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Background: Behavioral and psychological symptoms of dementia (BPSD) are common among people with dementia from the early stages and can appear even in mild cognitive impairment (MCI). However, the prognostic impact of BPSD is unclear. This study examined the association between BPSD and mortality among people with cognitive impairment., Methods: This longitudinal study involved 1,065 males and 1,681 females (mean age: 77.1 years for males and 78.6 years for females) with MCI or dementia diagnosis from the National Center for Geriatrics and Gerontology-Life Stories of People with Dementia (NCGG-STORIES), a single-center memory clinic-based cohort study in Japan that registered first-time outpatients from 2010-2018. Information about death was collected through a mail survey returned by participants or their close relatives, with an up to 8-year follow-up. BPSD was assessed using the Dementia Behavior Disturbance Scale (DBD) at baseline., Results: During the follow-up period, 229 (28.1%) male and 254 (15.1%) female deaths occurred. Cox proportional hazards regression analysis showed that higher DBD scores were significantly associated with increased mortality risk among males, but not females (compared with the lowest quartile score group, hazard ratios for the highest quartile score group were 1.59; 95% confidence interval, [CI] 1.11-2.29 for males and 1.06; 95% CI, 0.66-1.70 for females). Among the DBD items, lack of interest in daily living, excessive daytime sleep, and refusal to receive care had a higher mortality risk., Conclusion: The findings suggest a potential association between BPSD and poor prognosis among males with cognitive impairment.

Introduction/objectives: JAK/STAT signaling inhibition exerts therapeutic effects on angiogenesis in rheumatoid arthritis (RA). However, whether the inhibitory effect differs among JAK inhibitors because of differing selectivity is unknown. Therefore, we compared the inhibitory effects of tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib on angiogenesis., Method: RA-derived fibroblast-like synoviocytes (RA-FLS) were seeded on type I collagen gel, and human umbilical vein endothelial cells (HUVECs) were directly added. The control and aforementioned JAK inhibitors were added to the medium, followed by stimulation with interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). Each JAK inhibitor's concentration was determined based on estimated blood concentrations. The vascular endothelial growth factor (VEGF) concentration was evaluated with an enzyme-linked immunosorbent assay using the medium from the first exchange. A migration assay was performed, and HUVEC migration was evaluated using CD31 fluorescence immunostaining., Results: Hematoxylin-eosin staining showed that compared with the non-JAKi treatment group, the JAKi treatment group markedly degenerated in the sub-lining and deep lining, with decreased lymphocyte infiltration and neovascularization [Rooney's score subscale, non-JAKi vs JAKi (median, 6.5 vs 2.5, p = 0.005)]. In vitro, IL-6 and sIL-6R administration increased VEGF production from RA-FLS and promoted neovascularization in HUVECs, and JAK-inhibitor administration, which decreased VEGF production from RA-FLS and suppressed HUVEC migration, inhibited neovascularization in RA-FLS and HUVEC co-cultures., Conclusions: The JAK inhibitors suppressed IL-6-induced angiogenesis via decreased VEGF production and HUVEC migration in RA-FLS and HUVEC co-cultures. No significant differences were observed among the JAK inhibitors, whose anti-angiogenic effect may be an important mechanism for RA treatment. Key Points • JAK inhibitors inhibit angiogenesis in RA by reducing VEGF production from RA-derived fibroblast-like synoviocytes. • Our study provides new insights into RA treatment by elucidating the anti-angiogenic effect of JAK inhibitors., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Objective: This study aimed to analyze the clinical efficacy of JAK inhibitors in difficult-to-treat rheumatoid arthritis (D2TRA) and non-D2TRA patients and evaluate the factors influencing their efficacy using real-world data., Method: Here, 159 JAK inhibitor-treated patients with rheumatoid arthritis were categorized into D2TRA and non-D2TRA groups. Data including the Clinical Disease Activity Index (CDAI) at initiation and 6 months after drug administration, drug retention months, and reason for discontinuation due to toxic adverse events were collected., Results: The retention rates at 6 months were 64.0% (D2TRA) and 78.4% (non-D2TRA) and were significantly different between the two groups (p = 0.030). The discontinuation rate owing to toxic adverse events significantly differed between the two groups (p = 0.030). The CDAI-low disease activity (LDA) rates differed significantly between the two groups (non-D2TRA, 62.3%; D2TRA, 34%; p < 0.001). CDAI-LDA achievement at 6 months after drug introduction was significantly associated with the number of times that biologic and/or targeted synthetic disease-modifying anti-rheumatic drugs were previously used and the CDAI at baseline in all patients treated with JAK inhibitors. However, no predictive factors were identified for D2TRA patients treated with JAK inhibitors., Conclusion: Compared to non-D2TRA patients, D2TRA patients demonstrated significantly lower drug retention rates, CDAI-LDA achievement rates, and safety of JAK inhibitors. No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients. Key Points • The retention of JAK inhibitors were significantly lower for the treatment of D2TRA patients in comparison with non-D2TRA patients. • The efficacy and safety of JAK inhibitors were significantly lower for the treatment of D2TRA patients. • Number of previous uses of b/tsDMARDs and CDAI at baseline were identified as the predictive factors for resistance to CDAI-LDA achievement to JAK inhibitor treatment. • No significant predictive factor for CDAI-LDA achievement 6 months after drug introduction was detected in D2TRA patients., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Lacrimal punctal agenesis is an extremely rare condition with an unclear genetic basis. Here, we report a 3-year-old male patient harboring a hemizygous variant in glypican 4 (GPC4), which causes Keipert syndrome, who presented with complete lacrimal punctal agenesis, distinctive craniofacial features, mild developmental delay, mild intellectual disability, and autism. The craniofacial features included a prominent forehead, epicanthus, depressed and broad nasal bridge, hypoplastic columella, midface hypoplasia, tented upper lip, and low-set ears. Proband exome sequencing identified a hemizygous variant in GPC4: NM&#95;001448.3:c.1051C > T (p.Arg351*). The GPC4 variant was inherited from his heterozygous mother; X-inactivation followed a skewed pattern in his mother. This patient demonstrated clinical features consistent with Keipert syndrome including craniofacial features, brachydactyly, broad distal phalanx, broad first toe, and mild developmental delay; however, agenesis of the lacrimal puncta has not been reported previously in Keipert syndrome. Our findings suggest that GPC4, which encodes a heparan-sulfate proteoglycan, may play an important role in lacrimal morphogenesis. Our observations also suggest that Keipert syndrome should be considered in patients with lacrimal punctal agenesis., (© 2024 Wiley Periodicals LLC.)

Background: Previous studies examining sex differences in patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) have indicated that women have favorable outcomes; however, detailed evidence remains lacking. We aimed to investigate sex differences in the backgrounds and outcomes of patients undergoing ECPR for OHCA., Methods: This study was a secondary analysis of the registry from the SAVE-J II study, a retrospective multicenter study conducted in Japan from 2013 to 2018. Adult patients without external causes who underwent ECPR for OHCA were included. The primary outcome was a favorable neurological outcome (Cerebral Performance Status 1 or 2) at hospital discharge. We used multilevel logistic regression to evaluate the association of sex differences, adjusting for center-level (hospital) and individual-level variables (patient background, cardiac arrest situation, and in-hospital intervention factors). For sensitivity analyses, we performed three models of multilevel logistic regression when selecting confounders., Results: Among the 1819 patients, 1523 (83.7%) were men, and 296 (16.3%) were women. The median age (61.0 vs. 58.0 years), presence of a witness (78.8% vs. 79.2%), and occurrence of bystander CPR (57.5% vs. 61.6%) were similar between groups. Women were more likely to present with an initial non-shockable rhythm (31.7% vs. 49.7%), as well as a non-shockable rhythm at hospital arrival (52.1% vs. 61.5%) and at ECMO initiation (48.1% vs. 57.1%). The proportion of favorable neurological outcomes was 12.3% in males and 15.9% in females (p = 0.10). Multilevel logistic regression analysis showed that the female sex was significantly associated with a favorable neurologic outcome at discharge (adjusted odds ratio: 1.60 [95% confidence interval: 1.05-2.43]; p = 0.03). This advantage in women was consistently observed in the sensitivity analyses., Conclusions: The female sex is significantly associated with favorable neurological outcomes at hospital discharge in patients who received ECPR for OHCA., (© 2024. The Author(s).)

The cell culture-based isolation of novel coronavirus SARS-CoV-2 from clinical specimens obtained from patients with suspected COVID-19 is important not only for laboratory diagnosis but also for obtaining live virus to characterize emerging variants. Previous studies report that monkey kidney-derived VeroE6/TMPRSS2 cells allow efficient isolation of SARS-CoV-2 from clinical specimens because these cells show stable expression of the receptor molecule monkey ACE2 and the serine-protease TMPRSS2. Here, we demonstrated that VeroE6 cells overexpressing human ACE2 and TMPRSS2 (Vero E6-TMPRSS2-T2A-ACE2 cells) are superior to VeroE6/TMPRSS2 for isolating SARS-CoV-2 from clinical specimens. These cells showed a 1.6-fold increase in efficiency in SARS-CoV-2 isolation, and were particularly effective for clinical specimens with a relatively low viral load (< 10 6 copies/mL). When using vesicular stomatitis virus (VSV) pseudoviruses (VSV/SARS-2pv) bearing the spike proteins of all of the tested SARS-CoV-2 strains, Vero E6-TMPRSS2-T2A-ACE2 cells showed a 2- to fourfold increase in infectivity. Furthermore, the results of virus titration and neutralization antibody assays using Vero E6-TMPRSS2-T2A-ACE2 cells were different from those using VeroE6/TMPRSS2, highlighting the importance of selecting appropriate cell culture systems to determine SARS-CoV-2 infectivity., (© 2024. The Author(s).)

Background The production of inflammatory cytokines is reportedly increased in patients with coronavirus disease 2019 (COVID-19), causing the migration of neutrophils and monocytes to lung tissues. This disrupts the air-blood barrier by damaging the bronchial epithelial and vascular endothelial cells. As multiorgan dysfunction in sepsis is considered to be partly caused by complement activation, which can cause lung injury in patients with COVID-19. There are limited studies examining the link between complement activation in patients with COVID-19. This study aimed to AQinvestigate the association of complement activation with the pathophysiology of COVID-19. Twenty-seven patients with COVID-19 were enrolled in this study and classified into two groups depending on the indication for mechanical ventilation. Plasma complement factors (C3a, C5a, Ba, and sC5b-9), complement regulators (sCD59 and factor H), interleukin-6 (IL-6), and syndecan-1 levels were measured using Enzyme-linked immunosorbent assay (ELISA). Results: All complement factors and regulators, IL-6, and syndecan-1 levels were significantly elevated in patients with COVID-19 compared with those in healthy controls. C5a and sC5b-9 levels were decreased significantly in the invasive mechanical ventilation (IMV) group compared with those in the non-IMV group. Syndecan-1 levels were significantly increased in the IMV group compared with those in the non-IMV group. Conclusions: Complement activation is an exacerbating factor for lung injury in patients with COVID-19. Complement factors are nonessential predictors of mechanical ventilation; however, syndecan-1 could be a biomarker of COVID-19 severity in patients., (© 2024. The Author(s).)

Objective: The role of Krüppel-like zinc finger transcription factor 15 (KLF15) in endochondral ossification during fracture healing remains unexplored. In this study, we aimed to elucidate the impact of KLF15 in a mouse model of tibial transverse fracture., Methods: We created tamoxifen-inducible, cartilage-specific KLF15 knockout mice (KLF15 KO). KLF15 fl/fl Col2-CreERT mice from the same litters as the KLF15 KO mice, but not treated with 4-hydroxytamoxifen, were used as controls (CT). At 10 weeks, male KLF15 KO and CT mice underwent tibial fracture followed by intramedullary nailing. Both groups were administered tamoxifen at days 0, 3, and 7 after surgery. The tibiae were harvested on post-surgery days 7, 10, and 14 for radiological assessment using micro-computed tomography. Histological staining (Safranin-O) and immunohistochemistry for KLF15, SOX9, Indian hedgehog (IHH), RUNX2, and Osterix were performed. Additionally, cartilage from mouse fetus was cultured for qRT-PCR and western blot analyses of KLF15, SOX9, IHH, Col2, RUNX2, Osterix, TGF-β, SMAD3, and phosphor-SMAD3., Results: The radiological assessment revealed that immature callus formation was delayed in KLF15 KO, compared with that in CT, peaking on day 14 compared with that on day 10 in CT. KLF15 KO mice exhibited delayed fracture healing and reduced Safranin-O staining at days 7 and 10 post-surgery. The ratio of cells positive for KLF15 and SOX9 was significantly lower in KLF15 KO than in CT, whereas the ratios for IHH, RUNX2, and Osterix showed no significant difference. RT-PCR revealed reduced expression of KLF15, SOX9, and COL2, with no significant changes in IHH, Osterix, RUNX2, TGF-β, and SMAD3. Western blot analysis indicated decreased SMAD3 phosphorylation in KLF15 KO mice., Conclusion: KLF15 regulates SOX9 via the TGF-β-SMAD3-SOX9 pathway, independent of IHH, in endochondral ossification. The KLF15 deficiency decreases SOX9 expression through reduced SMAD3 phosphorylation, subsequently delaying fracture healing., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Movements to raise lower garments in patients with stroke and hemiplegia consist of downward reach, non-paretic-side manipulation, and paretic-side manipulation. In this study, we focused on paretic-side manipulation, which is particularly difficult, and investigated the factors that make it challenging., Methods: Forty-eight patients with stroke and hemiplegia (23 and 25 patients in independent and dependent groups, respectively) participated in this study. First, we investigated the difficulty of each manipulation using a visual analog scale to confirm the usefulness of focusing on paretic-side manipulation. Characteristics of the paretic side manipulation were compared between the dependent and independent groups using a three-dimensional motion analysis system., Findings: The dependent group showed greater difficulty in manipulation on the paretic side compared to manipulation on the non-paretic side. The dependent group had a lower paretic limb loading ratio (p < 0.01), greater pelvic rotation angle (p < 0.01), and longer paretic side manipulation time (p < 0.01) than those in the independent group., Interpretation: The factors that contributed to greater difficulty in manipulating the paretic side were a lower limb loading rate and larger pelvic rotation angle toward the paretic side. These factors make it difficult to reach the lower garment and result in inefficient manipulation of the paretic side., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024. Published by Elsevier Ltd.)

FBXW7 (F-box and WD-repeat domain-containing 7) is a tumor suppressor gene, and its germline variants have been causally linked to Wilms tumors. Furthermore, germline variants of FBXW7 have also been implicated in a neurodevelopmental syndrome. However, little is known regarding the occurrence of Wilms tumor in patients with FBXW7-related neurodevelopmental syndrome. We identified a novel constitutional pathogenic variant of FBXW7 in a patient with intellectual disability, who also developed Wilms tumor. The variant was derived from his apparently normal mother, and was also detected in his sister who exhibited developmental delay. Furthermore, we detected a somatic nonsense variant on the paternal allele of FBXW7 in the tumor DNA. These results suggest that the development of Wilms tumor along with FBXW7-related neurodevelopmental syndrome follows the two-hit model, which needs to be validated to establish appropriate follow-up management and tumor surveillance., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Objective: The incidence rates of dementia, mild cognitive impairment, and cancer increase with age, posing challenges to affected individuals and their families. However, there are currently no clear cancer screening guidelines for individuals with cognitive impairment. This study analyzed the impact of carer health literacy on screening behaviors in this population., Methods: We conducted a postal follow-up survey, associated with the National Center for Geriatrics and Gerontology-Life STORIES of People with Dementia, that targeted primary carers to assess their reports regarding patient attendance at regular cancer screenings recommended by the Japanese Ministry of Health, Labor and Welfare, over the preceding 2 years. Screening rates were compared between the memory clinic cohort and the national average, and the influence of carer health literacy level on screening was analyzed., Results: Among the 826 total individuals analyzed, the memory clinic cohort exhibited lower breast cancer screening rates, at 11% among female patients aged 65-74 years versus the national average of 32%. Higher health literacy among carers was significantly associated with increased screening. For female patients, carers with high levels of communicative health literacy were more likely to ensure that patients attended screenings for gastric (adjusted odds ratio [AOR], 1.77; 95% confidence interval [CI], 1.03-3.04), colorectal (AOR, 1.70, 95% CI 1.08-2.70), and breast cancers (AOR, 3.08; 95% CI, 1.40-6.76). Among the male patients, high communicative health literacy was associated with increased lung cancer screening attendance (AOR, 1.82; 95% CI, 1.11-2.99)., Conclusions: Our research highlights a notable gap in cancer screening attendance between individuals with cognitive impairment and the general population, potentially arising from the intricate nature of screening procedures and the extensive burden on carers. More informed decisions and increased screening rates can be achieved through patient-centric communication strategies that accommodate the cognitive abilities of patients, ensuring the comprehensibility and accessibility of health-related information., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Gray-to-white matter ratio (GWR), measured by computed tomography (CT), is commonly used to predict poor neurological outcomes after out-of-hospital cardiac arrest (OHCA). The prognostic performance of GWR in OHCA patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) is not known., Methods: This study is a secondary analysis of data from the SAVE-J II registry, a retrospective, multicenter study. Participants were divided into four groups according to average GWR (aGWR) values ranging from 1.00 to 1.39, separated by 0.1 intervals. The aGWR values were calculated for bilateral basal ganglia, centrum semiovale, and high convexity obtained by head CT within 24 h after ECPR. Primary outcome was poor neurological outcomes at 30-day., Results: In total, 1,146 OHCA patients treated with ECPR were included in our analysis. Overall, participants with lower aGWR more likely had poor neurological outcomes, aGWR 1.00-1.09 (94.6%), aGWR 1.10-1-19 (87.8%), aGWR 1.20-1.29 (78.5%), and aGWR 1.30-1.39 (70.3%). Multivariable logistic regression showed that lower aGWR was associated with poor neurological outcome at 30-day, aGWR 1.30-1.39: reference, aGWR 1.00-1.09: adjusted odds ratio (aOR) 10.01 (95% confidence interval (CI) [3.58-27.99]), aGWR 1.10-1.19: aOR 4.83 (95% CI [2.31-10.12]), aGWR 1.20-1.29: aOR 2.16 (95% CI [1.02-4.55]). Receiver operating characteristic curve analysis revealed that the prognostic performance of aGWR had an area under the curve of 0.628, 95% CI [0.59-0.66]). The aGWR threshold of 1.005 for predicting poor neurological outcome reached 100% specificity with 0.1% sensitivity., Conclusion: Early neuro-prognostication depending on GWR may not be sufficient after ECPR and requires a multimodal approach., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

We report a case of severe central sleep apnea incidentally diagnosed during polysomnography for suspected obstructive sleep apnea. Characteristic clinical features included episodic hyperventilation followed by apnea from hypocapnia, which did not follow a Cheyne-Stokes pattern. Combined with the identification of cerebellar and brainstem malformations known as the "molar tooth sign" on a brain magnetic resonance imaging, developmental delay, and motor coordination problems, Joubert syndrome (a congenital disease) was first diagnosed at the age of 50 years. Central apneas were also observed during wakefulness, although not continuously. During sleep, continuous positive airway pressure and adaptive servo-ventilation were ineffective at the referring clinic and at our hospital. Supplemental oxygen decreased the frequency of central apneas and significantly shortened the duration of each central sleep apnea compared with room air. In contrast, the opposite response was observed with acetazolamide administration., Citation: Murashima R, Shiota S, Sugiyama A, et al. A case of middle-aged central sleep apnea due to Joubert syndrome with different treatment effects of oxygen and acetazolamide. J Clin Sleep Med . 2024;20(10):1705-1710., (© 2024 American Academy of Sleep Medicine.)

Introduction: This study aimed to clarify the validity of laparoscopic surgery for lower gastrointestinal perforation by comparing the clinical outcomes of laparoscopic and open emergency surgery., Methods: We reviewed the data of patients who underwent surgery for lower gastrointestinal perforation. Patients were categorized into two groups: the laparoscopic group who underwent laparoscopic surgery, and the open group who underwent laparotomy. Clinical and operative outcomes between the two groups were evaluated., Results: A total of 219 patients were included in the study. There were 66 and 153 patients with small bowel and colorectal perforations, respectively. The median operative time in the laparoscopic group was shorter than that in the open group (126 min vs. 146 min, p = .049). The mean amount of intraoperative blood loss was significantly lower in the laparoscopic group (50.4 mL vs. 400.1 mL, p < .001). The incidence of postoperative complication was higher in the open group (20.0% vs. 66.5%, p < .001), especially wound infection (0% vs. 26.3%, p = .002). Median hospital stays were 14 days and 24 days in the laparoscopic and open groups, respectively (p < .001). In the laparoscopic group, hospital mortality was 0%., Conclusions: The laparoscopic approach for small bowel and colorectal perforation in an emergency setting is a safe procedure in carefully selected patients and may contribute to decreased intraoperative blood loss, shortened hospital stay, and decreased incidence of postoperative complications, especially wound infection., (© 2024 The Author(s). Asian Journal of Endoscopic Surgery published by Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Purpose: Chordomas are malignant tumors that destroy bones, compress surrounding nerve tissues and exhibit phenotypes that recapitulate notochordal differentiation in the axial skeleton. Chordomas recur frequently, as they resist radio-chemotherapy and are difficult to completely resect, leading to repeated bone destruction and local expansion via unknown mechanisms. Here, using chordoma specimens and JHC7 chordoma cells, we asked whether chordoma cells possess bone-dissolving activity., Methods: CT imaging and histological analysis were performed to evaluate the structure and mineral density of chordoma-invaded bone and osteolytic marker expression. JHC7 cells were subjected to immunocytochemistry, imaging of cell fusion, calcium dynamics and acidic vacuoles, and bone lysis assays., Results: In patients, we found that the skull base invaded by chordoma was highly porous, showed low mineral density and contained brachyury-positive chordoma cells and conventional osteoclasts both expressing the osteolytic markers tartrate-resistant acid phosphatase (TRAP) and collagenases. JHC7 cells expressed TRAP and cathepsin K, became multinucleated via cell-cell fusion, showed spontaneous calcium oscillation, and were partly responsive to the osteoclastogenic cytokine RANKL. JHC7 cells exhibited large acidic vacuoles, and nonregulatory bone degradation without forming actin rings. Finally, bone-derived factors, calcium ions, TGF-β1, and IGF-1 enhanced JHC7 cell proliferation., Conclusion: In chordoma, we propose that in addition to conventional bone resorption by osteoclasts, chordoma cells possess bone-dissolving activity at the tumor-bone boundary. Furthermore, bone destruction and tumor expansion may occur in a positive feedback loop., (© 2024. The Author(s).)

Introduction: Many patients who have undergone a periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH) have had jobs preoperatively. Postoperative return to work and work productivity are important for livelihood security and the social economy. However, there is a lack of evidence on work productivity after PAOs. Therefore, this study investigated the return to work rates and influence of workload, clinical, and radiographic parameters on work productivity after a curved PAO., Materials and Methods: In this study, the data of 68 hip joints among 48 participants who underwent curved PAO for symptomatic DDH were analyzed. Correlations between postoperative work productivity and clinical, radiographic, and workload parameters were assessed. Work productivity was evaluated using the Work Productivity and Activity Impairment (WPAI) questionnaire. Clinical factors were assessed using the modified Harris Hip Scores (mHHS) and University of California, Los Angeles Activity scores. Preoperative and postoperative radiographic parameters were compared with postoperative work productivity. The workload was categorized using the Reichsausschuß für Arbeitszeitermittlung (REFA)-classification system., Results: Of the participants, 98% returned to work and 87.5% returned to their original jobs. Work productivity was significantly improved in all workload categories at the 1-year postoperative follow-up. Multivariate analysis demonstrated that preoperative Tönnis and REFA classification grades were significantly associated with the postoperative WPAI., Conclusion: Curved PAOs can improve postoperative work productivity and return to work rates. Preoperative progression of osteoarthritis and heavy workload affect postoperative work productivity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In diagnosing TAFRO syndrome, lymph node histology often may not be evaluated due to inapparent lymphadenopathy. In this study, we analyzed the differences in the pathophysiology of TAFRO syndrome with or without lymphadenopathy. We used an anonymous questionnaire to survey 70 hematologists at 50 hospitals in the Kanto Koshinetsu area of Japan from February to April 2020. We received 31 responses and collected 26 cases with TAFRO syndrome. Compared to cases with or without lymph node biopsy, clinical features and laboratory test findings in both groups were not significantly different, except for stronger renal insufficiency found in those without biopsy. It was also revealed that clinical features and laboratory test findings had no significant differences between the cases with and without lymphadenopathy. However, renal insufficiency was more pronounced in those without lymphadenopathy. There were no significant differences in pathophysiology between cases with or without lymphadenopathy in the group that did not undergo lymph node biopsy. In the treatment strategies, no significant differences were found dependent on lymphadenopathy. This study shows that lymphadenopathy in TAFRO syndrome may be secondary to inflammation and unrelated to the underlying disease.

Background: The uncultured adipose-derived stromal vascular fraction (SVF), consisting of adipose-derived stromal cells (ADSCs), M2 macrophages (M2Φ) and others, has shown therapeutic potential against osteoarthritis (OA), however, the mechanisms underlying its therapeutic effects remain unclear. Therefore, this study investigated the effects of the SVF on OA in a human-immunodeficient rat xenotransplantation model., Methods: OA model was induced in the knees of female immunodeficient rats by destabilization of the medial meniscus. Immediately after the surgery, human SVF (1 × 10 5 ), ADSCs (1 × 10 4 ), or phosphate buffered saline as a control group were transplanted into the knees. At 4 and 8 weeks postoperatively, OA progression and synovitis were analyzed by macroscopic and histological analyses, and the expression of collagen II, SOX9, MMP-13, ADAMTS-5, F4/80, CD86 (M1), CD163 (M2), and human nuclear antigen (hNA) were evaluated immunohistochemically. In vitro, flow cytometry was performed to collect CD163-positive cells as M2Φ from the SVF. Chondrocyte pellets (1 × 10 5 ) were co-cultured with SVF (1 × 10 5 ), M2Φ (1 × 10 4 ), and ADSCs (1 × 10 4 ) or alone as a control group, and the pellet size was compared. TGF-β, IL-10 and MMP-13 concentrations in the medium were evaluated using enzyme-linked immunosorbent assay., Results: In comparison with the control and ADSC groups, the SVF group showed significantly slower OA progression and less synovitis with higher expression of collagen II and SOX9, lower expression of MMP-13 and ADAMTS-5, and lower F4/80 and M1/M2 ratio in the synovium. Only the SVF group showed partial expression of hNA-, CD163-, and F4/80-positive cells in the rat synovium. In vitro, the SVF, M2Φ, ADSC and control groups, in that order, showed larger pellet sizes, higher TGF-β and IL-10, and lower MMP-13 concentrations., Conclusions: The M2Φ in the transplanted SVF directly affected recipient tissue, enhancing the secretion of growth factors and chondrocyte-protecting cytokines, and partially improving chondrocytes and joint homeostasis. These findings indicate that the SVF is as an effective option for regenerative therapy for OA, with mechanisms different from those of ADSCs., (© 2024. The Author(s).)

Cytoplasmic male sterility (CMS) is a mitochondrial-encoded trait that confers reproductive defects in males but not in females or any vegetative function. Why CMS is so often found in plants should be investigated from the viewpoint of mitochondrial phylogeny. Beta vulgaris, including the wild subspecies maritima and cultivated subspecies vulgaris (e.g., sugar beet), is known to be mitochondrially polymorphic, from which multiple CMS mitochondria have been found, but their evolutionary relationship has been obscure. We first refined the B. vulgaris reference mitochondrial genome to conduct a more accurate phylogenetic study. We identified mitochondrial single-nucleotide polymorphic sites from 600 B. vulgaris accessions. Principal component analysis, hierarchical clustering analysis, and creation of a phylogenetic tree consistently suggested that B. vulgaris mitochondria can be classified into several groups whose geographical distribution tends to be biased toward either the Atlantic or Mediterranean coasts. We examined the distribution of CMS-associated mitochondrial genes from Owen, E- and G-type CMS mitochondria. About one-third of cultivated beets had Owen-type CMS, which reflects the prevalence of using Owen-type CMS in hybrid breeding. Occurrence frequencies for each of the three CMS genes in wild beet were less than 4%. CMS genes were tightly associated with specific mitochondrial groups that are phylogenetically distinct, suggesting their independent origin. However, homologous sequences of the Owen type CMS gene occurred in several different mitochondrial groups, for which an intricate explanation is necessary. Whereas the origin of cultivated beet had been presumed to be Greece, we found an absence of Owen-type mitochondria in Greek accessions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kubota et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: This study aimed to investigate the factors of favorable neurological outcomes in patients with initial pulseless electrical activity (PEA) who underwent extracorporeal cardiopulmonary resuscitation (ECPR)., Methods: The study analyzed data from the SAVE-J II registry, a retrospective multicenter registry involving 36 participating institutions in Japan. Patients with initial PEA were included., Results: Overall proportion of patients with favorable neurological outcomes and survival rate at hospital discharge were 8.2 % and 16.9 %, respectively. Multivariate analysis revealed that no cardiac rhythm conversion to asystole, signs of life or pupil diameter, and transient return of spontaneous circulation were significantly associated with favorable neurological outcomes. Among the cause of cardiac arrest, patients with acute coronary syndrome and pulmonary embolism had higher proportions of favorable neurological outcomes (9.7 % and 19.3 %), whereas no patients with acute aortic disease or primary cerebral disease survived. The application of strict criteria for PEA using classification and regression tree analysis resulted in favorable neurological outcomes in 32.7 % of the patients., Conclusions: This study provides an overview of patients with PEA who underwent ECPR. Since several factors are associated with favorable neurological outcomes, patients with PEA may be candidates for ECPR if these factors are met., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

There are no studies examining the association between rewarming durations and neurological outcomes after extracorporeal cardiopulmonary resuscitation (ECPR) followed by targeted temperature management (TTM) for patients with out-of-hospital cardiac arrest (OHCA). This study aimed to examine the association between rewarming durations and neurological outcomes after ECPR with TTM for patients with OHCA. This was a secondary analysis of the Advanced Life Support Study Registry for Ventricular Fibrillation with Extracorporeal Circulation in Japan study, a retrospective, multicenter study. Patients with OHCA who underwent ECPR and completed a TTM of 34°C and <34°C were included. Favorable neurological outcomes (cerebral performance categories 1-2) and survival upon hospital discharge were the primary outcomes. In total, 407 patients were included, with favorable neurological outcomes upon hospital discharge in 106 patients. The numbers of patients with rewarming durations of <24 hours, 24 hours, and >24 hours were 178, 133, and 96, respectively. In the multivariable analysis, a rewarming duration of <24 hours was not significantly associated with favorable neurological outcomes [odds ratio (OR): 1.06, 95% confidence interval (CI): 0.60-1.87, p = 0.84] or survival (OR: 0.96, 95% CI: 0.58-1.57, p = 0.86) compared with that of 24 hours, and that of <24 hours was not significantly associated with favorable neurological outcomes (OR: 0.74, 95% CI: 0.40-1.71, p = 0.56) or survival (OR: 0.74, 95% CI: 0.42-1.28, p = 0.38) than that of >24 hours. A rewarming duration of <24 hours in TTM after ECPR for OHCA was not significantly associated with favorable neurological outcomes or survival than that of 24 hours or >24 hours.

TXNDC15 encodes thioredoxin domain-containing protein 15, a protein disulfide isomerase that plays a role in ciliogenesis. Biallelic TXNDC15 variants have been reported in six individuals of Meckel syndrome (MKS) with perinatal lethal phenotypes, but have not been reported in patients with Joubert syndrome (JS). Here, we describe a 1-year-old female patient with compound heterozygous TXNDC15 variants demonstrating cerebellar vermis hypoplasia with the molar tooth sign, mild holoprosencephaly, and cortical abnormalities. She had severe developmental delay and epilepsy. Her clinical features were similar to those of JS, but distinctive forebrain abnormalities were also noted including mild holoprosencephaly and cortical abnormalities, which have been reported in a severe form of ciliopathy. Biallelic TXNDC15 variants manifest as overlapping phenotypes of JS and MKS, including the molar tooth sign, cortical dysgenesis, and mild holoprosencephaly. This report supports the hypothesis that JS and MKS are spectrum ciliopathy disorders with overlapping causative genes and hypomorphic TXNDC15 variants might contribute to JS., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been detected or isolated from domestic cats. It is unclear whether cats play an important role in the SARS-CoV-2 transmission cycle. In this study, we examined the susceptibility of cats to SARS-CoV-2, including wild type and variants, by animal experiments. Cats inoculated with wild type, gamma, and delta variants secreted a large amount of SARS-CoV-2 for 1 week after the inoculation from nasal, oropharyngeal, and rectal routes. Only 100 TCID 50 of virus could infect cats and replicate well without severe clinical symptoms. In addition, one cat inoculated with wild type showed persistent virus secretion in feces for over 28 days post-inoculation (dpi). The titer of virus-neutralizing (VN) antibodies against SARS-CoV-2 increased from 11 dpi, reaching a peak at 14 dpi. However, the omicron variant could not replicate well in cat tissues and induced a lower titer of VN antibodies. It is concluded that cats were highly susceptible to SARS-CoV-2 infection, but not to the Omicron Variant, which caused the attenuated pathogenicity., (© 2024. The Author(s).)

Background: Stanford type B-acute aortic dissection (type B-AAD) is often life-threatening without invasive surgery. Multilineage-differentiating stress enduring cell (Muse cells), which comprise several percent of mesenchymal stem cells (MSCs), are endogenous pluripotent-like stem cells that selectively home to damaged tissue and replace damaged/apoptotic cells by in-vivo differentiation., Methods: Mortality, aortic diameter expansion, cell localization, cell differentiation, and inflammation of the dissected aorta were evaluated in type B-AAD model mice intravenously injected with human-Muse cells, -elastin-knockdown (KD)-Muse cells, -human leukocyte antigen-G (HLA-G)-KD-Muse cells, or MSCs, all without immunosuppressant., Results: Here, we show the Muse (50,000 cells) group has a lower incidence of aortic rupture and mortality of AAD compared with the MSC-50K (50,000 human-MSCs) and vehicle groups. Spectrum computed tomography in-vivo dynamics and 3-dimensional histologic analyses demonstrate that Muse cells more effectively home to the AAD tissue and survive for 8 weeks in the Muse group than in the MSC-750K (750,000 human-MSCs containing 50,000 Muse cells) group. Homing of Muse cells is impeded in the HLA-G-KD-Muse (50,000 cells) group. Differentiation of homed Muse cells into CD31(+) and alpha-smooth muscle actin (+) cells, production and reorganization of elastic fibers in the AAD tissue, and suppression of diameter expansion are greater in the Muse group than in the MSC-750K and elastin-KD-Muse (50,000 cells) groups., Conclusions: Intravenously administered Muse cells reconstruct the dissected aorta and improve mortality and diameter enlargement rates. Moreover, small doses of purified Muse cells are more effective than large doses of MSCs. HLA-G is suggested to contribute to the successful survival and homing of Muse cells., (© 2024. The Author(s).)

Objective: During total arch replacement (TAR) using frozen elephant trunk (FET) technique with Frozenix for true thoracic aortic aneurysm (tTAA), oversized FET tends to be chosen similar to the endovascular devise selection. However, the oversized FET is considered a risk factor for intimal injury. The appropriate size selection of FET remains insufficiently understood., Methods: Between October 2014 and March 2022, a total of 49 patients underwent TAR using Frozenix for tTAA. Out of 49 patients, four patients planned to staged surgery were excluded, 19 patients were operated on with an undersized Frozenix compared with the descending aorta (undersized FET group) and in 26 patients an equal or oversized Frozenix was used (oversized FET group). Clinical outcomes and postoperative diameter changes were investigated., Results: In-hospital mortality was 0%. The mean diameter of Frozenix and the descending aorta was 30.7 mm and 28.8 mm, respectively, in the oversized FET group, and 26.7 mm and 30.1 mm in the undersized FET group. Postoperative computed tomography (CT) demonstrated no endoleaks not only in the oversized FET group but also in the undersized FET group. CT also revealed that undersized FET had expanded more than the original diameter in all cases except for two, with an average of 2.47 ± 1.53 mm. Additionally, the descending aorta covered with Frozenix shrank in 10 patients (53%). Postoperative adverse aortic events were not observed., Conclusions: Undersized Frozenix tightly fit the descending aorta and resulted in complete sealing without endoleaks. Oversized FET is not strictly necessary considering the size-related adverse complications., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Developing long bones alter their shape while maintaining uniform cortical thickness via coordinated activity of bone-forming osteoblasts and bone-resorbing osteoclasts at periosteal and endosteal surfaces, a process we designate trans-pairing. Two types of trans-pairing shift cortical bone in opposite orientations: peri-forming trans-pairing (peri-t-p) increases bone marrow space and endo-forming trans-pairing (endo-t-p) decreases it, via paired activity of bone resorption and formation across the cortex. Here, we focused on endo-t-p in growing bones. Analysis of endo-t-p activity in the cortex of mouse fibulae revealed osteoclasts under the periosteum compressed by muscles, and expression of RANKL in periosteal cells of the cambium layer. Furthermore, mature osteoblasts were localized on the endosteum, while preosteoblasts were at the periosteum and within cortical canals. X-ray tomographic microscopy revealed the presence of cortical canals more closely associated with endo- than with peri-t-p. Sciatic nerve transection followed by muscle atrophy and unloading induced circumferential endo-t-p with concomitant spread of cortical canals. Such canals likely supply the endosteum with preosteoblasts from the periosteum under endo-t-p, allowing bone shape to change in response to mechanical stress or nerve injury., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin β1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Background/aim: The liver effectively restores both size and function following partial hepatectomy (PHx). Angiogenesis is crucial for the repair and regeneration of liver tissue post-PHx. Calcitonin gene-related peptide (CGRP) released from sensory nerves and its receptor-receptor activity-modifying protein 1 (RAMP1) are involved in angiogenesis. This study aimed to assess the role of RAMP1 signaling in angiogenesis during liver regeneration following PHx., Materials and Methods: RAMP1 deficient (RAMP1 -/- ) and wild-type (WT) mice were subjected to PHx., Results: RAMP1 -/- mice demonstrated delayed liver regeneration, indicated by lower liver-to-body weight ratios compared to WT mice. This was associated with lower levels of Ki67 + hepatocytes and hepatic trophic growth factors. Additionally, RAMP1 -/- mice exhibited lower levels of endothelial cell markers, including CD31, compared to WT mice. This reduction was associated with reduced levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor 3 (VEGFR3). In WT mice with PHx, the administration of a VEGFR3 inhibitor reduced the liver-to-body weight ratio, Ki67 + hepatocytes, and VEGF-C/VEGFR3 expression levels in the liver compared to those in the vehicle-treated group., Conclusion: The deletion of RAMP1 signaling suppresses liver regeneration and angiogenesis through VEGFR3. Specific activation of RAMP1 signaling may represent a potential therapeutic strategy for liver regeneration following PHx., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Noonan syndrome is a so-called "RASopathy," that is characterized by short stature, distinctive facial features, congenital heart defects, and developmental delay. Of individuals with a clinical diagnosis of Noonan syndrome, 80%-90% have pathogenic variants in the known genes implicated in the disorder, but the molecular mechanism is unknown in the remaining cases. Heterozygous pathogenic variants of ETS2 repressor factor (ERF), which functions as a repressor in the RAS/MAPK signaling pathway, cause syndromic craniosynostosis. Here, we report an ERF frameshift variant cosegregating with a Noonan syndrome-like phenotype in a family. The proband was a 3-year-old female who presented with dysmorphic facial features, including proptosis, hypertelorism, slightly down slanted palpebral fissures, low-set posteriorly rotated ears, depressed nasal bridge, short stature, and developmental delay. Exome sequencing of the proband identified a heterozygous ERF variant [NM&#95;006494.4: c.185del p.(Glu62Glyfs*15)]. Her mother and sister showed a similar phenotype and had the same heterozygous ERF variant. A large proportion of the previously reported patients with syndromic craniosynostosis and pathogenic ERF variants also showed characteristic features that overlap with those of Noonan syndrome. The present finding supports an association between heterozygous ERF variants and a Noonan syndrome-like phenotype., (© 2024 Wiley Periodicals LLC.)

Reducing the avascular necrosis (AVN) rate in infants treated for developmental dysplasia of the hip (DDH) is important. We previously reported the clinical outcomes of gradual reduction via ultrasound-guided flexion abduction continuous traction (FACT-R), which achieved a 99% reduction with an AVN rate of 1.0% in infants <12 months. Here, we investigated the clinical outcomes of late-detected DDH after FACT-R. Infants ≥12 months who were treated with FACT-R for DDH from January 1995 to 2007 and followed up for 6 years were enrolled. Treatment comprised continuous traction, a hip-spica cast, and an abduction brace. The rates of reduction, redislocation, AVN, and secondary osteotomy surgery were evaluated. In the study patients (n = 26, hips 30), the mean age at the time of traction therapy was 23 months (range: 13-44) and the mean follow-up was 12.5 years (range: 6-16.4). Female gender and the left side were predominant. The rates of reduction, redislocation, and AVN were 100%, 0%, and 0%, respectively. However, 25 hips (83%) required secondary osteotomy surgery, including Salter innominate osteotomy in 21 hips, Salter innominate osteotomy combined with femoral osteotomy in 3 hips, and triple pelvic osteotomy in 1 hip. They had a larger acetabular index after FACT-R (P = 0.04) and a longer duration of FACT-R (P = 0.05). All hips were successfully reduced, with no redislocation or AVN. However, most hips required a secondary osteotomy surgery because of residual dysplasia. Careful follow-up and informed consent for secondary osteotomy surgery is thus essential., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

There have been reports of the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from humans to various mammalian species. Some infected animals show clinical signs and may even die in rare cases. Outbreaks of SARS-CoV-2 have been reported in zoos where susceptible animals are bred in high population densities. However, there have been few reports of omicron variant outbreaks in zoo animals. From late 2022 to 2023, an outbreak of the SARS-CoV-2 omicron variant occurred in one Japanese zoo. A total of 24 lions were housed in the zoo; 13 of them showed respiratory symptoms, and the three oldest lions died. Molecular and histopathological analyses revealed that the deceased lions were infected with SARS-CoV-2 omicron BF.7.15. Virus-neutralization tests showed that all 21 lions were positive for antibodies against the omicron variant, but not against the delta variant. In addition, three tigers and one bear in the same or neighboring building as the lions possessed antibodies against the omicron variant. This is a very rare report on the outbreak of a SARS-CoV-2 omicron variant infection that resulted in the death of animals. This finding demonstrates the importance of continuous countermeasures to protect non-vaccinated animals from SARS-CoV-2 infection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The driving forces of chiral active particles and deformations of cells are often modeled by spatially inhomogeneous but temporally periodic driving forces. Such inhomogeneous oscillatory driving forces have only recently been proposed in the context of active matter, and their effects on the systems are not yet fully understood. In this work, we theoretically study the impact of spatially inhomogeneous oscillatory driving forces on continuous symmetry breaking. We first analyze the linear model for the soft modes in the ordered phase to derive the lower critical dimension of the model, and then analyze the spherical model to investigate more detailed phase behaviors. Interestingly, our analysis reveals that symmetry breaking occurs even in one and two dimensions, where the Hohenberg-Mermin-Wagner theorem prohibits continuous symmetry breaking in equilibrium. Furthermore, fluctuations of conserved quantities, such as density, are anomalously suppressed in the long-wavelength, i.e., show hyperuniformity.

Introduction: This study aimed to evaluate differences in the pattern of fixation with a rectangular tapered short stem (Fitmore stem) due to proximal femoral medullary cavity morphology based on periprosthetic bone mineral density (BMD) and radiological findings., Materials and Methods: We analyzed 105 consecutive patients (Dorr type A, 18; Dorr type B, 66; Dorr type C, 21) who underwent total hip arthroplasty using a Fitmore stem. Periprosthetic BMD was measured using dual-energy X-ray absorptiometry from 1 to 24 months postoperatively and radiological analysis was performed. Clinical outcomes were evaluated using the Harris hip score (HHS) and the University of California Los Angeles (UCLA) activity score preoperatively and 24 months postoperatively., Results: At 24 months postoperatively, Dorr type C had significantly decreased BMD changes in Gruen zones 2, 6, and 7 compared to Dorr types A and B, and conversely, significantly increased BMD changes in zone 4 (p < 0.05). Dorr type C had significantly greater subsidence than the other types (p < 0.01) and significantly higher cortical hypertrophy in zone 3 (p < 0.01). Stress shielding was not significantly different between Dorr types. The preoperative and postoperative HHS and UCLA activity scores showed no significant differences between the Dorr types., Conclusions: In Dorr type C, BMD significantly decreased in the proximal femur with a rectangular tapered short stem, suggesting that the stem was fixed at the distal part. Careful observation of this prosthesis over time is needed in patients with Dorr type C., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To examine cross-sectional associations between continuous glucose monitoring (CGM)-derived metrics and cerebral small vessel disease (SVD) in older adults with type 2 diabetes., Materials and Methods: In total, 80 patients with type 2 diabetes aged ≥70 years were analysed. Participants underwent CGM for 14 days. From the CGM data, we derived mean sensor glucose, percentage glucose coefficient of variation, mean amplitude of glucose excursion, time in range (TIR, 70-180 mg/dl), time above range (TAR) and time below range metrics, glycaemia risk index and high/low blood glucose index. The presence of cerebral SVD, including lacunes, microbleeds, enlarged perivascular spaces and white matter hyperintensities, was assessed, and the total number of these findings comprised the total cerebral SVD score (0-4). Ordinal logistic regression analyses were performed to examine the association of CGM-derived metrics with the total SVD score., Results: The median SVD score was 1 (interquartile range 0-2). Higher hyperglycaemic metrics, including mean sensor glucose, TAR >180 mg/dl, TAR >250 mg/dl, and high blood glucose index and glycaemia risk index, were associated with a higher total SVD score. In contrast, a higher TIR (per 10% increase) was associated with a lower total SVD score (odds ratio 0.73, 95% confidence interval 0.56-0.95). Glycated haemoglobin, percentage glucose coefficient of variation, mean amplitude of glucose excursions, time below range and low blood glucose index were not associated with total cerebral SVD scores., Conclusions: The hyperglycaemia metrics and TIR, derived from CGM, were associated with cerebral SVD in older adults with type 2 diabetes., (© 2024 John Wiley & Sons Ltd.)

Accurate prediction of the phospholipidosis-induction risk of drugs at early stages is important in drug development. So far, discrimination models for predicting the induction risk of cationic drugs have been proposed, but it is still challenging to accurately predict the risk of cationic drugs with intermediate hydrophobicity (logP). In this study, we introduced a parameter (Δlogk 40 ) reflecting not only hydrophobic interaction but also interactions with the polar headgroup between cationic drugs and phospholipids, obtained with liquid chromatography using an immobilized artificial membrane column. The parameter was used along with other physicochemical properties as features to construct discrimination models. Linear discriminant analysis, the modified Mahalanobis discriminant analysis, support vector machine, and random forest were employed for model construction. The results showed that all discrimination models exhibited good predictive performance, with the modified Mahalanobis discriminant analysis and random forest providing the best results for cationic drugs, suggesting that the usefulness of the parameter reflecting complex interactions between cationic drugs and immobilized artificial membrane for constructing discrimination models to predict the induction risk. Furthermore, by applying the parameter as a feature in constructing discrimination models, we demonstrated an improvement in the predictive performance for drugs with intermediate hydrophobicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Drug-induced cholestasis results in drug discontinuation and market withdrawal, and the prediction of cholestasis risk is critical in the early stages of drug development. Animal tests and membrane vesicle assay are currently being conducted to assess the risk of cholestasis in the preclinical stage. However, these methods have drawbacks, such as species differences with humans and difficulties in evaluating the effects of drug metabolism and other transporters, implying the need for a cholestasis risk assessment system using human hepatocytes. However, human hepatocytes hardly form functional, extended bile canaliculi, a requirement for cholestasis risk assessment. We previously established a culture protocol for functional, extended bile canaliculi formation in human iPSC-derived hepatocytes. In this study, we modified this culture protocol to support the formation of functional, extended bile canaliculi in human cryopreserved hepatocytes (cryoheps). The production of bile acids, which induces bile canaliculi extension, increased time-dependently during bile canaliculi formation using this protocol, suggesting that increased bile acid production may be involved in the extended bile canaliculi formation. We have also shown that our culture protocol can be applied to cryoheps from multiple donors and that bile canaliculi can be formed stably among different culture batches. Furthermore, this protocol enables long-term maintenance of bile canaliculi and scaling down to culture in 96-well plates. We expect our culture protocol to be a breakthrough for in vitro cholestasis risk assessment., (© 2024. The Author(s).)

The maintenance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among wildlife populations poses a potential risk for the emergence of novel variants. Therefore, monitoring SARS-CoV-2 infection among animals is crucial. As urban rodents live in close proximity to human habitats, there is concern that they may be a potential source of zoonoses. To examine the prevalence of SARS-CoV-2 in rodent populations, we analyzed 128 serum samples and 129 oral swabs collected from 128 brown rats (Rattus norvegicus) and 2 black rats (Rattus rattus) captured for pest control purposes in Tokyo, Japan, between May and December 2023. A virus-neutralizing test using the Omicron variant revealed no evidence of SARS-CoV-2 infection in these populations. Real-time RT-PCR from oral swabs did not detect any SARS-CoV-2 RNA-positive rats. These results indicate the low probability of SARS-CoV-2 circulation among rat populations in Tokyo.

Although patients who underwent night-time resuscitation for out-of-hospital cardiac arrest (OHCA) had worse clinical outcomes than those who underwent day-time resuscitation, the differences between the outcomes of patients with OHCA who underwent extracorporeal cardiopulmonary resuscitation (ECPR) in the day-time and night-time remain unclear. We analyzed data from the Study of Advanced Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan. Patients were categorized according to whether they received treatment during the day-time or night-time. The primary outcomes were survival to hospital discharge and favorable neurological outcome at discharge, and the secondary outcomes were estimated low-flow time, implementation time of ECPR, and complications due to ECPR. A multivariate logistic regression model adjusted for confounders was used for comparison. Among the 1644 patients, the night-time patients had a significantly longer ECMO implementation time and estimated low-flow time than the day-time patients, along with a significantly higher number of complications than the day-time patients. However, the survival and neurologically favorable survival rates did not differ significantly between the groups. Thus, although patients who underwent ECPR at night had an increased risk of longer implementation time and complications, their clinical outcomes did not differ from those who underwent day-time ECPR., (© 2024. The Author(s).)

Cyclic vomiting syndrome (CVS) is a chronic digestive disorder characterized by recurrent episodes of severe nausea and vomiting. The perioperative management of patients with CVS undergoing general anesthesia is challenging, especially when combined with obesity. This case report describes the successful management of a patient with CVS and obesity who underwent dental surgery under general anesthesia. A 21-year-old woman with CVS, obesity (body mass index, 35), and intellectual disability was scheduled for tooth extraction and composite resin restoration under general anesthesia. The patient was diagnosed with CVS at the age of 20 years with frequent vomiting attacks requiring hospitalization. Surgery was scheduled during the CVS remission to reduce the risk of perioperative vomiting. Preoperative laboratory test results were normal, including serum adrenocorticotropic hormone (ACTH), anti-diuretic hormone (ADH), and cortisol levels. General anesthesia was induced using remifentanil and propofol. Nasal endotracheal intubation was performed after rocuronium administration. Local anesthesia (2% lidocaine with 1:80,000 epinephrine) was used for all dental procedures. Postoperatively, midazolam was administered to control agitation. No postoperative vomiting occurred. Serum ACTH, ADH, and cortisol levels showed no significant changes before and after anesthesia, suggesting that hypothalamic-pituitary-adrenal (HPA) axis activation due to surgical stress did not occur. This case highlights the importance of careful perioperative planning and monitoring stress-related hormone levels in patients with CVS or obesity. An anesthetic approach using midazolam may effectively suppress HPA axis activation and prevent postoperative vomiting., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kuroda et al.)

In recent years, the functionality of myoelectric prosthetic hands has improved as motors have become smaller and controls have become more advanced. Attempts have been made to reproduce the rotation and flexion of the wrist by adding degrees of freedom to the wrist joint. However, it is still difficult to fully reproduce the functionality of the wrist joint owing to the weight of the prosthesis and size limitations. In this study, we developed a new socket and prosthetic hand control system that does not interfere with the wrist joint motion. This allows individuals with hand defects who previously used prosthetic hands with fixed wrist joints to freely use their remaining wrist functionality. In the pick-and-place experiment, where blocks were moved from higher to lower locations, we confirmed that the proposed system resulted in a lower elbow position compared with the traditional prosthesis, and the number of blocks transported increased. This significantly reduced the compensatory motion of the elbow and improved the user's performance compared with the use of a conventional prosthetic hand. This study demonstrates the usefulness of a new myoelectric prosthetic hand that utilizes the residual functions of people with hand deficiencies, which have not been utilized in the past, and the direction of its development., Competing Interests: Competing interests: The authors declare that they have no competing interests., (Copyright © 2024 Yuki Inoue et al.)

Conventional light diffusers have periodic surface profiles, periodic refractive index distributions, or light scattering layers containing colloids. In all such structures the optical directivity of the light diffuser is cannot typically be controlled. Here we propose an electrically tunable light diffuser based on the application of ultrasound to a nematic liquid crystal (LC) material. The ultrasonic LC diffuser consists of an LC layer sandwiched by two glass discs and an ultrasonic transducer. The electrodes of the transducer are divided in a circumferential direction so that a resonant non-coaxial flexural vibration mode can be generated on the diffuser by controlling the electrical input signals. A continuous reversed-phase sinusoidal electric signal to the transducer generates the non-coaxial resonant flexural vibration mode on the glass disc, inducing an acoustic radiation force acting on the boundary between the LC layer and glass discs. This effect changes the molecular orientation of the LC and the transmitted light distribution. The diffusion angle of the transmitted light depends on the input voltage amplitude, and the diffusion angle was maximized at 16.0 V. The vibrational distribution and the diffusion directivity could be rotated by adjusting the input voltages to different electrodes, meaning that an ultrasonic LC diffuser with a thin structure and no moving mechanical parts provided a tunable light-diffusing functionality with rotatable directivity., (© 2024. The Author(s).)

Background: Both kinematically-aligned (KA) total knee arthroplasty (TKA) and bicruciate stabilized (BCS) TKA aim to reproduce the physiological knee kinematics. In this study, we compared the femoro-tibial component rotational mismatch between patients who underwent modified KA-TKA and those who received guided-motion BCS-TKA, and its influence on the clinical outcomes., Methods: In this retrospective study, 77 consecutive patients were included and divided into two groups: subjects who underwent modified KA-TKA with Persona (KA Group; n = 42) and those who received BCS-TKA with JOURNEY II (BCS group; n = 35). Range of motion, the 2011 Knee Society Score (KSS), the rotational alignment of the femoral and tibial components, and the correlations between the rotational mismatch and the 2011 KSS subscales were examined., Results: The postoperative objective knee indicators (P = 0.0157), patient satisfaction (P = 0.0039) and functional activity scores (P = 0.0013) in the KA group were significantly superior to those in the BCS group 1 year postoperatively. There was no significant difference between the two groups observed in the rotational mismatch. In the BCS group, significant negative correlations were identified between the rotational mismatch and objective indicators, patient satisfaction, and functional activity scores but not in the KA group., Conclusions: The short-term clinical results following KA-TKA showed superior objective knee indicators, patient satisfaction and functional activity scores. A negative correlation was observed between component rotational mismatch and the 2011 KSS subscales in the BCS group, compared to no relationship found between the two in the KA group. These findings suggested that KA-TKA has a relatively higher tolerance for rotational mismatch than BCS-TKA., (© 2024. The Author(s).)

Chromic molecules change colour in response to external stimuli and are utilized in applications such as food additive detection, light dimmers, and biological probes. One of the common design strategies for organic chromic molecules is based on changes in the π-conjugation. We have hypothesized that non-alternant polyaromatic hydrocarbon (PAH) skeletons can be used as backbones for chromic molecules. Herein, we synthesized hydroxy-substituted dibenzo[ j , l ]fluoranthenes, a class of non-alternant PAHs, as novel chromic compounds and evaluated their halochromic properties by UV-vis and fluorescence spectroscopy. Under basic conditions, the 1-hydroxy derivatives show a hyperchromic shift, whereas the 9-hydroxy derivatives show a bathochromic shift and fluorescence although the skeleton of the chromophore is the same. Density functional theory calculations indicated that the different chromic properties are attributed to the differences in their resonance structures.

Aim: Extracorporeal cardiopulmonary resuscitation (ECPR) is used to resuscitate patients with cardiac arrest; however, its effect in treating hypothermic cardiac arrest has not been well studied. Therefore, in this study, we aimed to examine the characteristics and outcomes of patients with hypothermic cardiac arrest who underwent ECPR, using a multicenter out-of-hospital cardiac arrest (OHCA) registry in Japan., Methods: Baseline characteristics of patients with hypothermic OHCA and body temperature below 32 °C were assessed. Logistic regression analysis was performed to identify factors associated with in-hospital mortality and neurological outcomes in these patients. Outcomes of hypothermic and cardiogenic OHCA cases were compared using propensity-score matching to investigate differences among subgroups., Results: We included 2,157 patients, with 102 and 1,646 in the hypothermic and cardiogenic groups, respectively. Higher age and longer low-flow time were independent risk factors for mortality, and higher age was an independent risk factor for unfavorable neurological outcomes in the hypothermic OHCA group.Eighty matched pairs were selected during propensity-score matching, and the mortality rate was lower in the hypothermic group than in the cardiogenic group (46.2% vs. 77.5%; p < 0.01). Unfavorable neurological outcome rate was lower in the hypothermic group than in the cardiogenic group (62.5% vs. 87.5%; p < 0.01)., Conclusions: Increased age and prolonged low-flow time were identified as negative prognostic factors in patients with hypothermic OHCA who underwent ECPR. These patients showed lower mortality and unfavorable neurological outcome rates than patients with cardiogenic OHCA, suggesting that ECPR is a promising strategy for treating hypothermic OHCA., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Biallelic TOE1 variants can cause pontocerebellar hypoplasia type 7 (PCH7), a condition characterized by pontocerebellar hypoplasia with genital abnormality. TOE1 is a 3'-exonuclese for 3'-end maturation in small nuclear RNA. TOE1 pathogenic variants have been reported at the DEDD catalytic domain and zinc finger motif. Here, we describe a PCH7 patient with novel compound heterozygous TOE1 variants and a detailed clinical course. The patient was a 3-year-old female and showed developmental delay without cerebellar ataxic behavior. Head MRI revealed delayed myelination without pontocerebellar hypoplasia at 9 months of age. Progressive pontocerebellar atrophy was prominent at follow-up MRI. Cerebral abnormalities are characteristic features of PCH7 before pontocerebellar atrophy is observed. One variant, p.Arg331*, was located at the nuclear localization motif (NLM) and partially escaped from nonsense-mediated decay. This variant affected nuclear localization in mutant expressing cells, thus, the TOE1 variant at NLM leads to TOE1 dysfunction associated with nuclear mis-localization., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Epidermal melanin unit integrity is crucial for skin homeostasis and pigmentation. Epidermal growth factor (EGF) receptor (EGFR) is a pivotal player in cell growth, wound healing, and maintaining skin homeostasis. However, its influence on skin pigmentation is relatively unexplored. This study investigates the impact and underlying mechanisms of EGFR inhibitors on skin pigmentation. We evaluated EGF and EGFR expression in various skin cells using quantitative real-time PCR, Western blot, and immunofluorescence. EGF and EGFR were predominantly expressed in epidermal keratinocytes, and treatment with the EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and PD153035 significantly increased stem cell factor (SCF) and endothelin-1 (ET-1) expression in cultured keratinocytes. Enhanced melanocyte migration and proliferation were observed in co-culture, as evidenced by time-lapse live imaging and single-cell tracking assays. Furthermore, topical application of gefitinib to guinea pig dorsal skin induced increased pigmentation and demonstrated efficacy in mitigating rhododendrol-induced leukoderma. Suppression of EGF signaling indirectly enhanced skin pigmentation by upregulating SCF and ET-1 in epidermal keratinocytes. This novel mechanism highlights the pivotal role of EGF signaling in regulating skin pigmentation, and topical EGFR-TKI therapy at an appropriate dose may be a promising approach for depigmentation disorder management., (© 2024 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Background: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17., Method: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region., Results: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM&#95;033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency., Conclusion: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)