCD) typically presents as an asymptomatic tumour in the anterior or middle mediastinum. Occurrence in the paravertebral region is comparatively rare and it requires differentiation from neurogenic tumours by imaging. In our patient, preoperative imaging findings were atypical of schwannoma. Contrast‐enhanced MRI of the thoracic region showed a muscle‐like mass in contact with the pleura on T1‐weighted images. T2‐weighted images showed high signal, especially at the margins. Diffusion‐weighted images showed diffusion restriction around the limbus, and contrast‐enhanced T1‐weighted images displayed strong enhancement of the mass. Diagnosis could not be made preoperatively, although UCD was suspected. Thoracoscopic tumour resection was performed for definitive diagnosis and treatment and postoperative diagnosis was hyaline‐vascular‐type UCD. Diagnosis of neurogenic tumours can be difficult by imaging alone. When imaging findings are atypical, a definitive diagnosis is required, with consideration of the possibility of UCD.

BackgroundAlthough physical activity (PA) is recommended for patients with cancer, changes in PA across cancer diagnosis and treatment have not been objectively evaluated. ObjectiveThis study aimed to assess the impact of cancer diagnosis and treatment on PA levels. MethodsThis was a retrospective cohort study using a Japanese claims database provided by DeSC Healthcare Inc, in which daily step count data, derived from smartphone pedometers, are linked to the claims data. In this study, we included patients newly diagnosed with cancer, along with those newly diagnosed with diabetes mellitus for reference. We collected data between April 2014 and September 2021 and analyzed them. The observation period spanned from 6 months before diagnosis to 12 months after diagnosis. We applied a generalized additive mixed model with a cubic spline to describe changes in step counts before and after diagnosis. ResultsWe analyzed the step count data of 326 patients with malignant solid tumors and 1388 patients with diabetes. Patients with cancer exhibited a 9.6% (95% CI 7.1%-12.1%; P

Background Obsessive-compulsive disorder (OCD) is associated with an increased risk of morbidity and mortality due to cardiometabolic disorders. Whether this association is driven by familial factors is unknown. This population-based family study explored the familial co-aggregation of OCD and cardiometabolic disorders.Methods We identified 6 049 717 individuals born in Sweden between 1950 and 2008, including 50 212 individuals with OCD, and followed them up to 2020. These individuals were linked to their mothers, fathers, full siblings, maternal and paternal half siblings, aunts, uncles and cousins. We estimated the risk of cardiovascular diseases (CVD) and metabolic disorders (including obesity, type 2 diabetes and hyperlipidaemia), comparing the relatives of probands with and without OCD. Cox proportional hazards regression models, incorporating time-varying exposures, estimated HRs.Results OCD was associated with an increased risk of CVD (HR 1.47; 95% CI 1.43 to 1.51), obesity (HR 1.69; 95% CI 1.63 to 1.74), type 2 diabetes (HR 2.01; 95% CI 1.90 to 2.12) and hyperlipidaemia (HR 1.42; 95% CI 1.33 to 1.52). The relatives of probands with OCD exhibited small increased risks of CVD (HRs from 1.01 to 1.11) and obesity (HRs from 1.03 to 1.20). Slightly increased risks for type 2 diabetes were observed in mothers (HR 1.11; 95% CI 1.07 to 1.15) and full siblings (HR 1.12; 95% CI 1.05 to 1.20), while for hyperlipidaemia it was only observed in mothers (HR 1.06; 95% CI 1.02 to 1.10).Conclusions Our results do not support a major contribution of familial factors to the association between OCD and cardiometabolic disorders, suggesting a more prominent role of unique environmental factors.

Abstract Background Anamorelin is expected to improve cancer cachexia by increasing lean body mass (LBM) due to increased appetite and protein synthesis. However, the effect of anamorelin on cancer cachexia in real-world practice is unclear. The purpose of this study was to evaluate the efficacy and safety of anamorelin and to identify predictors of efficacy on treatment with anamorelin. Methods We retrospectively analyzed data from patients with cancer cachexia treated with chemotherapy between May 2021 and August 2022. Efficacy of anamorelin was evaluated using LBM, with “12-week sustained effective response” to anamorelin treatment defined as maintenance or an increase in LBM for 12 weeks. We examined factors associated with “12-week sustained effective response” to anamorelin treatment using a multivariable logistic model that included controlling nutritional status (CONUT) score, an objective assessment of nutritional disorders, and the modified Glasgow prognostic score (mGPS), which scores the cachexia status of cancer patients. To assess patient subjective quality of life (QOL) changes related to eating after starting anamorelin treatment, we used a questionnaire (QOL-ACD appetite-related items: Q8, 9, 11). Adverse events were evaluated in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results On analysis of data from 40 patients, 23 patients showed a 12-week sustained effective response to anamorelin (57.5%). At 12 weeks, LBM significantly increased by 1.63 ± 3.73 kg (mean ± SD). Multivariable logistic analysis revealed that a low CONUT score was significantly associated with “12-week sustained effective response” to anamorelin treatment (adjusted odds ratio: 13.5, 95% confidence intervals: 2.2–84.2, P = 0.004). QOL assessment showed a trend toward increased appetite and enjoyment of meals after anamorelin initiation. Five patients (12.5%) had an increase in HbA1c of more than 1.0% during the 12 weeks after the start of anamorelin. No patient had QT interval prolongation or grade 3 or higher hepatic transaminase elevation. Conclusion Anamorelin may maintain or increase LBM with tolerable safety in patients with cancer cachexia undergoing chemotherapy. A low CONUT score, despite meeting criteria for cancer cachexia, is suggested as a predictor for the efficacy of anamorelin, indicating that patients with a low CONUT score may benefit from early introduction of anamorelin.

Abstract Endoscopic submucosal dissection is a standard treatment for early esophageal squamous cell carcinoma. However, submucosal or lymphovascular invasion increases the risk of lymph node metastasis. Although 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) parameters are associated with prognosis in patients with advanced esophageal squamous cell carcinoma, the utility of FDG PET/CT in diagnosing superficial esophageal carcinoma remains unclear. This study aimed to investigate the association between FDG PET/CT parameters and histopathological findings in superficial esophageal carcinoma. Fifty-three patients with superficial esophageal cancer who underwent FDG PET/CT scans before undergoing interventions were retrospectively analyzed. The maximal standardized uptake value (SUVmax), metabolic tumor volume, and total lesion glycolysis were significantly higher in the cases with submucosal invasion (T1b) compared with those confined to the muscularis mucosa (T1a). In contrast, classification of intrapapillary capillary loops patterns with magnifying endoscopy did not yield statistical differences between T1a and T1b. Multivariable analysis revealed that SUVmax was the only independent predictor of submucosal and lymphovascular invasion. This study demonstrated that SUVmax may be useful in predicting submucosal and lymphovascular invasion. Thus, the value of SUVmax may guide clinical decision-making in superficial esophageal squamous cell carcinoma.

Notwithstanding the obvious interconnection between humans and the world that they share with non-human inhabitants, the impact of our changing climate on certain aspects of the public health ecosystem has been under-investigated. We briefly describe some of the possible climate-induced changes in the procurement, distribution, access and use of medications, including those for animals generally and livestock specifically. A fuller understanding of the effect of climate change on medicine supply, access, use and quality, including how these affect antimicrobial resistance, would contribute to the further development of the “One Health” and “One Health Systems” concepts. We suggest that this understanding is not yet available, even though the changing incidence of infectious diseases due to changing climate has been studied. There is a need for improved understanding of the impact of extremes of humidity and heat on medication quality and research into heat-stable medicines as well as strategies for the improving resilience of the pharmaceutical supply and distribution system in complex public health emergencies caused by aberrant weather patterns.

Abstract Aim Nonsuicidal self‐injury is common among adolescents. Dispelling related public misconceptions is essential for creating effective prevention and intervention strategies, as these myths contribute to stigmatization. This study examined the prevalence of self‐injury myths among the Japanese public and explored how demographics and personal experiences influence these beliefs. Methods A nationwide web‐based self‐report survey of 2000 Japanese adults (mean age = 44.6 ± 14.3 years) examined their agreement with 14 scientifically unsupported self‐injury beliefs. Endorsement rates for each myth were calculated, and the associations between myth beliefs and other variables were explored. Results Fourteen myths were analyzed, with endorsement rates of 21.0%–68.7%. Logistic regression analysis indicated that men were more likely to endorse the myth that self‐injury is uncommon (adjusted odds ratio [AOR] = 1.45, 95% confidence interval [CI] = 1.17–1.79), whereas women were more prone to myths about the rarity of self‐injury, using a single method, stimulation as the exclusive purpose, wrist‐cutting prevalence, and average onset age. Younger participants were more likely to believe that self‐injury is solely for stimulation than other age groups. Those with human‐service professional experience were more likely to view self‐injury as attention‐seeking compared to those without such experience (AOR = 1.62, 95% CI = 1.07–2.46). With some exceptions, individuals who expressed confidence in their ability to respond to self‐injurers were more likely to endorse the myths. Conclusion These findings highlight the need for targeted educational interventions to dispel misconceptions about self‐injury and improve public understanding of this complex behavior.

Background: Chickens are an important source of animal protein, nutrition, and income in many low- and middle-income countries (LMICs). They are also a major reservoir of enteropathogens that contribute to the burden of illnesses among children. Food systems present a risk for transmission of enteropathogens from poultry to humans, but there is a lack of population-level data on the pattern of purchase, ownership, and consumption of live chickens and their products in LMICs to better characterize that risk. Methods: To assess chicken purchase, ownership, and consumption practices, we conducted a population-based survey using a structured questionnaire in Maputo, Mozambique in 2021. Multi-stage cluster sampling was used to obtain a representative sample of households in our study area. To minimize sampling bias and ensure a representative sample, we applied survey weighting using district-level population data and estimated weighted population-level values. Results: Heads of 570 households in Maputo completed our survey. Approximately half of these households purchased broiler chicken meat (weighted percentage of households: 44.8 %) and eggs (46.5 %) in the previous week of the survey date, while indigenous chicken meat was less popular (1950, 1.1 %). The most common source of chicken products was corner stores (i.e., small convenience shops on streets), followed by wet markets. Live chickens were raised by 15.6 % of households, and chicken feces were observed on the floor or ground at the majority of these households during house visits. Discussion: Our findings suggest that poultry provides a major source of animal protein in this setting. Given the predicted growth of poultry farming in LMICs in the coming decades, implementing One Health-based food safety measures at primary sources of chicken products, such as corner stores and wet markets, will be critical to controlling zoonotic pathogen transmission risks.

Summary: Background: Emergence of SARS-CoV-2 variants that escape neutralising antibodies hampers the development of vaccines and therapeutic antibodies against SARS-CoV-2. IGHV3-53/3-66-derived public antibodies, which are generally specific to the prototype virus and are frequently induced in infected or vaccinated individuals, show minimal affinity maturation and high potency against prototype SARS-CoV-2. Methods: Monoclonal antibodies isolated from a Delta breakthrough infection case were analysed for cross-neutralising activities against SARS-CoV-2 variants. The broadly neutralising antibody K4-66 was further analysed in a hamster model, and the effect of somatic hypermutations was assessed using the inferred germline precursor. Findings: Antibodies derived from IGHV3-53/3-66 showed broader neutralising activity than antibodies derived from IGHV1-69 and other IGHV genes. IGHV3-53/3-66 antibodies neutralised the Delta variant better than the IGHV1-69 antibodies, suggesting that the IGHV3-53/3-66 antibodies were further maturated by Delta breakthrough infection. One IGHV3-53/3-66 antibody, K4-66, neutralised all Omicron subvariants tested, including EG.5.1, BA.2.86, and JN.1, and decreased the viral load in the lungs of hamsters infected with Omicron subvariant XBB.1.5. The importance of somatic hypermutations was demonstrated by the loss of neutralising activity of the inferred germline precursor of K4-66 against Beta and Omicron variants. Interpretation: Broadly neutralising IGHV3-53/3-66 antibodies have potential as a target for the development of effective vaccines and therapeutic antibodies against newly emerging SARS-CoV-2 variants. Funding: This work was supported by grants from AMED (JP23ym0126048, JP22ym0126048, JP21ym0126048, JP23wm0125002, JP233fa627001, JP223fa627009, JP24jf0126002, and JP22fk0108572), and the JSPS (JP21H02970, JK23K20041, and JPJSCCA20240006).

ABSTRACT The COVID‐19 pandemic made it difficult to obtain pharmaceutical‐grade injectable anaesthetics used in animal experiments in Japan. To address this problem, it is worth the effort to evaluate whether the use of non‐pharmaceutical‐grade sodium pentobarbital (PBNa) water solution can be an alternative one from the perspective of stability, physicochemical properties, bioavailability and so on. In this article, as a first step, we examined the stability of PBNa 5w/v% aqueous solution (PBNa 5% AS). PBNa 5% AS sample was prepared simply by dissolving non‐pharmaceutical‐grade PBNa into water and was stored at 25°C and 5°C for 15 days. Visual appearance, pH, osmolality and assay (contents of PBNa and related substances) were tested. The stability test results indicated that there was no profound change in these test items of the PBNa 5% AS under either storage condition, suggesting that the formulation was sufficiently stable in such a short term. The only observable change was an increase of an impurity under 25°C storage; however, it was at a negligible level. Moreover, as the pH of the formulation remained

The rates of appearance of new mutations play a central role in evolution. However, mutational processes in natural environments and their relationship with growth rates are largely unknown, particular in tropical ecosystems with high biodiversity. Here, we examined the somatic mutation landscapes of two tropical trees, Shorea laevis (slow-growing) and S. leprosula (fast-growing), in central Borneo, Indonesia. Using newly constructed genomes, we identified a greater number of somatic mutations in tropical trees than in temperate trees. In both species, we observed a linear increase in the number of somatic mutations with physical distance between branches. However, we found that the rate of somatic mutation accumulation per meter of growth was 3.7-fold higher in S. laevis than in S. leprosula. This difference in the somatic mutation rate was scaled with the slower growth rate of S. laevis compared to S. leprosula, resulting in a constant somatic mutation rate per year between the two species. We also found that somatic mutations are neutral within an individual, but those mutations transmitted to the next generation are subject to purifying selection. These findings suggest that somatic mutations accumulate with absolute time and older trees have a greater contribution towards generating genetic variation.

Abstract Nano/microfabrication is of fundamental importance both in scientific and industrial situations. There are, therefore, many attempts at realizing easier, quicker, and more precise fabrication of various structures; however, achieving this aim without a bulky and costly setup is still challenging. Here, we introduce a facile and versatile means of printing an ordered structure consisting of nanoscale stripes and more complicated geometries including pillars and wavy form with a lateral resolution of single micrometers. To this end, we prepare a polydimethylsiloxane (PDMS) slab with an oxygen plasma‐induced wrinkled surface where liquid PDMS exudes by syneresis. Since this liquid PDMS is automatically loaded, the printing is repeatable without inking. A substrate moderately wettable to the liquid PDMS as well as amount/property‐controlled syneresis is primarily important for the creation of well‐defined structures. Precisely controlling these conditions will make this method universally applicable to diverse substrates and liquids including suspensions.

Abstract Background Patients with inflammatory bowel disease (IBD) experience difficulties in daily life and demanding self-care needs. The goal of our support for patients is to ease their difficulties and improve their belief in their capacity to self-manage their disease (self-efficacy), by increasing their ability for self-care. The nurse’s contribution is vital in empowering patients and supporting them to better manage their disease. There is evidence that higher nurse staffing levels are associated with better patient outcomes in acute care settings, but little is known about the outpatient setting. The objective of this study was to explore the impact of multidisciplinary team care with abundant nurse staffing levels on patient-reported outcome measures (PROMs) among patients with IBD, encompassing Crohn’s disease (CD) and ulcerative colitis (UC), in clinical remission. Methods Patients with IBD in clinical remission were included because disease activity influences the patient’s subjective evaluation. A total of 499 valid responses from two different sources were analyzed: 318 from a specialized IBD clinic with abundant nurse staffing and a multidisciplinary care team (UC: 83, CD: 235) and 181 from an online survey panel (UC: 109, CD: 72). The IBD Self-Efficacy Scale (IBD-SES) and the difficulty of life scale (DLS) were used as disease-specific PROMs. Results In two multiple regression models adjusted by background characteristics (age, sex, diagnosis [UC/CD], employment status, use of biologics, and disease duration) using the IBD-SES or DLS as a dependent variable, the responses from clinic patients showed a more favorable score (higher self-efficacy or lower difficulty) than the online responses. Conclusions Multidisciplinary team care with abundant nurse staffing may improve self-efficacy and ease difficulties of life among patients with IBD in clinical remission. These results could help bring attention to nurse staffing in an outpatient setting, which has previously been overlooked, and be the first to provide evidence of its importance in encouraging enhanced staffing levels.

Abstract Background Mesonephric adenocarcinoma is an extremely rare subtype of uterine cervical cancer that is associated with a poor prognosis and for which a standardized treatment protocol has not been established. Carbon ion radiotherapy (CIRT) is an emerging radiotherapy modality that has been shown to have a favorable anti-tumor effect, even for tumors resistant to conventional photon radiotherapy or chemotherapy. However, there is no report on CIRT outcomes for mesonephric adenocarcinoma of the uterine cervix. Case presentation We treated a 47-year-old Japanese woman with mesonephric adenocarcinoma of the uterine cervix (T2bN0M0 and stage IIB according to the 7th edition of the Union for International Cancer Control and International Federation of Gynecology and Obstetrics, respectively) with CIRT combined with brachytherapy and concurrent chemotherapy. CIRT consisted of whole pelvic irradiation and boost irradiation to the gross tumor; 36.0 Gy (relative biological effectiveness [RBE]) in 12 fractions and 19.2 Gy (RBE) in 4 fractions, respectively, performed once a day, four times per week. Computed tomography-based image-guided adaptive brachytherapy was performed after completion of CIRT, for which the D90 (i.e., the dose prescribed to 90% of the target volume) for the high-risk clinical target volume was 20.4 Gy in a total of 3 sessions in 2 weeks. A weekly cisplatin (40 mg/m2) dose was administered concomitantly with the radiotherapy for a total of five courses. From 4 months post-CIRT, the patient developed metastasis of the lung, with a total of 10 lung metastases over 70 months; these lesions were treated on each occasion by photon stereotactic body radiotherapy and/or systemic therapy. At 8 years from initial treatment (i.e., 2 years after the last treatment), the patient is alive without any evidence of recurrence and maintains a high quality of life. Conclusions This is the first report of CIRT for treatment of mesonephric adenocarcinoma of the uterine cervix. The present case indicates the potential efficacy of CIRT in combination with brachytherapy for treatment of this disease.

Abstract Background The inflammatory bowel disease self-efficacy scale (IBD-SES) is an instrument used across many countries to measure important health outcomes of patients with inflammatory bowel disease (IBD). We aimed to develop and validate a substantially shorter version of this scale to reduce patients’ response burden. Methods A total of 919 patients with IBD, 482 recruited from an IBD clinic and 437 recruited online, completed the Japanese version of the original, 29-item IBD-SES. These data were then used to develop a shorter version of the scale. The original 29 items of the IBD-SES were reduced with three analytic steps: assessing ceiling and floor effect, testing correlation between items, and assessing test-retest reliability. The resulting 13-item IBD-SES was evaluated for construct validity by confirmatory factor analysis, criterion validity by Pearson correlation coefficients with original version, and internal consistency by item-total correlations and the Cronbach’s α coefficient. Results The short version consisted of the same four subscales “managing stress and emotions,” “managing medical care,” “managing symptoms and disease,” and “maintaining remission” as the original scale. The fit indices of the final model were as follows: normed chi-square, 7.18 (p

Introduction: This study focuses on developing and validating an e-learning educational program for nurturing inflammatory bowel disease (IBD) nursing specialists. Methods: The program was developed using the attention, relevance, confidence, and satisfaction models within the instructional design framework. The program validation encompassed four steps: (1) nurses took a basic IBD knowledge test (pretest), (2) participants scoring

Background/purpose: The number of middle-aged and elderly orthodontic patients is increasing due to changes in age composition. It is important to investigate the detailed mechanisms of bone remodeling in orthodontic tooth movement (OTM) in the elderly. However, there are few reports on the mechanism of tooth movement in the elderly. The purpose of the present study was to analyze OTM and osteoclastogenesis in aged mice and to elucidate the mechanism. Materials and methods: It has been reported that tumor necrosis factor (TNF)-α plays an important role in osteoclast formation and OTM. First, 8-week-old and 78-week-old male C57BL/6J mice were subcutaneously injected with TNF-α into the calvaiae, and micro-CT, tartrate-resistant acid phosphatase (TRAP) staining, and real-time PCR were performed to evaluate osteoclast formation and bone resorption. Furthermore, osteoclastogenesis by TNF-α and receptor activator of nuclear factor-kappa B ligand (RANKL) using bone marrow cells was evaluated in vitro. Finally, a nickel-titanium closed-coil spring was attached, mesial movement of the maxillary left first molar was performed, and tooth movement distance and osteoclast formation were evaluated. Results: Compared to 8-week-old mice, 78-week-old mice had decreased TNF-α-induced bone resorption, osteoclastogenesis, and TRAP and cathepsin K expression in the calvariae. In vitro osteoclast formation also decreased in 78-week-old mice. Furthermore, tooth movement distance and osteoclastogenesis were reduced. Conclusion: OTM decreased in aged mice, which was shown to be caused by a decrease in osteoclastogenesis. Therefore, it was suggested that it is necessary to keep in mind that tooth movement may be suppressed when treating elderly patients.

Abstract Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer.

Abstract Several studies have evaluated immune checkpoint inhibitors (ICIs) for metastatic uveal melanoma; however, the efficacy of ICIs in the previous studies varied greatly. In this systematic review, we searched for prospective or retrospective studies on single or dual-ICIs for metastatic uveal melanoma treatment. A random-effect model meta-analysis with generic inverse-variance was conducted, and 36 articles representing 41 cohorts of 1414 patients with metastatic uveal melanoma were included. The pooled outcomes were as follows: objective response rate (ORR) was 5.6% (95% confidence interval [95%CI] 3.7–7.5%; I2, 36%), disease control rate (DCR) was 32.5% (95% CI 27.2–37.7%; I2, 73%), median progression-free survival was 2.8 months (95% CI 2.7–2.9 months; I2, 26%), and median overall survival (OS) was 11.2 months (95% CI 9.6–13.2 months; I2, 74%). Compared to single-agent ICI, dual ICI led to better ORR (single-agent: 3.4% [95% CI 1.8–5.1]; dual-agent: 12.4% [95% CI 8.0–16.9]; P

Abstract Background Human Papillomavirus-associated oropharyngeal cancer (HPV-OPC) incidence is increasing among men in the United States. Poor dental health has previously been associated with risk of head and neck cancers, oral HPV infection, and persistence but it is not understood whether dental health is associated with outcomes. We sought to determine the association of dental health with progression free survival and overall mortality among men with an HPV-OPC. Methods A cross sectional study of men diagnosed with HPV-OPC between 2014–2020 at Moffitt Cancer Center in Tampa, FL was conducted. Dental records were abstracted for assessment of dental fitness prior to cancer treatment. Five dental factors including number of teeth lost, pocket depth, gingival score, loss of attachment, and bone loss were individually examined. Risk factor and outcome data were collected from a patient risk questionnaire and medical record. Using item response theory, an overall dental fitness score from five dental factors was developed in which missing data were multiply imputed. Cox proportional hazards model was used to assess whether dental factors were associated with progression-free survival or overall mortality. Results Among 206 HPV-OPC cases, median follow-up was 3.4 years (IQR: 2.4–4.4) during which 40 cases involved progression or mortality and 25 deaths occurred. Overall dentition was significantly associated with progression free survival (p = 0.04) and with overall survival (p = 0.03) though findings were not significant after adjustment for age at diagnosis, stage, and smoking history (p = 0.146 and p = 0.120, respectively). A pocket depth of 7 mm or more was associated with overall survival (HR: 5.21; 95% CI: 1.43—19.11) and this remained significant after adjustment for confounding (aHR: 4.14; 95% CI: 1.72—16.26). Conclusions Among men diagnosed with an HPV-associated OPC in the US, worse dental health was associated with reduced progression free survival and overall survival, but not after adjustment for confounders. Further studies are needed to examine whether dental health is associated with other prognostic factors and subsequent treatment-related outcomes.

Abstract Objective Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early‐onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. Methods Our research commenced with an in‐depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early‐onset ALS (onset age of

Abstract Background Undernutrition and underweight are osteoporosis risk factors. Therefore, improving the health of underweight young women in Japan is an important medical issue. However, few studies have evaluated the association between being preconception underweight and postnatal osteoporotic fractures in young women. Methods This retrospective cohort study used a Japanese nationwide claims database (JMDC Inc.) to evaluate the effect of preconception underweight on the incidence of osteoporotic fracture within two years after delivery. Data from 16,684 mothers who delivered their first singleton babies between January 2006 and December 2020 were analysed. The combination of disease codes of fractures at sites associated with osteoporosis and medical procedures for fractures was defined as the incidence of osteoporotic fractures, whereas the body mass index (BMI) recorded 12–36 months before delivery was used as the exposure. We estimated the incidence of osteoporotic fractures by BMI category using a Kaplan–Meier curve and examined the fracture risk using Cox hazard regression analyses. Results Fifty-one women (0.31%) were affected by osteoporotic fractures within two years of delivery. More than 80% of these were rib fractures, and approximately 65% of fractures occurred after the first year postpartum. Preconception underweight (BMI

Pakistan is the fifth most populous country in the world. Its ecological environment is facing numerous stresses such as climate change, rapid urbanization, natural disasters, and a decline in air quality. Thus, the scientific understanding of spatial and temporal changes in Pakistan's ecological environment is crucial for formulating an informed strategy for regional sustainability. This study used the Google Earth Engine platform and the Remote Sensing Ecological Index (RSEI) to investigate ecological vulnerability in three provinces of Pakistan for 1990, 2000, 2010, and 2020. Landsat 5 and Landsat 8 datasets are used to construct RSEI indicators and Principal Component Analysis (PCA) is adopted to objectively compute RSEI for the past three decades. The results indicated that (1) the ecological vulnerability of the Punjab province exhibited a slightly improved trend from 1990 to 2020 with overall dominance of ‘moderate’ level vulnerability in all four years; (2) The Sindh province has exhibited a declining trend of the ecological environment with ‘poor’ ecological vulnerability contributing to 28.6% of the total area in 2020 as compared to 1.04% of the total area in 1990; and (3) The ecological environment of Balochistan province has shown resilience to some extent during 1900–2010 with the dominance of a ‘moderate’ level of ecological vulnerability. However, a decline is observed between 2010 and 2020. These research results can provide support for the Punjab, Sindh, and Balochistan provinces in achieving sustainable development while conserving the regional ecological environment.

BackgroundThe rate of recurrent spontaneous preterm delivery (sPTD) ranges between 27% and 34% and is 22.3% in Japan. Although it currently remains unclear whether probiotics prevent sPTD, retrospective studies recently reported a reduction in the rate of recurrent sPTD with the administration of probiotics including Clostridium spp., which induce regulatory T cells that play an important role in maintaining pregnancy. ObjectiveThe objective of this trial is to evaluate the preventative effects of available oral probiotics, including Clostridium butyricum, on recurrent sPTD. MethodsThis is a prospective, single-arm, nonblinded, multicenter trial in Japan. The sample size required for this trial is 345 pregnant women with a history of sPTD, considering a clinically significant reduction in the relative risk of 30% (risk ratio=0.7). The primary endpoint is the rate of recurrent sPTD at

Serotonin is an essential neuromodulator that affects behavioral and cognitive functions. Previous studies have shown that activation of serotonergic neurons in the dorsal raphe nucleus (DRN) promotes patience to wait for future rewards. However, it is still unclear whether serotonergic neurons also regulate persistence to act for future rewards. Here we used optogenetic activation and inhibition of DRN serotonergic neurons to examine their effects on sustained motor actions for future rewards. We trained mice to perform waiting and repeated lever-pressing tasks with variable reward delays and tested effects of optogenetic activation and inhibition of DRN serotonergic neurons on task performance. Interestingly, in the lever-pressing task, mice tolerated longer delays as they repeatedly pressed a lever than in the waiting task, suggesting that lever-pressing actions may not simply be costly, but may also be subjectively rewarding. Optogenetic activation of DRN serotonergic neurons prolonged waiting duration in the waiting task, consistent with previous studies. However, its effect on lever presses was nuanced, and was detected only by focusing on the period before premature reward check and by subtracting the trends within and across sessions using generalized linear model. While optogenetic inhibition decreased waiting, it did not affect lever pressing time or numbers. These results revealed that the necessity of motor actions may increase motivation for delayed rewards and that DRN serotonergic neurons more significantly promote waiting rather than persistent motor actions for future rewards.