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Ovarian cancer is classified as type 1 or 2, representing low- and high-grade serous carcinoma (LGSC and HGSC), respectively. LGSC arises from serous borderline tumor (SBT) in a stepwise manner, while HGSC develops from serous tubal intraepithelial carcinoma (STIC). Rarely, HGSC develops from SBT and LGSC. Herein, we describe the case of a patient with HGSC who presented with SBT and LGSC, and in whom we analyzed the molecular mechanisms of carcinogenesis. We performed primary debulking surgery, resulting in a suboptimal simple total hysterectomy and bilateral salpingo-oophorectomy due to strong adhesions. The diagnosis was stage IIIC HGSC, pT3bcN0cM0, but the tumor contained SBT and LGSC lesions. After surgery, TC (Paclitaxel + Carbopratin) + bevacizumab therapy was administered as adjuvant chemotherapy followed by bevacizumab as maintenance therapy. The tumor was chemo-resistant and caused ileus, and bevacizumab therapy was conducted only twice. Next-Generation Sequencing revealed KRAS (p.G12V) and NF2 (p.W184*) mutations in all lesions. Interestingly, the TP53 mutation was not detected in every lesion, and immunohistochemistry showed those lesions with wild-type p53. MDM2 was amplified in the HGSC lesions. DNA methylation analysis did not show differentially methylated regions. This case suggests that SBT and LGSC may transform into HGSC via p53 dysfunction due to MDM2 amplification.

Abstract Background Cystinosis is a lysosomal storage disorder characterized by an autosomal recessive phenotype. Intermediate cystinosis, which progresses slowly and causes renal failure, accounts for approximately 5% of all cystinosis cases. Patients with intermediate cystinosis may not exhibit the typical symptoms of cystinosis, such as Fanconi syndrome and ocular symptoms. Because of its diverse clinical presentation and rarity, intermediate cystinosis can be difficult to diagnose. Additionally, few patients can tolerate cystine-depleting drugs, such as cysteamine, because of their complicated administration schedules and side effects. We report a case of intermediate cystinosis that was treated with cysteamine for 10 years. Case presentation Urinary abnormalities were first diagnosed when the patient was 3 years of age during a health examination specifically for 3-year-old children, which is unique to Japan. Cystinosis was diagnosed when the patient was 12 years of age. Cysteamine therapy was initiated and regular cystine concentration measurements were performed. Although proteinuria persisted, the patient’s renal function progressed slowly. Two renal biopsies were performed, and multinucleated podocytes and cystine crystals without focal segmental glomerulosclerosis lesions were observed in the biopsy specimens. The patient’s renal function remained stable. Conclusions This case of intermediate cystinosis was treated with cysteamine over the course of 10 years. Intermediate cystinosis requires an appropriate diagnosis and long-term treatment.

Abstract Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, how the body remembers exposure to an adverse environment during development is poorly understood. Herein, we explore the effects of prenatal vitamin D deficiency on immune cell proportions in offspring using vitamin D deficient mice established by dietary manipulation. We found that prenatal vitamin D deficiency alters immune cell proportions in offspring by changing the transcriptional properties of genes downstream of vitamin D receptor signaling in hematopoietic stem and progenitor cells of both the fetus and adults. Moreover, further investigations of the associations between maternal vitamin D levels and cord blood immune cell profiles from 75 healthy pregnant women and their term offspring also confirm that maternal vitamin D levels in the second trimester significantly affect immune cell proportions in the offspring. These findings imply that the differentiation properties of hematopoiesis act as long-term memories of prenatal vitamin D deficiency exposure in later life.

Abstract Background Generalized myasthenia gravis (gMG) can be managed with acetylcholinesterase inhibitors (AChEis; e.g., pyridostigmine), corticosteroids, other immunosuppressive drugs (e.g., tacrolimus), and their combinations. Intravenous immunoglobulin (IVIg) or plasmapheresis (PLEX) may be administered if symptoms persist. PLEX and IVIg are also mainstays of treatment for myasthenic crisis. Recently, efgartigimod was approved in Japan for treating adults with gMG (irrespective of the antibody status) who do not have a sufficient response to corticosteroids and nonsteroidal immunosuppressive therapies. Efgartigimod is generally safe and well tolerated. However, since phase III trials of efgartigimod excluded those with myasthenic crisis, the efficacy of efgartigimod in treating myasthenic crisis is still unclear. Moreover, there are no reports that efgartigimod therapy can reduce the dose of corticosteroids needed to achieve a minimal manifestation status. Case presentation We report the case of a 70-yeat-old woman with gMG who developed a myasthenic crisis. After she was diagnosed with gMG, the patient had been treated with oral corticosteroids and tacrolimus for 1 year. However, she refused to continue taking the medication, and two weeks later, she developed ptosis, dysphagia and dyspnea. The patient was intubated and treated with efgartigimod in combination with steroid therapy, and she recovered without PLEX or IVIg. Afterward, when she experienced worsening of fatigue and increased levels of anti-acetylcholine receptor antibodies, efgartigimod therapy was effective. The patient achieved minimal manifestation status even after the reduction of corticosteroids and showed improvements in the Myasthenia Gravis Activities of Daily Living scales after 4 cycles of efgartigimod infusion. Conclusions Our case suggests that efgartigimod can be an alternative drug for achieving minimal manifestation status in patients with myasthenic crisis. Considering its strong efficacy and safety, efgartigimod could be expanded to use as bridging therapy in the acute and chronic phases of gMG.

Abstract The cellular origin of clear cell ovarian carcinoma (CCOC), a major histological subtype of ovarian carcinoma remains elusive. Here, we explored the candidate cellular origin and identify molecular subtypes using integrated genomic/epigenomic analysis. We performed whole exome-sequencing, microarray, and DNA methylation array in 78 CCOC samples according to the original diagnosis. The findings revealed that ARID1A and/or PIK3CA mutations were mutually exclusive with DNA repair related genes, including TP53, BRCA1, and ATM. Clustering of CCOC and other ovarian carcinomas (n = 270) with normal tissues from the fallopian tube, ovarian surface epithelium, endometrial epithelium, and pelvic peritoneum mesothelium (PPM) in a methylation array showed that major CCOC subtypes (with ARID1A and/or PIK3CA mutations) were associated with the PPM-lile cluster (n = 64). This cluster was sub-divided into three clusters: (1) mismatch repair (MMR) deficient with tumor mutational burden-high (n = 2), (2) alteration of ARID1A (n = 51), and (3) ARID1A wild-type (n = 11). The remaining samples (n = 14) were subdivided into (4) ovarian surface epithelium-like (n = 11) and (5) fallopian tube-like (considered as high-grade serous histotype; n = 3). Among these, subtypes (1–3) and others (4 and 5) were found to be associated with immunoreactive signatures and epithelial-mesenchymal transition, respectively. These results contribute to the stratification of CCOC into biological subtypes.

Abstract HMGA1 is an abundant non-histone chromatin protein that has been implicated in embryonic development, cancer, and cellular senescence, but its specific role remains elusive. Here, we combine functional genomics approaches with graph theory to investigate how HMGA1 genomic deposition controls high-order chromatin networks in an oncogene-induced senescence model. While the direct role of HMGA1 in gene activation has been described previously, we find little evidence to support this. Instead, we show that the heterogeneous linear distribution of HMGA1 drives a specific 3D chromatin organization. HMGA1-dense loci form highly interactive networks, similar to, but independent of, constitutive heterochromatic loci. This, coupled with the exclusion of HMGA1-poor chromatin regions, leads to coordinated gene regulation through the repositioning of genes. In the absence of HMGA1, the whole process is largely reversed, but many regulatory interactions also emerge, amplifying the inflammatory senescence-associated secretory phenotype. Such HMGA1-mediated fine-tuning of gene expression contributes to the heterogeneous nature of senescence at the single-cell level. A similar ‘buffer’ effect of HMGA1 on inflammatory signalling is also detected in lung cancer cells. Our study reveals a mechanism through which HMGA1 modulates chromatin compartmentalization and gene regulation in senescence and beyond.

Abstract Determining the content of the nutrient choline in foods and obtaining the required amount from the diet are crucial. One way to measure choline in foods is by converting choline esters to free choline via acid hydrolysis, followed by quantifying the total choline, as adopted by the AOAC method (AOAC-Choline); however, certain choline esters are difficult to hydrolyse. Here, we investigated various acid hydrolysis conditions to establish a reliable method for determining the total choline in foods by detecting free choline using highly sensitive and selective mass spectrometry. Hydrolysis in 0.055 mol/L HCl for 8 h in an autoclave (121 °C) was found to be optimal for the hydrolysis of choline esters in various foods. Twenty-four foods, including grains, seed, vegetables, fruits, mushroom, algae, fish, meats, beverage, processed foods, and egg, were measured. The trends in the total choline content were consistent with previous reports; however, the choline content was 10–20% higher than that measured using AOAC-Choline. Therefore, re-evaluation of the total choline content in foods using our constructed method is recommended. This reassessment will allow for a more reliable determination of choline intake for maintaining health.

Abstract Background A recent Phase 2/3 study in Japanese patients showed that caplacizumab was effective in treating immune-mediated thrombotic thrombocytopenic purpura (iTTP), with a low rate of iTTP recurrence. ADAMTS13 activity is monitored weekly during caplacizumab treatment to guide discontinuation of caplacizumab and consequently avoid exacerbations or relapse. The aim of this study was to assess changes in ADAMTS13 activity/inhibitor levels during caplacizumab treatment in this patient population. Methods A post hoc analysis of the Phase 2/3 study in Japanese patients was conducted. Patients ≥ 18 years old with confirmed iTTP received 10 mg of caplacizumab daily in conjunction with therapeutic plasma exchange (TPE) and immunosuppression for 30 days post-TPE. Outcomes included time to recovery of ADAMTS13 activity, ADAMTS13 activity level at treatment end, incidence of ADAMTS13 inhibitor re-elevation (ie, inhibitor boosting) during treatment, time to platelet count recovery, number of days of TPE, and safety. Outcomes according to presence of inhibitor boosting were also assessed. Results Nineteen patients had confirmed iTTP and were included in this analysis. Median (95% confidence interval) time to recovery of ADAMTS13 activity to ≥ 10%, ≥ 20%, and ≥ 60% was 14.6 (5.9–24.8), 18.5 (5.9–31.8), and 47.5 (18.5–60.9) days, respectively. Median (range) ADAMTS13 activity level at caplacizumab treatment end was 62.0% (29.0–101.0). Nine patients had ADAMTS13 inhibitor boosting. Delayed response of ADAMTS13 activity was observed in patients with inhibitor boosting. The median time to platelet count response and median number of TPE days were shorter in patients with inhibitor boosting compared with patients without inhibitor boosting. Rituximab was administered to almost all patients with inhibitor boosting (88.9%), after completion of TPE. Patients without inhibitor boosting who were treated with rituximab received it prior to completion of TPE. Only one patient experienced a recurrence, which occurred shortly after caplacizumab discontinuation due to an adverse event. Conclusions In patients with iTTP, caplacizumab with TPE and immunosuppression may reduce the risk of ADAMTS13 inhibitor boosting if rituximab is administered early in the iTTP treatment period. Early administration of rituximab in addition to caplacizumab may prevent iTTP recurrence with inhibitor boosting. Trial registration NCT04074187.

Abstract Aims Cardiac resynchronization therapy (CRT) is an established treatment for drug‐refractory heart failure (HF) in patients with left bundle branch block (LBBB). Acute haemodynamic improvement after CRT implantation may enable the intensification of HF medication soon thereafter. Immediate pharmacotherapy intensification (IPI) after CRT implantation achieves a synergetic effect, possibly leading to a better prognosis. This study aimed to explore the incidence, characteristics, and impact of IPI on real‐world outcomes among CRT recipients with a history of hospitalization for acute HF. Methods and results This multicentre retrospective study enrolled CRT recipients with LBBB morphology, a QRS width ≥120 ms, a left ventricular ejection fraction ≤35%, and New York Heart Association II–IV HF symptoms. All patients had previous HF hospitalizations within the previous year and received guideline‐directed medical therapy before CRT implantation. Patient baseline characteristics, including HF medication, were collected. IPI was defined as the intensification of beta‐blockers, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists within 30 days of CRT implantation. The primary endpoint was all‐cause death or first hospitalization for HF; the secondary endpoint was all‐cause death. We enrolled 194 patients (75% male; mean age, 65 ± 13 years; 78% with non‐ischaemic cardiomyopathy). One hundred five (54%) patients received IPI. Patients who received IPI exhibited a significantly shorter QRS duration (159 ± 26 vs. 171 ± 32 ms; P = 0.004), higher estimated glomerular filtration rate (55.2 ± 20.0 vs. 47.8 ± 24.7 mL/min/1.73 m2; P = 0.022), and more dilated cardiomyopathy. During a median follow‐up period of 29 months, 70 (36%) patients reached the primary endpoint and 42 (22%) patients died. Patients with IPI showed significantly better outcomes for the primary and secondary endpoints than patients without IPI. The volumetric responder ratio at 6 months after implantation was not significantly different between patients with and without IPI; however, patients who received IPI had reduced mortality even at 6 months after implantation. In the multivariate analysis, IPI was an independent predictor of the primary endpoint (hazard ratio, 0.51; 95% confidence interval, 0.27–0.97; P = 0.043). Conclusions Immediate intensification of HF medication was achieved in 54% of CRT recipients and was significantly higher in patients without excessive QRS prolongation, preserved renal function, and dilated cardiomyopathy than others. In patients with LBBB morphology and QRS ≥ 120 ms, IPI was associated with a significantly better prognosis and fewer HF hospitalizations after CRT implantation than others.

Objective: Reports demonstrating the effectiveness and safety of strut-adjusted volume implants (SAVI) in Japan are limited. Therefore, this study aimed to compare the treatment outcomes of SAVI and whole-breast irradiation (WBI) at a single facility. Materials and Methods: Data were retrospectively extracted from the medical records of patients treated with SAVI or WBI following partial mastectomy (Bp). Patients undergoing Bp, sentinel lymph node biopsy, and SAVI spacer insertion followed by brachytherapy with the SAVI device were compared to those followed with WBI. Local recurrence was assessed annually by physical examination, bilateral mammography, and breast ultrasonography. Results: The SAVI and WBI groups comprised 53 and 113 patients, with a median age of 55 and 52 years, respectively; among them, 47 and 91 patients had a pathological tumor diameter ≤2 cm and six and 22 had a pathological tumor diameter >2 cm, respectively. Recurrence events, acute adverse events, and late adverse events were observed in the SAVI and WBI groups in 1 and 3 (p = 0.726), 24 and 79 (p = 0.01), and 24 and 18 patients (p = 0.00002), respectively, with median observation periods of 60.0 and 47.8 months, respectively. All adverse events were grades 1–2, with dermatitis being the most common in the acute phase. In the late phase, pigmentation was common in both groups. Conclusion: The local recurrence rate does not differ between SAVI and WBI within the relatively short-term follow-up period. Longer follow-up is required to confirm our results in the Japanese population.

Abstract Human norovirus (HuNoV) is an enteric infectious pathogen belonging to the Caliciviridae family that causes occasional epidemics. Circulating alcohol-tolerant viral particles that are readily transmitted via food-borne routes significantly contribute to the global burden of HuNoV-induced gastroenteritis. Moreover, contact with enzymes secreted by other microorganisms in the environment can impact the infectivity of viruses. Hence, understanding the circulation dynamics of Caliciviridae is critical to mitigating epidemics. Accordingly, in this study, we screened whether environmentally abundant secretase components, particularly proteases, affect Caliciviridae infectivity. Results showed that combining Bacillaceae serine proteases with epsilon-poly-l-lysine (EPL) produced by Streptomyces—a natural antimicrobial—elicited anti-Caliciviridae properties, including against the epidemic HuNoV GII.4_Sydney_2012 strain. In vitro and in vivo biochemical and virological analyses revealed that EPL has two unique synergistic viral inactivation functions. First, it maintains an optimal pH to promote viral surface conformational changes to the protease-sensitive structure. Subsequently, it inhibits viral RNA genome release via partial protease digestion at the P2 and S domains in the VP1 capsid. This study provides new insights regarding the high-dimensional environmental interactions between bacteria and Caliciviridae, while promoting the development of protease-based anti-viral disinfectants.

Platinum(II) complexes of square-planar geometry are interesting from a crystal engineering viewpoint because they exhibit strong luminescence based on the self-assembly of molecular units. The luminescence color changes in response to gentle stimuli, such as vapor exposure or weak mechanical forces. Both the molecular and the crystal designs for soft crystals are critical to effectively generate the chromic luminescence phenomenon of Pt(II) complexes. In this topical review, strategies for fabricating chromic luminescent Pt(II) complexes are described from a crystal design perspective, focusing on the structural regulation of Pt(II) complexes that exhibit assembly-induced luminescence via metal–metal interactions and structural control of anionic Pt(II) complexes using cations. The research progress on the evolution of various chromic luminescence properties of Pt(II) complexes, including the studies conducted by our group, are presented here along with the latest research outcomes, and an overview of the frontiers and future potential of this research field is provided.

ABSTRACT Aims To evaluate the relationship between diabetes treatment status and occupational accidents. Methods A cross‐sectional study was conducted using an online questionnaire survey completed in March 2022 among workers aged 20 years or older. The questionnaire included questions about diabetes treatment status and occupational accidents. The association between the treatment status of diabetes and occupational accidents was examined using a logistic regression analysis. Results The study included 25,756 participants with no diabetes, 1,364 participants receiving diabetes treatment, 177 participants who had interrupted diabetes treatment, and 396 participants who needed diabetes treatment but had not seen a doctor. Compared with those with diabetes treatment, the odds ratio of occupational accidents among participants without diabetes was 0.40 (95% CI: 0.32–0.49), the odds ratio among participants with interrupted diabetes treatment was 4.15 (95% CI: 2.86–6.01), and the odds ratio among participants who needed diabetes treatment but had not seen a doctor was 1.25 (95% CI: 0.89–1.77). Conclusions This study showed that diabetes treatment status was related to occupational accidents, and it may be important for workers with diabetes to be supported to balance their diabetes management and their work commitments.

ABSTRACT Aims/Introduction In 2021, the guidelines on gestational weight gain (GWG) were revised and increased by 2–3 kg in Japan. This study aimed to investigate whether the revised guidelines would increase the incidence of babies with excessive birth weight in mothers with diabetes. Materials and Methods This retrospective study included 369 deliveries of women with diabetes whose pre‐pregnancy body mass index was below 30 kg/m2 between 1982 and 2021. The primary outcome measure was large for gestational age (LGA). We compared the incidence of LGA between women who gained weight within the previous guidelines and women who gained weight within the revised guidelines. We also compared the incidence of macrosomia, preeclampsia, small for gestational age (SGA), and low birth weight. Results The incidence of LGA was not significantly different between women who gained weight within the revised guidelines and those within the previous guidelines (34.6% [95% confidence interval 25.6–44.6%] for the revised guidelines vs 28.9% [21.6–37.1%] for the previous guidelines; P = 0.246). Neither was the incidence of macrosomia or preeclampsia significantly different (8.7% [4.0–15.8%] vs 5.6% [2.5–10.8%] and 5.8% [2.1–12.1%] vs 6.3% [2.9–11.7%]; P = 0.264 and 0.824, respectively), while women who gained weight within the revised guidelines had a lower incidence of SGA (1.9% [0.2–6.8%] vs 10.6% [6.0–16.8%]; P = 0.001) and low birth weight (1.0% [0.02–5.2%] vs 7.0% [3.4–12.6%]; P = 0.023). Conclusions The revised GWG guidelines could be beneficial in women with diabetes in terms of delivering babies with appropriate birth weight.

Background/purpose: Self-assessment in dental education is considered a fundamental skill for proficient oral healthcare providers. While previous studies looked at self-assessment in education, few have done so at Japanese institutions. This study aimed to assess potential associations between gender and self-assessment skills in Japanese dental students. Materials and methods: Dental students from Niigata University (n = 301) completed preclinical prosthodontic exercises and self-assessed their practical exam performance. Three calibrated faculty evaluated students’ work using the same rubric. The difference between student self-assessment score and mean faculty grade was defined as the student-faculty (S-F) gap, indicating how accurately students evaluated their work. The gap scores were stratified by quartiles by faculty grade and by gender. Regression analysis was used to investigate potential associations. Results: Students mean S-F gap was 2.9 ± 10.5 % with a significant negative association to faculty grades (coefficient, −0.32; P

At the major vernalization locus ‘Vrn-D1’, the spring allele, Vrn-D1a, and two winter alleles, Vrn-D1b and vrn-D1, have been identified in wheat. We conducted field trials to determine the effects of alleles on growth and yield-related traits, using near-isogenic lines developed in the genetic background of spring type wheat cultivars, ‘Abukumawase’ and ‘Asakazekomugi’, both of which carry the Vrn-D1a allele. Although maturity date of three alleles was same, the panicle development occurred earlier in the following order of genotype: Vrn-D1a > Vrn-D1b > vrn-D1. There was a significant difference in panicle development even between two winter type alleles vrn-D1 and Vrn-D1b. Grain yield and the spikelet number per spike of the original spring type cultivars were lower than those of the winter type NILs. In addition, while the young panicle development of the tillers in the spring type cultivars was found to be two weeks to one month later in the tillers than that in the main stem, young panicle development of the main stem and tillers in the winter type NILs were almost identical. Hence, winter type wheat bearing vrn-D1 which exhibit later panicle development than that bearing Vrn-D1b, was elucidated to might be more useful especially in areas with high risk of frost damage. Spring type wheat had a lower sink capacity and grain yield, meanwhile that was considered to prevent severe frost damage by allowing late-developed tillers to survive.

Background The purpose of this study was to clarify fading, red, green, and blue values (RGB) change, and color reproducibility for nipple–areola complex (NAC) tattoos.

Abstract Individuals experience difficulty falling asleep in a new environment, termed the first night effect (FNE). However, the impact of the FNE on sleep-induced brain plasticity remains unclear. Here, using a within-subject design, we found that the FNE significantly reduces visual plasticity during sleep in young adults. Sleep-onset latency (SOL), an indicator of the FNE, was significantly longer during the first sleep session than the second session, confirming the FNE. We assessed performance gains in visual perceptual learning after sleep and increases in the excitatory-to-inhibitory neurotransmitter (E/I) ratio in early visual areas during sleep using magnetic resonance spectroscopy and polysomnography. These parameters were significantly smaller in sleep with the FNE than in sleep without the FNE; however, these parameters were not correlated with SOL. These results suggest that while the neural mechanisms of the FNE and brain plasticity are independent, sleep disturbances temporarily block the neurochemical process fundamental for brain plasticity.

Background: Effective near-miss management is important in preventing workplace accidents. A company's inadequate response to near-miss reports can lead workers to feel insecure and dissatisfied with the company. We investigated the relationship between companies' responses to near-miss reports and turnover intentions of workers. Methods: We conducted a cross-sectional study using online self-administered questionnaire survey to workers aged ≥20 years in Japan in March 2022. The analysis included 5,071 participants who had near-miss experiences and reported them to their companies. The independent variable was companies' responses to near-miss reports, classified into three categories: adequate response group, inadequate response group, and no response group. The dependent variable was turnover intentions. We calculated the odds ratio and 95% confidential interval (CI) using multilevel logistic regression analyses nested for industries and adjusted for covariates. Results: Of the 5,071 participants, 3,058 (60.3%) were adequate response group, 1,484 (29.3%) were inadequate response group, and 529 (10.4%) were no response group. In multivariable adjusted model, compared with adequate response group, the odds ratio of inadequate response group and no response group were 1.80 (95% CI: 1.56–2.08) and 2.63 (95% CI: 2.15–3.22), respectively. Conclusion: Our results suggested that there was a relationship between companies' responses to the near-miss reports and turnover intentions of workers. It is important not only to collect near-misses but also to respond appropriately to the reports and provide feedback to workers.

Background: We examined the association between supervisor consultation, as an actual practice representing supervisor support, and work engagement. Methods: This was a prospective cohort study in Japan, involving 14,026 participants who met the requirement for a one-year follow-up. Supervisor consultation was measured using a single question, and work engagement was defined using the Japanese version of the nine-item Utrecht Work Engagement Scale (UWES-9). Associations were examined using linear regression analysis. Results: Supervisor consultation was positively associated with work engagement after adjusting for gender, age, education, income, and industry (β = 3.474; p

Abstract The growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable modules. PHLEX generates single-cell identities, cell densities within tissue compartments, marker positivity calls and spatial metrics such as cellular barrier scores, along with summary graphs and spatial visualisations. PHLEX was developed using imaging mass cytometry (IMC) in the TRACERx study, validated using published Co-detection by indexing (CODEX), IMC and orthogonal data and benchmarked against state-of-the-art approaches. We evaluated its use on different tissue types, tissue fixation conditions, image sizes and antibody panels. As PHLEX is an automated and containerised Nextflow pipeline, manual assessment, programming skills or pathology expertise are not essential. PHLEX offers an end-to-end solution in a growing field of highly multiplexed data and provides clinically relevant insights.

Abstract Background Regeneration of injured tissue is dependent on stem/progenitor cells, which can undergo proliferation and maturation processes to replace the lost cells and extracellular matrix (ECM). Bone has a higher regenerative capacity than other tissues, with abundant mesenchymal progenitor cells in the bone marrow, periosteum, and surrounding muscle. However, the treatment of bone fractures is not always successful; a marked number of clinical case reports have described nonunion or delayed healing for various reasons. Supplementation of exogenous stem cells by stem cell therapy is anticipated to improve treatment outcomes; however, there are several drawbacks including the need for special devices for the expansion of stem cells outside the body, low rate of cell viability in the body after transplantation, and oncological complications. The use of endogenous stem/progenitor cells, instead of exogenous cells, would be a possible solution, but it is unclear how these cells migrate towards the injury site. Methods The chemoattractant capacity of the elastin microfibril interface located protein 2 (Emilin2), generated by macrophages, was identified by the migration assay and LC–MS/MS. The functions of Emilin2 in bone regeneration were further studied using Emilin2 –/– mice. Results The results show that in response to bone injury, there was an increase in Emilin2, an ECM protein. Produced by macrophages, Emilin2 exhibited chemoattractant properties towards mesenchymal cells. Emilin2 –/– mice underwent delayed bone regeneration, with a decrease in mesenchymal cells after injury. Local administration of recombinant Emilin2 protein enhanced bone regeneration. Conclusion Emilin2 plays a crucial role in bone regeneration by increasing mesenchymal cells. Therefore, Emilin2 can be used for the treatment of bone fracture by recruiting endogenous progenitor cells.

Background: Chikungunya virus (CHIKV) is an alphavirus (genus Alphavirus, family Togaviridae) that is primarily transmitted to humans by Aedes mosquitoes, and can be transmitted from mother to child. Little is known about CHIKV transmission in Vietnam, where dengue is endemic and Aedes mosquitoes are abundant. This study aimed to determine the prevalence and characteristics of vertical CHIKV infection in a birth cohort, and seroprevalence of anti-CHIKV antibodies with or without confirmation by neutralization tests among women bearing children in Vietnam. Methods: We collected umbilical cord blood plasma samples from each newly delivered baby in Nha Trang, Central Vietnam, between July 2017 and September 2018. Samples were subjected to molecular assay (quantitative real-time RT-PCR) and serological tests (anti-CHIKV IgM capture and IgG indirect enzyme-linked immunosorbent assay, and neutralization tests). Results: Of the 2012 tested cord blood samples from newly delivered babies, the CHIKV viral genome was detected in 6 (0.3%) samples by RT-PCR, whereas, 15 samples (0.7%) were anti-CHIKV-IgM positive. Overall, 18 (0.9%, 95% CI: 0.6–1.5) samples, including three positives for both CHIKV IgM and viral genome on RT-PCR, were regarded as vertical transmission of CHIKV infection. Of the 2012 cord blood samples, 10 (0.5%, 95% CI: 0.2–0.9) were positive for both anti-CHIKV IgM and IgG. Twenty-nine (1.4%, 95% CI: 1.0–2.1) were seropositive for anti-CHIKV IgG while 26 (1.3%, 95% CI: 0.8–1.9) of them were also positive for neutralizing antibodies, and regarded as seropositive with neutralization against CHIKV infection. Conclusion: This is the first report of a possible CHIKV maternal-neonatal infection in a birth cohort in Vietnam. The findings indicate that follow-up and a differential diagnosis of CHIKV infection in pregnant women are needed to clarify the potential for CHIKV vertical transmission and its impact in the newborn.

Abstract is missing (Short communication)

Introduction: Proton beam therapy (PBT) may reduce the number of adverse events in treatment of patients with pediatric cancer. However, it is difficult to evaluate whether the actual therapeutic effect is truly equivalent to that of photon radiotherapy. To compare photon radiotherapy and PBT, a meta-analysis and systematic review were performed. Methods: The meta-analysis used papers from 1990 to 2023 in which postoperative local photon radiotherapy or PBT was performed for pediatric intracranial ependymomas. Fifteen articles (5 PBT, 9 photon radiotherapy, one both) were selected based on administration of radiotherapy as local irradiation. Results: Among the 15 chosen articles, the 1- to 5-year overall survival (OS) rates (photon radiotherapy vs. PBT) were 95.4 % (95 % confidence interval (CI) 92.8–97.1 %) vs. 97.2 % (95.7–98.2 %); 88.3 % (85.0–90.9 %) vs. 93.5 % (91.4–95.1 %); 81.2 % (76.9–84.8 %) vs. 91.1 % (88.4–93.2 %); 76.9 % (71.2–81.6 %) vs. 86.1 % (81.9–89.4 %); and 73.8 % (68.3–78.5 %) vs. 84.7 % (79.9–88.5 %), respectively. The 1- to 5-year local control (LC) rates (photon radiotherapy vs. PBT) were 90.9 % (95 % CI 83.9–94.9 %) vs. 91.0 % (88.7–92.9 %); 81.5 % (68.9–89.4 %) vs. 85.7 % (82.0–88.6 %); 77.3 % (62.8–86.8 %) vs. 82.6 % (79.1–85.5 %); 74.6 % (57.7–85.6 %) vs. 78.3 % (71.6–83.5 %); and 72.6 % (51.4–85.8 %) vs. 79.0 % (73.4–83.5 %), respectively. The meta-regression analysis identified relationships of modality (photon radiotherapy vs. PBT), age at irradiation, pathology (Grade 2 vs. Grade 3), and tumor removal (complete resection vs. none) with significantly better 3-year OS after PBT and better 1- to 5-year LC at a younger age. Conclusion: In postoperative local irradiation of ependymomas in children, proton beam therapy had outcomes comparable to those of photon radiotherapy.

Numerous health concerns, primarily kidney injury, have been reported with the use of Beni-kōji CholesteHelp, a functional food containing red yeast rice. Here, we describe 2 cases of kidney injury caused by beni-kōji. The first case had normal kidney function before consuming the product. After several months of use, she developed hypertension. After 6 months of supplement consumption, her estimated glomerular filtration rate (eGFR) dropped to 22.5 mL/min/1.73 m2. A spot urine sample showed a urinary protein-to-creatinine ratio of 2.03 g/g, leading to the diagnosis of Fanconi syndrome. Kidney biopsy showed tubular degeneration. Thirty-five days after discontinuing the supplement, proteinuria resolved and the eGFR returned to baseline level. The second case, who had diabetes and normal kidney function, experienced severe kidney injury (eGFR, 3.5 mL/min/1.73 m2) after 4 months of Beni-kōji CholesteHelp use. He required hemodialysis for >2 weeks but recovered kidney function after the product was discontinued. Kidney biopsy showed tubular injury similar to the first case and glomeruli changes consistent with diabetic nephropathy. These cases indicate that beni-kōji use is associated with tubular toxicity. Further studies are required to identify the precise etiology and mechanism of kidney injury.

This current case report describes a Japanese woman in her 80s with xerostomia who presented with salivary gland dysfunction. She was positive for isolated anti-Ro52/SS-A antibody as determined by a chemiluminescent enzyme immunoassay and positive on a fluorescence enzyme immunoassay that recognizes both Ro52 and Ro60 antigens. A high serum concentration of anti-Ro52/SS-A antibody was determined by an enzyme-linked immunosorbent assay. A high anti-centromere antibodies (ACA) titre was also observed. Although Raynaud’s phenomenon or a high serum immunoglobulin G concentration were not observed, Masson-trichrome staining of the patient’s labial salivary glands showed considerable fibrosis. Her serum type I and type II interferon concentrations were normal. The present patient is the first with Sjögren’s syndrome (SS) to exhibit isolated anti-Ro52/SS-A antibody and ACA without anti-Ro60/SS-A antibody. This current case report presents her case together with those of four other SS patients who were positive for isolated anti-Ro52/SS-A antibody. The SS literature also includes cases positive for ACA and describes clinical characteristics. The other four SS patients with isolated anti-Ro52/SS-A antibody described here had no ACA; interstitial pneumonia and polyneuropathy were observed in these cases, although there was no consistent tendency regarding types I and II interferon.

Background Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC. Methods and Results We recruited children with left ventricular noncompaction from Japanese multi‐institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy‐associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0–6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate (P=0.0009). Conclusions Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease‐causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality‐related cardiac phenotypes.

Introduction: The career of the surgeon is challenging, and scientific research has identified a prevalence of burnout in approximately 1/3 of plastic surgeons. The data on well-being and factors associated with greater happiness available specifically to plastic surgery are inconsistent and limited. The objective is to evaluate the happiness of plastic surgeons in São Paulo and which factors are associated with greater happiness. Method: This was a primary, observational, descriptive, and cross-sectional study. An online survey was conducted using a validated instrument, the Subjective Happiness Scale (SHS), which was sent to members of the Brazilian Society of Plastic Surgery-São Paulo (SBCP-SP) from December 2020 to July 2021. Sociodemographic and occupational characteristics were related to the degree of happiness measured. Results: The response rate was 12.18%, n = 268, with 70.1% males and 29.9% females. The score obtained using the SHS was 5.51 ± 0.13, and the mean score for males was 5.49 and for females was 5.57. A total of 143 (53.36%) of the participants were associate members, and 125 (46.64%) were full members of the SBCP. A total of 177 (66.04%) stated that if they could go back in time, they would choose plastic surgery again as a specialty, 62 (23.13%) perhaps, and 27 (10.82%) said that they would not. Conclusion: Plastic surgery in the state of São Paulo, Brazil, allows professionals in the specialty to have a career with high levels of happiness, including for females.

Background: A majority of Japanese care managers lack medical qualifications, feel uncomfortable discussing future medical choices and believe that it is not their responsibility. Objectives: As there is a paucity of care manager intervention studies, this study aimed to measure changes in advance care planning engagement among long-term care service users before and after intervention by care managers with communication training. Design: A multi-institutional pre- and post-pilot comparative study Methods: A multi-institutional pre- and post-trial study was performed from August 2022 to January 2023 (trial ID: 000048573). Nine trained care managers communicated with 30 long-term care service users regarding advance care planning, and the pre- and post-trial advance care planning engagement scores were compared. Additionally, the post-trial impact of events score was investigated. Results: All 30 long-term care service users completed the trial. The advance care planning engagement score increased after the trial. The sample size was considered adequate for future trials. Years of experience as a care manager, impact of events score, and having a clinical frailty scale of ⩾5 were significant explanatory variables that affected the objective variable of the difference between pre- and post-trial advance care planning engagement score. Conclusion: This study on the impact of advance care planning communication interventions by trained care managers offers insights into determining appropriate sample sizes and identifying factors influencing future research outcomes. Advance care planning engagement of long-term care service users might change before and after intervention by care managers through advance care planning communication. Trial registration: University Hospital Medical Information (UMIN) Network Trial ID: 000048573.