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Sepsis menyebabkan kematian terbesar, tingkat mortalitas sepsis tinggi dan dapat mencapai 50% pada syok sepsis. Tatalaksana resusitasi pada syok sepsis menggunakan vasopresor. norepinephrine saat ini adalah rekomendasi utama pada syok sepsis, vasopressin digunakan sebagai obat lini kedua untuk mengurangi efek samping yang disebabkan oleh obat seperti norephinephrine, dan juga membantu pada keadaan syok resisten-katekolamin. Penelitian ini merupakan penelitian uji klinis dengan metode acak tersamar ganda. Penelitian ini bertujuan untuk mengetahui perbandingan penggunaan vasopressin dan norephinephrine sebagai vasopresor pada pasien syok sepsis di ICU RSUP H. Adam Malik Medan. Pencatatan hasil dilakukan setelah diberikan intervensi (T0), 6 jam (T1), dan 24 jam (T2). Sampel yang diperoleh pada penelitian ini berjumlah 36 pasien dengan 13 pasien dalam kelompok vasopressin dan 13 pasien dalam kelompok norepinephrine. Rerata TDS, TDD dan Mean Arterial Pressure (MAP) T0, T1, dan T2 kelompok norepinephrine lebih tinggi bila dibanding dengan dengan kelompok vasopressin. pH pada kelompok norepinephrine lebih rendah bila dibanding dengan dengan kelompok vasopressin. Simpulan, terdapat perbedaan yang signifikan antara norepinephrine dengan vasopressin sebagai vasopressor, dimana MAP dan kadar laktat, pada kelompok Norepinephrine lebih tinggi bila dibanding dengan dengan vasopressin. Sedangkan pH didapatkan lebih rendah pada kelompok norepinpehrine pada jam ke-24 dibanding dengan kelompok vasopressin.

Isocyanide is a promising synthetic reagent not only as a one-carbon homologation reagent but also as a nitrogen source for nitrogen-containing molecules. Because of their isoelectronic structure with carbon monoxide, isocyanides also react with nucleophiles, electrophiles, carbon radicals, and transition metal reagents, and are widely used in organic synthesis. On the other hand, the use of isocyanides in reactions with heteroatom radicals is limited. However, the reaction of isocyanides with heteroatom radicals is a promising synthetic tool for the construction of nitrogen-containing organic molecules modified with a variety of heteroatoms. In this Perspective, we review the addition and cyclization reactions of heteroatom radicals with isocyanides and discuss the synthetic prospects of the reaction of isocyanides with heteroatom radicals.

Amyand's hernia is a rare type of inguinal hernia characterized by the presence of the vermiform appendix within the hernia sac. It was named after Claudius Amyand who performed the world's first successful appendectomy on an 11-year-old boy with a right inguinal hernia in 1735 and discovered a herniated appendix during surgery.This condition warrants urgent surgical treatment, with the type of surgical intervention depending on the appendix's condition. However, the nonspecific clinical presentation often complicates the preoperative diagnosis, emphasizing the critical role of imaging in surgical planning.Herein, we present the case of a 74-year-old male who presented with fever, inguinal swelling, and discomfort. Clinical suspicion of inguinal and scrotal inflammation prompted us to perform a prompt CT scan. This radiological evaluation led to a preoperative diagnosis of a Type 3 Amyand's hernia.This case highlights the significance of CT scans in the accurate and timely diagnosis of Amyand's hernia. Distinguishing between various types of Amyand's hernia is pivotal as it profoundly influences surgical decision-making and postoperative outcomes. By sharing this case, we contribute to current knowledge about Amyand's hernia, increase clinical awareness of the condition, and emphasize the crucial role of imaging in its management.

Dural dryness makes suturing difficult during dural closure after craniotomy. In this case, dural plasty is often performed using a membrane taken from the surrounding tissue (e.g., fascia or periosteum) or an artificial replacement membrane. Herein, we introduce our novel “roll-up technique” to reduce the utilization of substitute membranes and explore its effectiveness in dural closure. We retrospectively examined the medical records of 50 patients who underwent craniotomy for the first time for supratentorial intracranial lesions between 2015 and 2022. Furthermore, we divided them into two groups: (1) the conventional technique group, which consisted of patients in whom the dura mater was flipped after incision and protected with a moistened gauze (n = 23), and (2) the roll-up technique group, which consisted of patients in whom the dura mater was incised in a U shape, rolled up, and protected with a moist gauze (n = 27). After surgery, we compared the success rates of primary closure, operating time, craniotomy area, and percentage of complications (e.g., cerebrospinal fluid [CSF] leakage or infection) between the groups. Dural closure without dural substitutes using the roll-up technique had a higher success rate than that using the conventional technique (26/27 [96.3%] cases vs. 14/23 [60.9%] cases; P = 0.003). Postoperative CSF leakage or infection did not occur, and no statistically significant difference was observed in the operating time between the groups (P = 0.247). The roll-up technique for dural closure may effectively prevent post-incisional dural shrink after craniotomy.

Abstract Background This study validated the accuracy of the acromion marker cluster (AMC) and scapula spinal marker cluster (SSMC) methods compared with upright four-dimensional computed tomography (4DCT) analysis. Methods Sixteen shoulders of eight healthy males underwent AMC and SSMC assessments. Active shoulder elevation was tracked using upright 4DCT and optical motion capture system. The scapulothoracic and glenohumeral rotation angles calculated from AMC and SSMC were compared with 4DCT. Additionally, the motion of these marker clusters on the skin with shoulder elevation was evaluated. Results The average differences between AMC and 4DCT during 10°−140° of humerothoracic elevation were − 2.2° ± 7.5° in scapulothoracic upward rotation, 14.0° ± 7.4° in internal rotation, 6.5° ± 7.5° in posterior tilting, 3.7° ± 8.1° in glenohumeral elevation, − 8.3° ± 10.7° in external rotation, and − 8.6° ± 8.9° in anterior plane of elevation. The difference between AMC and 4DCT was significant at 120° of humerothoracic elevation in scapulothoracic upward rotation, 50° in internal rotation, 90° in posterior tilting, 120° in glenohumeral elevation, 100° in external rotation, and 100° in anterior plane of elevation. However, the average differences between SSMC and 4DCT were − 7.5 ± 7.7° in scapulothoracic upward rotation, 2.0° ± 7.0° in internal rotation, 2.3° ± 7.2° in posterior tilting, 8.8° ± 7.9° in glenohumeral elevation, 2.0° ± 9.1° in external rotation, and 1.9° ± 10.1° in anterior plane of elevation. The difference between SSMC and 4DCT was significant at 50° of humerothoracic elevation in scapulothoracic upward rotation and 60° in glenohumeral elevation, with no significant differences observed in other rotations. Skin motion was significantly smaller in AMC (28.7 ± 4.0 mm) than SSMC (38.6 ± 5.8 mm). Although there was smaller skin motion in AMC, SSMC exhibited smaller differences in scapulothoracic internal rotation, posterior tilting, glenohumeral external rotation, and anterior plane of elevation compared to 4DCT. Conclusion This study demonstrates that AMC is more accurate for assessing scapulothoracic upward rotation and glenohumeral elevation, while SSMC is preferable for evaluating scapulothoracic internal rotation, posterior tilting, glenohumeral external rotation, and anterior plane of elevation, with smaller differences compared to 4DCT.

Abstract Coral polyps are composed of four tissues; however, their characteristics are largely unexplored. Here we report biological characteristics of tentacles (Te), mesenterial filaments (Me), body wall (Bo), and mouth with pharynx (MP), using comparative genomic, morpho-histological, and transcriptomic analyses of the large-polyp coral, Fimbriaphyllia ancora. A draft F. ancora genome assembly of 434 Mbp was created. Morpho-histological and transcriptomic characterization of the four tissues showed that they have distinct differences in structure, primary cellular composition, and transcriptional profiles. Tissue-specific, highly expressed genes (HEGs) of Te are related to biological defense, predation, and coral-algal symbiosis. Me expresses multiple digestive enzymes, whereas Bo expresses innate immunity and biomineralization-related molecules. Many receptors for neuropeptides and neurotransmitters are expressed in MP. This dataset and new insights into tissue functions will facilitate a deeper understanding of symbiotic biology, immunology, biomineralization, digestive biology, and neurobiology in corals.

Abstract It has been reported that strong discomfort associated with clusters of circles and holes (trypophobia), including lotus pod seeds, manifests in individuals as young as 4 or 5 years old. This study investigated how the size and number of circles within clusters affected discomfort levels in adults and in children aged 4–9 years. In Experiment 1, we confirmed that the remote experimental procedure could evoke discomfort when participants were presented with cluster images. The findings reveal that children as young as 4 or 5 years old consistently experienced discomfort when rating trypophobic images, even printed images rated in real time during video calls. In Experiment 2, we explored the impact of cluster size, considering both the size and number of circles, in a remote experiment. The results indicate that discomfort tended to increase with cluster size in both children and adults, with the effect becoming more pronounced with age.

Abstract We study the interior metric of 4D spherically symmetric static black holes by using the semi-classical Einstein equation and find a consistent class of geometries with large curvatures. We approximate the matter fields by conformal fields and consider the contribution of the 4D Weyl anomaly, giving a state-independent constraint. Combining this with an equation of state yields an equation that determines the interior geometry completely. We explore the solution space of the equation in a non-perturbative manner for $$\hbar $$ ħ . First, we find four types of asymptotic behaviors and examine the general features of the solutions. Then, by imposing physical conditions, we obtain approximately a general class of interior geometries: various combinations of dilute and dense structures without a horizon or singularity. This represents the diversity of the interior structure. Finally, we show that the number of possible patterns of such interior geometries corresponds to the Bekenstein–Hawking entropy.

AbstractThe gut microbiota (GM) is essential for mammalian health. Although the association between infant GM and breast milk (BM) composition has been well established in humans, such a relationship has not been investigated in horses. Hence, this study was conducted to analyze the GM formation of foals during lactation and determine the presence of low-molecular-weight metabolites in mares’ BM and their role in shaping foals’ GM. The fecal and BM samples from six pairs of foals and mares were subjected to 16S ribosomal RNA metagenomic and metabolomic analyses, respectively. The composition of foal GM changed during lactation time; hierarchical cluster analysis divided the fetal GM into three groups corresponding to different time points in foal development. The level of most metabolites in milk decreased over time with increasing milk yield, while threonic acid and ascorbic acid increased. Further analyses revealed gut bacteria that correlated with changes in milk metabolites; for instance, there was a positive correlation between Bacteroidaceae in the foal’s gut microbiota and serine/glycine in the mother’s milk. These findings help improve the rearing environment of lactating horses and establish artificial feeding methods for foals.

Abstract Introduction This study aimed to evaluate the effectiveness of ensitrelvir, an oral antiviral, in reducing hospitalization risk in outpatients at high-risk for severe COVID-19 during the Omicron era. Methods This was a retrospective study using a large Japanese health insurance claims database. It included high-risk outpatients for severe symptoms who received their first COVID-19 diagnosis between November 2022 and July 2023. The study included outpatients aged ≥ 18 years. The primary endpoint was all-cause hospitalization during the 4-week period from the date of outpatient diagnosis and medication, comparing the ensitrelvir group (n = 5177) and the no antiviral treatment group (n = 162,133). The risk ratio and risk difference were evaluated after adjusting patient background distribution by the inverse probability of treatment weight (IPTW) method. Secondary endpoints were incidence of respiratory and heart rate monitoring, oxygen therapy, ventilator use, intensive care admission, and all-cause death. Results The risk ratio for all-cause hospitalization between the ensitrelvir group (n = 167,385) and the no antiviral treatment group (n = 167,310) after IPTW adjustment was 0.629 [95% confidence interval (CI) 0.420, 0.943]. The risk difference was − 0.291 [95% CI − 0.494, − 0.088]. The incidence of both respiratory and heart rate monitoring and oxygen therapy was lower in the ensitrelvir group. Ventilator use, intensive care admission, and all-cause death were difficult to assess because of the limited events. Conclusions The incidence of all-cause hospitalization was significantly lower in the ensitrelvir group than in the no antiviral treatment group, suggesting ensitrelvir is an effective treatment in patients at risk of severe COVID-19.

Abstract Background In gonochoristic animals, the sex determination pathway induces different morphological and behavioral features that can be observed between sexes, a condition known as sexual dimorphism. While many components of this sex differentiation cascade show high levels of diversity, factors such as the Doublesex-Mab-3-Related Transcription factor (DMRT) are widely conserved across animal taxa. Species of the phylum Tardigrada exhibit remarkable diversity in morphology and behavior between sexes, suggesting a pathway regulating this dimorphism. Despite the wealth of genomic and zoological knowledge accumulated in recent studies, the sexual differences in tardigrades genomes have not been identified. In the present study, we focused on the gonochoristic species Paramacrobiotus metropolitanus and employed omics analyses to unravel the molecular basis of sexual dimorphism. Results Transcriptome analysis between sex-identified specimens revealed numerous differentially expressed genes, of which approximately 2,000 male-biased genes were focused on 29 non-male-specific genomic loci. From these regions, we identified two Macrobiotidae family specific DMRT paralogs, which were significantly upregulated in males and lacked sex specific splicing variants. Furthermore, phylogenetic analysis indicated all tardigrade genomes lack the doublesex ortholog, suggesting doublesex emerged after the divergence of Tardigrada. In contrast to sex-specific expression, no evidence of genomic differences between the sexes was found. We also identified several anhydrobiosis genes that exhibit sex-biased expression, suggesting a possible mechanism for protection of sex-specific tissues against extreme stress. Conclusions This study provides a comprehensive analysis for analyzing the genetic differences between sexes in tardigrades. The existence of male-biased, but not male-specific, genomic loci and identification of the family specific male-biased DMRT subfamily provides the foundation for understanding the sex determination cascade. In addition, sex-biased expression of several tardigrade-specific genes which are involved their stress tolerance suggests a potential role in protecting sex-specific tissue and gametes.

Abstract Background One significant challenge in addressing the coronavirus disease 2019 (COVID-19) pandemic is to grasp a comprehensive picture of its infectious mechanisms. We urgently need a consistent framework to capture the intricacies of its complicated viral infectious processes and diverse symptoms. Results We systematized COVID-19 infectious processes through an ontological approach and provided a unified description framework of causal relationships from the early infectious stage to severe clinical manifestations based on the homeostasis imbalance process ontology (HoIP). HoIP covers a broad range of processes in the body, ranging from normal to abnormal. Moreover, our imbalance model enabled us to distinguish viral functional demands from immune defense processes, thereby supporting the development of new drugs, and our research demonstrates how ontological reasoning contributes to the identification of patients at severe risk. Conclusions The HoIP organises knowledge of COVID-19 infectious processes and related entities, such as molecules, drugs, and symptoms, with a consistent descriptive framework. HoIP is expected to harmonise the description of various heterogeneous processes and improve the interoperability of COVID-19 knowledge through the COVID-19 ontology harmonisation working group.

Background Fibrates have renal toxicity limiting their use in subjects with chronic kidney disease (CKD). However, pemafibrate has fewer toxic effects on renal function. In the present analysis, we evaluated the effects of pemafibrate on the renal function of diabetic subjects with or without CKD in a real-world clinical setting. Methods We performed a sub-analysis of data collected during a multi-center, prospective, observational study of the effects of pemafibrate on lipid metabolism in subjects with type 2 diabetes mellitus complicated by hypertriglyceridemia (the PARM-T2D study). The participants were allocated to add pemafibrate to their existing regimen (ADD-ON), switch from their existing fibrate to pemafibrate (SWITCH), or continue conventional therapy (CTRL). The changes in estimated glomerular filtration rate (eGFR) over 52 weeks were compared among these groups as well as among subgroups created according to CKD status. Results Data for 520 participants (ADD-ON, n=166; SWITCH, n=96; CTRL, n=258) were analyzed. Of them, 56.7% had CKD. The eGFR increased only in the SWITCH group, and this trend was also present in the CKD subgroup (P

Abstract Objectives Thoracoscopy under local anaesthesia is widely performed to diagnose malignancies and infectious diseases. However, few reports have described the use of this procedure for diagnosing and treating intrathoracic infections. This study aimed to evaluate the safety and efficacy of thoracoscopy under local anaesthesia for the management of intrathoracic infections. Results Data from patients who underwent thoracoscopy procedures performed by chest physicians under local anaesthesia at our hospital between January 2018 and December 2023 were retrospectively reviewed. We analysed their demographic factors, reasons for the examinations, diseases targeted, examination lengths, anaesthetic methods used, diagnostic and treatment success rates, as well as any adverse events. Thirty patients were included. Of these, 12 (40%) had thoracoscopies to diagnose infections, and 18 (60%) had them to treat pyothorax. In terms of diagnosing pleurisy, the causative microorganism of origin was identified via thoracoscopy in only three of 12 (25.0%) patients. For diagnosing pyothorax, the causative microorganism was identified in 7 of 18 (38.9%) patients. Methicillin-resistant Staphylococcus aureus was the most common causative microorganism identified. The treatment success rates were very high, ranging between 94.4 and 100%, whereas the identification rate of the causative microorganisms behind infections was low, ranging between 25.0 and 38.9%. The most frequent adverse events included perioperative hypoxaemia and pain. There were two (6.7%) serious adverse events of grade ≥ 3, but none resulted in death. Conclusions The efficacy of managing intrathoracic infections through thoracoscopy under local anaesthesia is commendable. Nonetheless, the diagnostic accuracy of the procedure, regarding the precise identification of the causative microorganisms responsible for intrathoracic infections, persists at a notably low level, presenting a substantial clinical hurdle.

Abstract Although cellular senescence is a key factor in organismal aging, with both positive and negative effects on individuals, its mechanisms remain largely unknown. Thus, integrating knowledge is essential to explain how cellular senescence manifests in tissue damage and age-related diseases. Here, we propose an ontological model that organizes knowledge of cellular senescence in a computer-readable form. We manually annotated and defined cellular senescence processes, molecules, anatomical structures, phenotypes, and other entities based on the Homeostasis Imbalance Process ontology (HOIP). We described the mechanisms as causal relationships of processes and modelled a homeostatic imbalance between stress and stress response in cellular senescence for a unified framework. HOIP was assessed formally, and the relationships between cellular senescence and diseases were inferred for higher-order knowledge processing. We visualized cellular senescence processes to support knowledge utilization. Our study provides a knowledge base to help elucidate mechanisms linking cellular and organismal aging.

Introduction CHARGE syndrome is a rare disorder that causes congenital abnormalities in multiple organs, including secondary hypogonadism. We report, herein, a unique case of CHARGE syndrome with both primary and secondary hypogonadism and discuss the possible causes and pathogenesis in this patient. Case presentation A 15‐year‐old boy with delayed secondary sexual characteristics and non‐palpable testes was referred to our hospital. Physical examination and detection of a chromodomain‐helicase‐deoxyribonucleic acid‐binding protein 7 gene mutation confirmed CHARGE syndrome. Hormone stimulation tests suggested both primary and secondary hypogonadism. Laparoscopic bilateral orchiectomy was performed because of decreased testosterone production and atrophy in both testes. Pathological examination of the testes revealed maturation arrest, germ cell neoplasm in situ, and decreased expression of steroid synthase. Conclusion This appears to be the first report of CHARGE syndrome with both primary and secondary hypogonadism demonstrated in endocrinological and histological examinations.

AbstractThe recognition by cytotoxic T cells (CTLs) is essential for the clearance of SARS-CoV-2 virus-infected cells. Several viral proteins have been described to be recognized by CTLs. Among them, the spike (S) protein is one of the immunogenic proteins. The S protein acts as a ligand for its receptors, and several mutants with different affinities for its cognate receptors have been reported, and certain mutations in the S protein, such as L452R and Y453F, have been found to inhibit the HLA-A24-restricted CTL response. In this study, we conducted a screening of candidate peptides derived from the S protein, specifically targeting those carrying the HLA-A24 binding motif. Among these peptides, we discovered that NF9 (NYNYLYRLF) represents an immunogenic epitope. CTL clones specific to the NF9 peptide were successfully established. These CTL clones exhibited the ability to recognize endogenously expressed NF9 peptide. Interestingly, the CTL clone demonstrated cross-reactivity with the Y453F peptide (NYNYLFRLF) but not with the L452R peptide (NYNYRYRLF). The CTL clone was able to identify the endogenously expressed Y453F mutant peptide. These findings imply that the NF9-specific CTL clone possesses the capability to recognize and respond to the Y453F mutant peptide.

Abstract Background Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. Methods This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. Results During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22–4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10–30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. Conclusions Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

Abstract Background Patients with a history of hepatitis B virus (HBV) infection who are receiving immunosuppressive therapy are at risk of HBV reactivation and disease. Therefore, HBV screening is required prior to administering antirheumatic drugs with immunosuppressive effects. This study aimed to determine the status of hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis B surface antibody (HBsAb) screening prior to the initiation of drug therapy, including new antirheumatic drugs, in patients with rheumatoid arthritis. Methods This retrospective cross-sectional study used data from April 2014 to August 2022 from the Japanese hospital-based administrative claims database. The inclusion criteria were rheumatoid arthritis and first prescription date of antirheumatic drugs. Results A total of 82,282 patients with rheumatoid arthritis who were first prescribed antirheumatic drugs between April 2016 and August 2022 were included. Of the eligible patients, 9.7% (n=7,959) were screened for all HBV (HBsAg, HBsAb, and HbcAb) within 12 months prior to the date of initial prescription. The HBsAg test was performed in 30.0% (n=24,700), HBsAb test in 11.8% (n=9,717), and HBcAb test in 13.1% (n=10,824) of patients. The proportion of patients screened for HBV infection has been increasing since 2018; however, the proportion of patients screened for rheumatoid arthritis remains low. Conclusions Our findings suggest that HBV screening may be insufficient in patients who received antirheumatic drugs. With the increasing use of new immunosuppressive antirheumatic drugs, including biological agents, healthcare providers should understand the risk of HBV reactivation and conduct appropriate screening.

Abstract Homologous recombination (HR) repairs DNA damage including DNA double-stranded breaks and alterations in HR-related genes results in HR deficiency. Germline alteration of HR-related genes, such as BRCA1 and BRCA2, causes hereditary breast and ovarian cancer (HBOC). Cancer cells with HR deficiency are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents. Thus, accurately evaluating HR activity is useful for diagnosing HBOC and predicting the therapeutic effects of anti-cancer agents. Previously, we developed an assay for site-specific HR activity (ASHRA) that can quantitatively evaluate HR activity and detect moderate HR deficiency. HR activity in cells measured by ASHRA correlates with sensitivity to the PARP inhibitor, olaparib. In this study, we applied ASHRA to lymphoblastoid cells and xenograft tumor tissues, which simulate peripheral blood lymphocytes and tumor tissues, respectively, as clinically available samples. We showed that ASHRA could be used to detect HR deficiency in lymphoblastoid cells derived from a BRCA1 pathogenic variant carrier. Furthermore, ASHRA could quantitatively measure the HR activity in xenograft tumor tissues with HR activity that was gradually suppressed by inducible BRCA1 knockdown. The HR activity of xenograft tumor tissues quantitatively correlated with the effect of olaparib. Our data suggest that ASHRA could be a useful assay for diagnosing HBOC and predicting the efficacy of PARP inhibitors.

Abstract Better understanding of the earliest molecular pathologies of all neurodegenerative diseases is expected to improve human therapeutics. We investigated the earliest molecular pathology of spinocerebellar ataxia type 1 (SCA1), a rare familial neurodegenerative disease that primarily induces death and dysfunction of cerebellum Purkinje cells. Extensive prior studies have identified involvement of transcription or RNA-splicing factors in the molecular pathology of SCA1. However, the regulatory network of SCA1 pathology, especially central regulators of the earliest developmental stages and inflammatory events, remains incompletely understood. Here, we elucidated the earliest developmental pathology of SCA1 using originally developed dynamic molecular network analyses of sequentially acquired RNA-seq data during differentiation of SCA1 patient-derived induced pluripotent stem cells (iPSCs) to Purkinje cells. Dynamic molecular network analysis implicated histone genes and cytokine-relevant immune response genes at the earliest stages of development, and revealed relevance of ISG15 to the following degradation and accumulation of mutant ataxin-1 in Purkinje cells of SCA1 model mice and human patients.

Background: Disaster survivors experience deterioration in lifestyles and an increase in constipation. After the Great East Japan Earthquake in 2011, some survivors were evacuated for a long term, even after moving to temporary housing and public reconstruction housing. However, annual changes in constipation and the association between lifestyles and constipation among the survivors are still unknown. Methods: Overall, 9,234 survivors aged 18 years or older participated in this 9-year follow-up survey after the disaster. Information about the prevalence of constipation and lifestyle factors (diet, physical activity, and mental health) was collected using a self-reported questionnaire. Their dietary intake was categorized into the following two dietary patterns: prudent (fish and shellfish, soybean products, vegetables, fruits, and dairy products) and meat (meat and eggs). Odds ratios for constipation according to lifestyle factors were calculated using a generalized linear mixed model. Results: In women, the prevalence of constipation was the highest at baseline (8.7%) and remained around 5% afterward. In both men and women, older age, poor mental health, and poor physical activity were significantly associated with higher odds ratios of constipation. Moreover, a lower frequency of meals and a lower prudent dietary score were significantly associated with women’s constipation. Conclusion: The prevalence of constipation was the highest at baseline and remained around 5% in women. Lifestyle factors, such as poor mental health, physical inactivity, and low frequency of meals were associated with constipation. Our findings suggest continuous support for the survivors with constipation for medium- to long-term after disasters.

Abstract An ultrapure deep-blue multi-resonance-induced thermally activated delayed fluorescence material (DOB2-DABNA-A) is designed and synthesized. Benefiting from a fully resonating extended helical π-conjugated system, this compound has a small ΔE ST value of 3.6 meV and sufficient spin–orbit coupling to exhibit a high-rate constant for reverse intersystem crossing (k RISC = 1.1 × 106 s–1). Furthermore, an organic light-emitting diode employing DOB2-DABNA-A as an emitter is fabricated; it exhibits ultrapure deep-blue emission at 452 nm with a small full width at half maximum of 24 nm, corresponding to Commission Internationale de l’Éclairage (CIE) coordinates of (0.145, 0.049). The high k RISC value reduces the efficiency roll-off, resulting in a high external quantum efficiency (EQE) of 21.6% at 1000 cd m–2.

This study examined the association between human activities and precipitation in dry areas, focusing on nomadic people in Djibouti. Nomadic communities often lack access to essential social services, and water resource management is crucial for their survival and social welfare. Understanding how they respond to variations in water availability could contribute to effective policy implementation. Using satellite-derived information, this study found that nighttime light brightness increased in response to precipitation around wadis, with potential water spring locations, and decreased with distance from a wadi. Specifically, we observed no effect when the distance was more than 5 km. Furthermore, no effect of precipitation was found in urban areas, while a positive effect was found in remote areas. These findings suggest that the activity of nomadic people increases around wadis in response to increased water resource availability, indicating that water supply is important for settlement projects because it can reduce water-seeking costs and improve social welfare. This study provides the first empirical evidence using satellite data and statistical analysis to show that water availability is critical for nomadic communities which can inform better resource management and policy decisions in African countries.

Whether the association between metabolic syndrome (MetS) and functional disability differs depending on sex or age remains unknown. To determine the association between MetS and functional disability in older people separately by sex and age groups. A total of 11 083 participants (4407 men and 6676 women) aged 65 years or over without functional disability were enrolled. MetS was defined according to the revised NCEP ATP III guidelines. Functional disability was defined by a new certification in the long-term care insurance in Japan. Cox proportional hazards models were used to assess the risk of functional disability with adjustment for possible confounding factors. Over the mean observation period of 10.5 years, 1282 men and 2162 women experienced functional disability. For those aged 65 to 74 years, HRs (95% CIs) for functional disability in the MetS group were 1.33 (1.07-1.66) in men and 1.15 (1.000-1.32) in women. For those aged 75 years or older, there was no significant association in men or women. In subjects with a severe care need level, there was a marginal significant association in men aged 65 to 74 years. Among the MetS components that independently increased the risk of functional disability were glucose intolerance and elevated blood pressure (men and women aged 65-74 years), obesity (women aged 65-74 years), and glucose intolerance (women aged 75 years or older). MetS contributed to an increase in a high risk of future functional disability among individuals aged 65 to 74 years. In this age group, improvement of lifestyle, health promotion and interventions for MetS from middle age may prevent future functional disability.

Background Immunosuppressive conditions within the tumor microenvironment (TME) can allow tumors to evade the immune system, including by hampering programmed death ligand 1 (PD-L1) inhibitor activity. Interleukin (IL)-8 contributes to immunosuppression and fibrosis in the TME. AMY109, a humanized anti-IL-8 monoclonal antibody, reduced fibrosis and decreased immunosuppressive cells in tumor tissue in animals. Combining AMY109 with atezolizumab (anti-PD-L1 antibody) may enhance its antitumor effects by making the TME more favorable to PD-L1 inhibition.Methods This multicenter, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and clinical activity of AMY109 plus atezolizumab in patients with previously treated advanced solid tumors and Eastern Cooperative Oncology Group performance status 0 or 1. Patients received AMY109 (2–45 mg/kg) plus atezolizumab (1200 mg) intravenously every 3 weeks in part 1, and AMY109 (15–45 mg/kg) plus atezolizumab (1200 mg) in part 2. Primary endpoints were the dose-limiting toxicity (DLT), safety, and pharmacokinetics of AMY109 and atezolizumab in Part 1, and safety and antitumor activity per investigator-assessed Response Evaluation Criteria in Solid Tumors 1.1 in part 2. Exploratory analyses of peripheral and tumor biomarker were conducted.Results Overall, 38 patients (18 in part 1 and 20 in part 2) were enrolled. Part 1 showed no DLTs and a dose-proportional increase in AMY109 exposure over 2–45 mg/kg, with no apparent change in mean atezolizumab serum concentrations across AMY109 dosing. Plasma IL-8 concentration accumulation was seen in all dose cohorts after AMY109 initiation. Grade 1–3 treatment-related adverse events (AEs) occurred in 21 of 38 patients (55%). Treatment-related serious AEs occurred in two patients (5%). No AEs led to treatment withdrawal. Partial responses (PRs) occurred in 2 of 38 patients; the confirmed objective response rate was 5%. These patients had uterocervical and pancreatic cancer, respectively, and had been treated for >500 days at the cut-off date: one had received 45 mg/kg of AMY109 throughout, and the other received 30 mg/kg of AMY109 until cycle 5, then 45 mg/kg thereafter.Conclusions With no DLTs, AMY109 plus atezolizumab was well tolerated in patients with advanced solid tumors, with no new safety signals. AMY109 showed a dose-proportional increase in exposure. The PRs in two patients were durable.

Purpose: Although good mid-term results of the first- and second-generation cementless stems have been reported, no study has compared outcomes between generations. This study aimed to compare the mid-term results of Accolade Ti–12Mo–6Zr–2Fe (TMZF) and Accolade II over a 5-year period. Methods: This retrospective, single-institution, single-surgeon observational study included patients who underwent primary total hip arthroplasty using the Accolade TMZF (n ​= ​71, group I) or Accolade II (n ​= ​73, group II) between January 2009 and July 2015. Revision and conversion cases were excluded. Functional evaluations were performed using the Japanese Orthopaedic Association hip (JOA) score. Radiographic evaluations were performed using anteroposterior radiographs. Spot welds, radiolucency, cortical hypertrophy, and stress shielding around the stem were assessed for each Gruen zone. Subsidence and stem alignment were evaluated. Results: The 5-year postoperative stem survival rate was 100% in both groups. The JOA score improved from 44.0 ​± ​10.2 to 90.6 ​± ​7.6 in group I and from 49.1 ​± ​10.1 to 91.7 ​± ​6.6 in group II. There were no significant differences in preoperative and postoperative JOA scores and subscale scores in either group. Significant spot welds were observed in group II in Gruen zones 3 and 5. Stress shielding progressed over time in both groups, and the prevalence of grade 3 shielding was significantly lower in group II (p ​= ​0.028). Conclusion: Both stems had a survival rate of 100%. The incidence of severe stress shielding seemed to be lower with Accolade II, but further investigations should be needed.

Abstract Background Imeglimin is a new anti-diabetic drug which promotes insulin secretion from pancreatic β-cells and reduces insulin resistance in insulin target tissues. However, there have been no reports examining the possible anti-atherosclerotic effects of imeglimin. In this study, we investigated the possible anti-atherosclerotic effects of imeglimin using atherosclerosis model ApoE KO mice treated with streptozotocin (STZ). Methods ApoE KO mice were divided into three groups: the first group was a normoglycemic group without injecting STZ (non-DM group, n = 10). In the second group, mice were injected with STZ and treated with 0.5% carboxymethyl cellulose (CMC) (control group, n = 12). In the third group, mice were injected with STZ and treated with imeglimin (200 mg/kg, twice daily oral gavage, n = 12). We observed the mice in the three groups from 10 to 18 weeks of age. Plaque formation in aortic arch and expression levels of various vascular factors in abdominal aorta were evaluated for each group. Results Imeglimin showed favorable effects on the development of plaque formation in the aortic arch in STZ-induced hyperglycemic ApoE KO mice which was independent of glycemic and lipid control. Migration and proliferation of vascular smooth muscle cells and infiltration of macrophage were observed in atherosclerotic lesions in STZ-induced hyperglycemic ApoE KO mice, however, which were markedly reduced by imeglimin treatment. In addition, imeglimin reduced oxidative stress, inflammation and inflammasome in hyperglycemic ApoE KO mice. Expression levels of macrophage makers were also significantly reduced by imeglimin treatment. Conclusions Imeglimin exerts favorable effects on the development of plaque formation and progression of atherosclerosis.

Abstract Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all cancers. To improve PDAC therapy, we establish screening systems based on organoid and co-culture technologies and find a payload of antibody–drug conjugate (ADC), a bromodomain and extra-terminal (BET) protein degrader named EBET. We select CEACAM6/CD66c as an ADC target and developed an antibody, #84.7, with minimal reactivity to CEACAM6-expressing normal cells. EBET-conjugated #84.7 (84-EBET) has lethal effects on various PDAC organoids and bystander efficacy on CEACAM6-negative PDAC cells and cancer-associated fibroblasts. In mouse studies, a single injection of 84-EBET induces marked tumor regression in various PDAC-patient-derived xenografts, with a decrease in the inflammatory phenotype of stromal cells and without significant body weight loss. Combination with standard chemotherapy or PD-1 antibody induces more profound and sustained regression without toxicity enhancement. Our preclinical evidence demonstrates potential efficacy by delivering BET protein degrader to PDAC and its microenvironment via CEACAM6-targeted ADC.

Abstract A superconductor-insulator transition (SIT) in two dimensions is a prototypical quantum phase transition (QPT) with a clear quantum critical point (QCP) at zero temperature (T = 0). The SIT is induced by a field B and observed in disordered thin films. In some of weakly disordered or crystalline thin films, however, an anomalous metallic (AM) ground state emerges over a wide B range between the superconducting and insulating phases. It remains a fundamental open question how the QPT picture of the SIT is modified when the AM state appears. Here we present measurements of the Nernst effect N, which has great sensitivity to the fluctuations of the superconducting order parameter. From a thorough contour map of N in the B-T plane, we found a thermal-to-quantum crossover line of the superconducting fluctuations, a so-called ghost-temperature line associated with the QPT, as well as a ghost-field line associated with a thermal transition. The QCP is identified as a T = 0 intercept of the ghost-temperature line inside the AM state, which verifies that the AM state is a broadened critical state of the SIT.

Abstract Background ECPELLA, a combination of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) and Impella, a percutaneous left ventricular (LV) assist device, has emerged as a novel therapeutic option in patients with severe cardiogenic shock (CS). Since multiple cardiovascular and pump factors influence the haemodynamic effects of ECPELLA, optimising ECPELLA management remains challenging. In this study, we conducted a comprehensive simulation study of ECPELLA haemodynamics. We also simulated global oxygen delivery (DO2) under ECPELLA in severe CS and acute respiratory failure as a first step to incorporate global DO2 into our developed cardiovascular simulation. Methods and results Both the systemic and pulmonary circulations were modelled using a 5-element resistance‒capacitance network. The four ventricles were represented by time-varying elastances with unidirectional valves. In the scenarios of severe LV dysfunction, biventricular dysfunction with normal pulmonary vascular resistance (PVR, 0.8 Wood units), and biventricular dysfunction with high PVR (6.0 Wood units), we compared the changes in haemodynamics, pressure–volume relationship (PV loop), and global DO2 under different VA-ECMO flows and Impella support levels. Results In the simulation, ECPELLA improved total systemic flow with a minimising biventricular pressure–volume loop, indicating biventricular unloading in normal PVR conditions. Meanwhile, increased Impella support level in high PVR conditions rendered the LV–PV loop smaller and induced LV suction in ECPELLA support conditions. The general trend of global DO2 was followed by the changes in total systemic flow. The addition of veno-venous ECMO (VV-ECMO) augmented the global DO2 increment under ECPELLA total support conditions. Conclusions The optimal ECPELLA support increased total systemic flow and achieved both biventricular unloading. The VV-ECMO effectively improves global DO2 in total ECPELLA support conditions.

Abstract Background Bone metastases are frequently observed in advanced cancer, and bone modifying agents are used to prevent or treat skeletal-related events. Zoledronic acid is contraindicated in patients with severe renal impairment (Ccr

Abstract Background Obstructive sleep apnea (OSA) occurs more commonly in asthma patients than in the general population because these conditions share some comorbidities. In Japan, the prevalence of OSA in the general population is reported to be approximately 20%; however, few reports have described the prevalence of OSA in asthma patients. Furthermore, the characteristics of Japanese patients with OSA and asthma are not clear. Methods Adult asthma patients were recruited from the outpatient departments of our institution between August 31, 2017, and March 31, 2019. In all included patients, the presence and severity of OSA were evaluated by the Epworth Sleepiness Scale (ESS) and a home sleep test (HST) using portable polysomnography (PSG). The rate of coexisting OSA in asthma patients and the characteristics of those patients according to the severity of OSA were investigated. Results Fifty-three patients were included. OSA was detected in 36 (67.9%) patients (mild, n = 15; moderate, n = 14; and severe, n = 7). Patients with OSA had significantly higher body mass index, Brinkman index, apnea-hypopnea index (AHI), and 3% oxygen desaturation index (ODI) values in comparison to those without OSA, while the percentage of the predicted value of forced vital capacity (%FVC) and lowest SpO2 levels were significantly lower. As the severity of OSA increased, age, brain natriuretic peptide level, AHI, and 3%ODI increased, and in contrast, FVC, %FVC, forced expiratory volume in one second (FEV1), percentage of the predicted value of FEV1 (%FEV1), Epworth Sleepiness Scale (ESS), 3%ODI, and lowest SpO2 levels decreased. In particular, the fact that the ESS value was inversely correlated with the severity of OSA in our patients was different from the general characteristics of OSA. Moreover, the AHI value was negatively correlated with FVC, %FVC, FEV1, and %FEV1. BMI was the only independent factor for the presence of OSA, and for asthma severity (FEV1, % of predicted), there was a weak correlation with smoking history. Conclusions This is the first report to investigate the prevalence of OSA in Japanese asthma patients, using an HST. This study suggests that an HST should be performed in addition to the sleep interview for asthma patients with refractory disease, a low pulmonary function, advanced age, and high BMI because the more severe the OSA, the lower the ESS value may be.

We report a rare case of a primary renal neuroendocrine tumor. The patient was a 64-year-old woman. The patient's chief complaint was gross hematuria. Dynamic contrast-enhanced computed tomography (CT) revealed a hypovascular mass 13 cm in diameter in the right kidney. The border of the mass was clear. A grossly contrast-impaired area and internal granular calcification were observed. A right radical nephrectomy was performed. Macroscopically, the mass was hemorrhaged and necrotic. It was diagnosed as a neuroendocrine tumor (NET) (Grade 2) histologically. Findings, such as hypovascularity, calcification, and necrosis, in our case were similar to those in previous reports. These findings are considered relatively characteristic of primary renal NETs.

Abstract Purpose We investigated the effects of a surgical mask and an N95 mask on speech intelligibility using explicit and ambiguous sentences in Japanese. In addition, the effects of background noise specific to an operating room environment on the speech intelligibility of these sentences were also investigated. Methods We created 20 sets of five sentences; 10 sets consisting of explicit words, and 10 containing ambiguous words. Each set was recorded by a speaker while wearing a surgical mask or an N95 mask, combined with a face shield. A total of four combinations of speech data were created. Each subject was asked to listen to one set from each of the four combinations and write down the speech. The test was performed in normal background noise as well as in noise levels of 50, 60, and 70 dB. Results Twenty-eight volunteers were included in this study. In the tests for explicit sentences, intelligibility of speech with an N95 mask was significantly lower than that with a surgical mask in the presence of 60 dB noise. As for explicit sentences produced with a surgical mask, intelligibility was significantly decreased in the presence of 70 dB noise. Regarding explicit sentences produced with an N95 mask, intelligibility was significantly decreased in the presence of 60 and 70 dB noise. In the tests for ambiguous sentences, intelligibility of speech produced with an N95 mask was not significantly lower than that with a surgical mask at all noise levels. As for ambiguous sentences produced with a surgical mask, no significant decrease in intelligibility was observed at any noise level. Regarding ambiguous sentences produced with an N95 mask, intelligibility was significantly decreased in the presence of 60 and 70 dB noise. Conclusion Speech intelligibility was impaired both with a surgical mask and an N95 mask in the normal background noise specific in an operating room during surgery, even if the speech consisted of explicit words. The impairment of speech intelligibility was significantly exacerbated with the use of ambiguous language and in the background noise typical in an operating room environment. Speech intelligibility was further reduced with the use of an N95 mask. Trial Registration Registered at the University Hospital Medical Information Network Clinical Trials Registry on March 7, 2023 (UMIN R000050373).

Abstract Radiotherapy with deep inspiration breath hold (DIBH) reduces doses to the lungs and organs at risk. The stability of breath holding and reproducibility of tumor location are higher during expiration than during inspiration; therefore, we developed an irradiation method combining DIBH and real-time tumor-tracking radiotherapy (RTRT) (DBRT). Nine patients were enrolled in this study. Fiducial markers were placed near tumors using bronchoscopy. Treatment planning computed tomography (CT) was performed thrice during DIBH, assisted by spirometer-based device. Each CT scan was fused using fiducial markers. Gross tumor volume (GTV) was contoured for each dataset and summed to create GTVsum; adding a 5-mm margin around GTVsum generated the planning target volume. The prescribed dose was mainly 42 Gy in four fractions. The treatment plan was created using DIBH CT (DBRT-plan), with a similar treatment plan created for expiratory CT for cases for which DBRT could not be performed (conv-plan). Vx defined as the volume of the lung received x Gy, and the mean lung dose, V20, V10, and V5 were evaluated. DBRT was completed in all patients. Mean dose, V20, and V10 were significantly lower in the DBRT-plan than in the conv-plan (all p = 0.003). Mean rates of decrease for mean dose, V20, and V10 were 14.0%, 27.6%, and 19.1%, respectively. No significant difference was observed in V5. We developed DBRT, a stereotactic body radiation therapy performed with the DIBH technique; it combines a spirometer-based breath-hold support system with an RTRT system. All patients who underwent DBRT completed the procedure without any technical or mechanical complications. This is a promising methodology that may significantly reduce lung doses.

Abstract In this study, a high-throughput fabrication method called laser-assisted direct roller imprinting (LADRI) was developed to lower the cost of nanoimprinting large-area polymer films and to address problems associated with nanoimprinting, namely, microstructural damage and precision in flatness of entire film. With LADRI, the laser directly heats the microstructured surface of the roller mold, which heats and melts the surface of a polymethyl methacrylate (PMMA) film to replicate the microstructures on the mold rapidly. In this study, the effects of laser power density, scanning speed, size of the microstructures, and contact pressure on the replication speed were investigated experimentally. The replication speed increased as the power and scanning speed increased. However, because the film required heating until it filled the entire depth of the microstructure, an appropriate replication speed was necessary. This result was supported by simulation of the temperature distribution inside the mold and the PMMA using transient heat conduction analyses. To demonstrate the applications of LADRI, two different optical surfaces were replicated: an antireflection (AR) structure with conical structures sized several hundred nanometers and a light-extraction structure with a microlens array (MLA) comprising 10 μm lenses, for display and illumination, respectively. The replication degree of the MLA was governed by the contact pressure. Polymer flow simulation indicated that the heat conduction and flow speeds of the melted PMMA surface were comparable within several tens of micrometers. In addition, the reflectivity of the AR structure decreased from 4 to 0.5%, and the light intensity of the light-extraction structure increased by a factor of 1.47.

Abstract Background Uterine leiomyomas are common for reproductive-aged women and affect women’s quality of life due to heavy menstrual bleeding or dysmenorrhea. Leiomyomas grow according to estradiol exposure and decrease after post-menopause. In case serious symptoms are caused by leiomyomas, pharmacotherapy or surgical treatment is proposed. Prior to surgical treatment, pharmacotherapies aimed at the reduction of leiomyoma and uterine volume or improvement of anemia are introduced to conduct minimum invasive surgery (i.e., to reduce blood loss or surgical duration). Recently, relugolix (40 mg orally once daily) as a gonadotropin-releasing hormone (GnRH) receptor antagonist has proved its sufficient efficacy in suppressing estradiol levels without the transient estradiol flare-up compared with GnRH agonist. However, long-term administration should not be permitted liable to for climacteric disorder or osteoporosis, and evidence is lacking on the actual efficacy and extent of adverse effects of the every-other-day dosing regimen. This trial aimed to prove non-inferiority in volume reduction effect on leiomyoma and safety (i.e., reduction of adverse effects) by every-other-day administration after 2 months of everyday administration compared to daily administration throughout the duration. Methods A minimization adaptive randomized control trial (RCT) will be conducted. Patients (over 20 years old) harboring leiomyoma who will be undergoing surgical treatment will be invited to participate. Patients who are enrolled in the intervention group will receive every-other-day administration for 16 weeks after 8 weeks of daily administration. Patients who are enrolled in the control group will receive daily throughout the 24 weeks. The primary outcome is the leiomyoma volume reduction, and the secondary endpoints are the reduction of uterine volume, the occurrence of the climacteric disorder, genital bleeding days, change rate of serum hormone or bone turnover markers, and bone mineral density after 24 weeks compared to before administration. Discussion This study aims to prove both the non-inferiority in leiomyoma volume reduction and superiority in adverse effects occurrence reduction, which will provide a novel method to escape adverse effects while maintaining the effect of leiomyoma reduction. Trial registration Japan Registry of Clinical Trials jRCTs051230078. Registered on 26 July 2023.

Abstract Background and Objectives The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late‐onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. Methods We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat‐primed PCR, and long‐read sequencing. Results Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270–316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow‐up study conducted after a mean period of 6 years did not reveal any significant progression. Discussion This study highlights the importance of FGF14 GAA repeat analysis in patients with late‐onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA‐FGF14‐related diseases.

Early life environment influences mammalian brain development, a growing area of research within the Developmental Origins of Health and Disease framework, necessitating a deeper understanding of early life factors on children’s brain development. This study introduces a mouse model, LAO1 knockout mice, to investigate the relationship between breast milk, the gut microbiome, and brain development. The results reveal that breast milk‘s reactive oxygen species (ROS) are vital in shaping the neonatal gut microbiota. Decreased hydrogen peroxide (H2O2) levels in milk disrupt the gut microbiome and lead to abnormal metabolite production, including D-glucaric acid. This metabolite inhibits hippocampal myelin formation during infancy, potentially contributing to behavioral abnormalities observed in adulthood. These findings suggest that H2O2 in breast milk is crucial for normal gut microbiota formation and brain development, with implications for understanding and potentially treating neurodevelopmental disorders in humans.

Abstract Background Asparaginase is essential for treating T‐cell acute lymphoblastic leukemia (T‐ALL). Despite the ongoing debate on whether T‐ALL and T‐cell lymphoblastic lymphoma (T‐LBL) are the same disease entity or two distinct diseases, patients with T‐LBL often receive the same or similar treatment protocols as those with T‐ALL. Methods The outcomes of patients with or without L‐asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL‐02 and ALL‐97 for T‐ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB‐NHL03 and JACLS NHL‐98 for T‐LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L‐asparaginase discontinuation as a time‐dependent variable. Results In total, 199 patients with T‐ALL, and 133 patients with T‐LBL were included. L‐asparaginase discontinuation compromised event‐free survival (EFS) of T‐ALL patients (ALL‐02: HR 3.32, 95% confidence interval [CI] 1.40–7.90; ALL‐97: HR 3.39, 95%CI 1.19–9.67). Conversely, EFS compromise was not detected among T‐LBL patients (ALB‐NHL03: HR 1.39, 95%CI 0.41–4.68; NHL‐98: HR 0.92, 95%CI 0.11–7.60). Conclusion The effects of L‐asparaginase discontinuation differed between T‐ALL and T‐LBL. We assume that the differential impact results from (1) the inherent differential response to L‐asparaginase between them and/or (2) a less stringent assessment of early treatment response in T‐LBL than in T‐ALL. Given the poor salvage rate of refractory or relapsed T‐ALL and T‐LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required.

Abstract Purpose Since June 2020, boron neutron capture therapy (BNCT) has been a health care service covered by health insurance in Japan to treat locally advanced or recurrent unresectable head and neck cancers. Therefore, we aimed to assess the clinical outcomes of BNCT as a health insurance treatment and explore its role among the standard treatment modalities for head and neck cancers. Materials and Methods We retrospectively analyzed data from patients who were treated using BNCT at Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, between June 2020 and May 2022. We assessed objective response rates based on the Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events based on the Common Terminology Criteria for Adverse Events, version 5.0. Additionally, we conducted a survival analysis and explored the factors that contributed to the treatment results. Results Sixty‐nine patients (72 treatments) were included in the study, with a median observation period of 15 months. The objective response rate was 80.5%, and the 1‐year locoregional control, progression‐free survival, and overall survival rates were 57.1% (95% confidence interval [CI]: 43.9%–68.3%), 42.2% (95% CI: 30.1%–53.8%), and 75.4% (95% CI: 62.5%–84.5%), respectively. Locoregional control was significantly longer in patients with earlier TNM staging and no history of chemotherapy. Conclusions BNCT may be an effective treatment option for locally advanced or recurrent unresectable head and neck cancers with no other definitive therapies. If definitive surgery or radiation therapy are not feasible, BNCT should be considered at early disease stages.

Fibrocartilaginous entheses consist of tendons, unmineralized and mineralized fibrocartilage, and subchondral bone, each exhibiting varying stiffness. Here we examined the functional role of sclerostin, expressed in mature mineralized fibrochondrocytes. Following rapid mineralization of unmineralized fibrocartilage and concurrent replacement of epiphyseal hyaline cartilage by bone, unmineralized fibrocartilage reexpanded after a decline in alkaline phosphatase activity at the mineralization front. Sclerostin was co-expressed with osteocalcin at the base of mineralized fibrocartilage adjacent to subchondral bone. In Scx-deficient mice with less mechanical loading due to defects of the Achilles tendon, sclerostin+ fibrochondrocyte count significantly decreased in the defective enthesis where chondrocyte maturation was markedly impaired in both fibrocartilage and hyaline cartilage. Loss of the Sost gene, encoding sclerostin, elevated mineral density in mineralized zones of fibrocartilaginous entheses. Atomic force microscopy analysis revealed increased fibrocartilage stiffness. These lines of evidence suggest that sclerostin in mature mineralized fibrochondrocytes acts as a modulator for mechanical tissue integrity of fibrocartilaginous entheses.