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Indium-alkyl NCN pincer complexes supported by amine and imine donors are active catalysts for the ring opening polymerization of lactide. The amine indium complexes are significantly more active for polymerization due to the decoordination of the amine donors at higher temperatures. Solid state structures of the imine and amine indium complexes indicate that the imine-indium bonds are stronger than the analogous amine-indium bonds. Higher molecular weight polymers that were not observable by MALDI-TOF were shown to be linear by comparing their intrinsic viscocities with those of known linear polymers. The alkyl indium complexes are more active than the analogous alkyl aluminum complexes but are prone to transesterification reactions.

Purpose: This study investigated the clinical features and surgical outcomes of full-thickness macular holes (FTMHs) without focal vitreomacular traction (VMT) and discusses possible underlying mechanisms., Methods: This was a retrospective observational study included patients aged 18 years or older with stage 2 FTMHs who underwent pars plana vitrectomy at three hospitals between December 2016 and March 2024. Patients diagnosed without focal VMT in the macula were classified as VMT- and those with focal VMT were classified as VMT+. Medical records and comprehensive ophthalmologic examinations, including best-corrected visual acuity (BCVA) and optical coherence tomography assessments, were reviewed., Results: This study analyzed 94 eyes that underwent surgery for stage 2 MHs. Patients in the VMT- were younger (VMT- vs VMT+: 63.6 vs 69.1 years, P = 0.008), had a longer axial length (AL) (25.2 vs 24.0 mm, P = 0.004), and had better preoperative BCVA [0.41 (20/43) vs 0.66 (20/74) logMAR, P = 0.002 ] compared with the VMT+. The VMT- had a higher prevalence of epiretinal proliferation (EP) compared with the VMT+ (76 vs 5 %, P<0.001). Postoperatively, no significant difference in visual outcomes was found between the two groups . VMT- showed significantly thicker central retinal thickness at 1 month (244 vs 201 μm, P = 0.021) and poorer external limiting membrane status at 1 month compared with the VMT+., Conclusions: FTMHs without focal VMT were associated with younger age, longer AL, better baseline visual acuity, and a higher incidence of EP compared with FTMHs with VMT.

Inflammatory breast cancer (IBC) is the most aggressive and lethal breast cancer subtype but lacks unequivocal genomic differences or robust biomarkers that differentiate it from non-IBC. Here, Thermostable Group II intron Reverse Transcriptase RNA-sequencing (TGIRT-seq) revealed myriad differences in tumor samples, Peripheral Blood Mononuclear Cells (PBMCs), and plasma that distinguished IBC from non-IBC patients and healthy donors across all tested receptor-based subtypes. These included numerous differentially expressed protein-coding gene and non-coding RNAs in all three sample types, a granulocytic immune response in IBC PBMCs, and over-expression of antisense RNAs, suggesting wide-spread enhanced transcription in both IBC tumors and PBMCs. By using TGIRT-seq to quantitate Intron-exon Depth Ratios (IDRs) and mapping reads to both genome and transcriptome reference sequences, we developed methods for parallel analysis of transcriptional and post-transcriptional gene regulation. This analysis identified numerous differentially and non-differentially expressed protein-coding genes in IBC tumors and PBMCs with high IDRs, the latter reflecting rate-limiting RNA splicing that negatively impacts mRNA production. Mirroring gene expression differences in tumors and PBMCs, over-represented protein-coding gene RNAs in IBC patient plasma were largely intronic RNAs, while those in non-IBC patients and healthy donor plasma were largely mRNA fragments. Potential IBC biomarkers in plasma included T-cell receptor pre-mRNAs and intronic, LINE-1, and antisense RNAs. Our findings provide new insights into IBC and set the stage for monitoring disease progression and response to treatment by liquid biopsy. The methods developed for parallel transcriptional and post-transcriptional gene regulation analysis have potentially broad RNA-seq and clinical applications., Competing Interests: Conflict-of-interest statement AML is an inventor on patents owned by the University of Texas at Austin for TGIRT enzymes and other stabilized reverse transcriptase fusion proteins and methods for non-retroviral reverse transcriptase template switching. AML, JY, and HX are inventors on a patent application filed by the University of Texas for the use of intron RNAs as biomarkers. DW, XW, JY, HX, EAF-K, NTU, and AML are inventors on a patent application filed jointly by UT Austin and MD Anderson entitled "Methods and Compositions for Diagnosing, Treating and/or Preventing Inflammatory Breast Cancer" based on potential RNA biomarkers identified in this study.

Bohring-Opitz syndrome (BOS) is a rare disease with a characteristic facial appearance and limb position. This report describes a case of BOS complicated by persistent pulmonary hypertension of the newborn (PPHN) and formation of abnormal alveoli that was confirmed by autopsy. A female neonate was born by cesarean section at 37 weeks and 2 days of gestation and found to have a nevus flammeus, exophthalmos, abnormal palate, retraction of the mandible, and a posture characteristic of BOS. The patients had severe PPHN requiring inhalation of nitric oxide. Genetic testing revealed a de novo frameshift variant in ASXL1. Autopsy revealed that the lung was at the saccular stage, equivalent to 28-34 weeks of gestation. This is the first report to present pathological evidence of immaturity of the lung that may be associated with PPHN in a patient with BOS caused by a variant in ASXL1., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: To assess the real-world outcome of best-corrected visual acuity (BCVA) following 2-year intervention for treatment-naïve diabetic macular edema (DME) since the approval of anti-vascular endothelial growth factor (VEGF) therapy., Methods: A total of 1,780 treatment-naïve eyes with DME for which intervention was initiated between 2015 and 2019, and which were followed for 2 years, were extracted from the longitudinal medical records of 37 retinal disease institutions in Japan. Interventions included anti-VEGF therapy, topical corticosteroid therapy, macular photocoagulation, and vitrectomy. The baseline and final BCVA, and the number and timing of interventions were recorded. Eyes were classified according to the year in which intervention was initiated., Results: Over a 2-year period, BCVA improved annually, finally reaching 7 letters. The proportion of eyes in which good vision was maintained (BCVA >20/40) increased to 73.3% in the latest period. The administration of anti-VEGF therapy remained stable, accounting for approximately 90% of eyes. Notably, the proportion of eyes receiving anti-VEGF drugs as first-line treatment increased dramatically to approximately 80%., Conclusion: Anti-VEGF therapy has become the first-line treatment since the approval of anti-VEGF drugs for DME. These findings reflect the evolution of DME treatment and highlight the superiority of anti-VEGF therapy and its increased uptake over time., Competing Interests: Conflict of Interest: The authors declare no conflicts of interest in association with the present study., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: Cancer-associated macrophage-like cells (CAMLs) are rare, gigantic, and atypical circulating cells found exclusively in the peripheral blood of patients with solid cancers. Obesity-induced hypoxia attracts macrophages to the tumor microenvironment, where they contribute to establishing chronic inflammation, leading to cancer progression. We hypothesized that obese patients with advanced breast cancer may have CAML profiles different from those of nonobese patients, and these profiles may correlate with proinflammatory markers or other macrophage-related markers. Methods: We prospectively collected 20 mL of peripheral blood from patients diagnosed with stage 2-4 breast cancer. We identified CAMLs using the CellSieve microfiltration system and in parallel quantified the proinflammatory and macrophage-related markers using a multiplex cytokine panel. We further evaluated C-X-C chemokine receptor type 4 (CXCR4) expression in CAMLs to investigate its relationship to the macrophage differentiation. We estimated the association between CAML characteristics and body mass index (BMI), body composition, and cytokines/chemokines. Results: Thirty patients were included in the study, and 28 samples were analyzed. Higher BMI was significantly correlated with the increased maximum CAML size ( P = 0.035). Patients with higher BMIs had significantly increased macrophage-colony stimulating factor (M-CSF) levels in plasma ( P = 0.007), and obese patients trended towards higher tumor necrosis factor-alpha, MIP-1α and M-CSF expression ( P <0.10). Body composition analysis showed that the M-CSF and SAT amounts were significantly correlated ( P = 0.010). MIP-1α expression was significantly correlated with average CXCR4 CAML expression ( P = 0.003). Conclusion: We discovered larger CAML size was associated with SAT-dominant obesity with increased macrophage-related and proinflammatory markers in obese than in nonobese breast cancer patients., Competing Interests: Competing Interests: D.L.A. and C.-M.T. are employees of Creatv Microtech. The remaining authors declare that they have no competing interests., (© The author(s).)

Purpose: Since the introduction of the Exeter stem for clinical use in Japan in 1996, the number of stems used has continued to rise owing to its favorable results. We investigated the outcomes of patients who had previously undergone total hip arthroplasty with the Exeter stem in Japan with a 10-year + follow-up period., Methods: This retrospective cohort study used clinical and radiographic data of 682 cases of primary total hip arthroplasty performed using the Exeter stem., Results: The mean postoperative follow-up period was 13.3 years. Femoral-side revision was required in 14 hips, with no cases of aseptic stem loosening-associated revision observed. Kaplan-Meier survival analysis predicted 97.3% 15-year survival when revision for any reason was used as the endpoint., Conclusion: The obtained findings suggested the excellent long-term stability of the Exeter stem for primary total hip arthroplasty in Japan., (© 2024. The Author(s).)

Fabry disease is an X-linked hereditary disorder caused by deficient α-galactosidase A (GLA) activity. Patients with Fabry disease are often treated with enzyme replacement therapy (ERT). However, ERT often induces the formation of neutralizing antidrug antibodies (ADAs), which may impair the therapeutic efficacy. Here, we report the case of a 32-year-old man with Fabry disease and resultant neutralizing ADAs who was treated by switching from agalsidase-α to agalsidase-β. We monitored biomarkers, such as plasma globotriaosylsphingosine (lyso-Gb3), urinary globotriaosylceramide (Gb3), urinary mulberry bodies, renal and cardiac parameters, and disease severity during the treatment period. Although plasma lyso-Gb3 and urinary Gb3 levels quickly decreased within two months after the initiation of ERT with agalsidase-α, they gradually increased thereafter. The urinary mulberry bodies continued to appear. Both the ADA titer and serum mediated GLA inhibition rates started to increase after two months. Moreover, 3.5 years after ERT, the vacuolated podocyte area in the renal biopsy decreased slightly from 23.1 to 18.9%. However, plasma lyso-Gb3 levels increased, and urinary Gb3, mulberry body levels, and ADA titers remained high. Therefore, we switched to agalsidase-β which reduced, but did not normalize, plasma lyso-Gb3 levels and stabilized renal and cardiac parameters. Disease severity was attenuated. However, urinary Gb3 and mulberry body levels did not decrease noticeably in the presence of high ADA titers. The kidneys take up a small amount of the administered recombinant enzyme, and the clearance of Gb3 that has accumulated in the kidney may be limited despite the switching from agalsidase-α to agalsidase-β., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022., Methods: From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022., Results: Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467., Conclusion: The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.

Background: Although excellent long-term results have been reported for the Exeter stem, stem fracture is recognized as a rare complication. However, there have been no reports on the incidence and risk factors for stem fractures based on detailed population information. This study aimed to clarify the incidence of Exeter hip stem fracture based on detailed population information from seven Exeter stem teaching centers in Japan and to examine the risk factors for stem fracture., Methods: A total of 8,499 primary total hip arthroplasties (THA) and 636 revision hip arthroplasties (revisions) performed at seven Exeter teaching hospitals between 1999 and 2021 were included and retrospectively investigated based on medical records., Results: Stem fractures were identified in two primary THA (fracture rate: 0.02%) and two revision THA (fracture rate: 0.21%) cases. The stem length was ≤125 mm in three out of these four cases. Revision and 30 stem were the risk factors for stem fractures. Weight and body mass index (BMI) were not significantly associated with the occurrence of stem fractures., Conclusions: In Western countries, the incidence of Exeter stem fractures is reportedly 0.017-0.15% for primary THA and 0.99-1.21% for revision THA. In this study, the incidence of primary THA was 0.02%, which is similar to the lowest reported rate, whereas the incidence of revision THA was 0.21%, which is lower than that reported in previous studies. Revision surgery had the same risk factors as those reported in the West-namely, stem length ≤125 mm (except for the 30 stem) and BMI, which were not risk factors in Japanese patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Accumulating toxicities hinder indefinite chemotherapy for many patients with metastatic/recurrent HER2-negative breast cancer. We conducted a phase II trial of pembrolizumab monotherapy following induction chemotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative inflammatory breast cancer (IBC) and non-IBC triple-negative breast cancer (TNBC) and a biomarker study., Patients and Methods: Patients with a complete response, partial response, or stable disease (SD) after at least three cycles of chemotherapy for HER2-negative breast cancer received pembrolizumab, regardless of programmed death-ligand 1 expression. Pembrolizumab (200 mg) was administered every 3 weeks until disease progression, intolerable toxicity, or 2 years of pembrolizumab exposure. The endpoints included the 4-month disease control rate (DCR), progression-free survival (PFS), overall survival, and response biomarkers in the blood., Results: Of 43 treated patients, 11 had metastatic IBC and 32 non-IBC TNBC. The 4-month DCR was 58.1% [95% confidence interval (CI), 43.4-72.9]. For all patients, the median PFS was 4.8 months (95% CI, 3.0-7.1 months). The toxicity profile was similar to the previous pembrolizumab monotherapy study. Patients with high T-cell clonality at baseline had a longer PFS with pembrolizumab treatment than did those with low T-cell clonality (10.4 vs. 3.6 months, P = 0.04). Patients who achieved SD also demonstrated a significant increase in T-cell clonality during therapy compared with those who did not achieve SD (20% vs. 5.9% mean increase, respectively; P = 0.04)., Conclusions: Pembrolizumab monotherapy achieved durable treatment responses. Patients with a high baseline T-cell clonality had prolonged disease control with pembrolizumab., (©2024 American Association for Cancer Research.)

Purpose: To clarify how body mass index (BMI) affects the development and temporal trend of breast cancer-related lymphedema (BCRL)., Methods: This is a prospective study in which patients with operable breast cancer were registered in a single institute between November 2009 and July 2010. The incidence of lymphedema at 1, 3, and 5 years after surgery was assessed according to BMI, and the trend of newly developed BCRL was examined. Obesity was defined as BMI ≥25 in accordance with the Japan Society for the Study of Obesity., Results: A total of 368 patients were included in this study. The multivariate analysis of the whole population showed that high BMI, axillary dissection, and radiotherapy remained as risk factors for BCRL. Patients with high BMI showed a significantly higher incidence of new lymphedema than those with low BMI at 1 year (p < 00.001) regardless of axillary procedures (39.1 % vs 16.3 % for axillary dissection; 15.6 % vs 1.5 % for sentinel lymph node biopsy) but not at 3 and 5 years. Once BCRL developed, patients with high BMI showed slow recovery and 50.0 % of the patients retained edema at 5 years while patients with low BMI showed rapid recovery and 26.7 % retained after 3 years (p = 0.04)., Conclusion: The preoperative BMI affected the incidence and temporal trend of BCRL regardless of axillary procedures or radiotherapy. Patients with high BMI should be given appropriate information about BCRL before surgery with careful follow-up for BCRL after treatment., Competing Interests: Declaration of competing interest This research did not use any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All authors have no financial and personal relationships with other people or organizations that could influence this work., (© 2024 Published by Elsevier Ltd.)

This study aimed to assess the feasibility of a skin marker-less patient setup using a surface-guided radiotherapy (SGRT) system for extremity radiotherapy. Twenty-five patients who underwent radiotherapy to the extremities were included in this retrospective study. The first group consisted of 10 patients and underwent a traditional setup procedure using skin marks and lasers. The second group comprised 15 patients and had a skin marker-less setup procedure that used an SGRT system only. To compare the two setup procedures for setup accuracy, the mean 3D vector shift magnitude was 0.9 mm for the traditional setup procedure and 0.5 mm for the skin marker-less setup procedure (p < 0.01). In addition, SGRT systems have been suggested to improve the accuracy and reproducibility of patient setups and consistently reduce interfractional setup errors. These results indicate that a skin marker-less patient setup procedure using an SGRT system is useful for extremity irradiation., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Background and Objectives : Faricimab is a vascular endothelial growth factor A and angiopoietin-2 bispecific antibody. It is a novel therapeutic approach distinct from previous anti-vascular endothelial growth factor agents. This study aimed to evaluate the efficacy of switching from aflibercept to faricimab in the treatment of diabetic macular edema (DME) refractory to aflibercept, with a specific focus on the resolution of macular edema. Materials and Methods : The medical records of 29 eyes of 21 patients with DME that were refractory to intravitreal injections of aflibercept (IVAs) and who had completed the clinical follow-up of at least four intravitreal injections of faricimab (IVFs) were reviewed. The central retinal thickness (CRT), best-corrected visual acuity (BCVA), and the mean period (weeks) until the next injection were measured after the second-to-last IVA, first-to-last IVA, last IVA, and first to fourth IVFs following the transition to IVF. Results : The mean time from the first IVF to the assessment of effectiveness was significantly shorter than the time to the last IVA; however, no significant difference was found in the time from the second, third, and fourth IVFs to the assessment. The mean CRTs after the first and second IVFs were not significantly different from the CRT after the last IVA, but the mean CRT after the third and fourth IVFs was significantly thinner than that after the last IVA ( p = 0.0025 and p = 0.0076, respectively). The mean BCVAs after the third and fourth IVFs significantly improved compared with that after the last IVA ( p = 0.0050 and p = 0.0052, respectively). Conclusions : When switching the treatment to IVF for eyes with IVA-resistant DME, better treatment outcomes are achieved if IVF is performed three or more times.

Purpose: Many stage III inflammatory breast cancer (IBC) patients experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to allow surgery, while some require additional NAC. We evaluated the pathologic complete response (pCR), breast cancer-free survival (BCFS) and overall survival (OS) among patients requiring 1 vs. 2-3 lines (L) of NAC prior to surgery., Methods: Stage III IBC patients from 2 institutions who received 1L or 2-3L of NAC prior to surgery were identified. Hormone receptor and HER2 status, grade, and pCR were evaluated. BCFS and OS were evaluated by the Kaplan-Meier method. Multivariable Cox models were utilized to estimate the hazard ratio (HR)., Results: 808 eligible patients (1997-2020) were identified (median age 51 years, median follow-up 69 months). 733 (91%) had 1L and 75 (9%) had 2-3L of NAC. Grade III, triple-negative and HER2-positive disease were more prevalent in 2-3L patients. 178 (24%) 1L and 14 (19%) 2-3L patients had pCR. 376 1L patients and 41 2-3L patients had recurrences. The 5-year BCFS was worse for the 2-3L group (33 vs. 46%, HR = 1.37; 95% CI 0.99-1.91). However, in 192 patients with a pCR, BCFS was similar (76 vs. 83% in 1L vs. 2-3L, respectively). There were 308 deaths (276 among 1L and 32 among 2-3L patients). The 5-year OS in 1L vs. 2-3L was 60 vs. 53% (HR = 1.32, 95% CI 0.91-1.93)., Conclusions: Among stage III IBC patients, pCR rates were similar, irrespective of the NAC lines number, and BCFS and OS were comparable with pCR after 1L and 2-3L., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To clarify the abilities of circumpapillary retinal nerve fiber layer thickness (cpRNFLT) obtained by optical coherence tomography (OCT) and circumpapillary vessel density (cpVD) measured by OCT-angiography to distinguish different stages in primary open-angle glaucoma determined by 24-2 or 30-2 static visual field (VF) testing., Methods: This retrospective study includes 25 healthy normal eyes of 25 subjects and 87 primary open-angle glaucoma eyes of 87 patients. Areas under the receiver operating characteristic curves (AUROC) were evaluated for determining glaucoma stages using cpRNFLT and cpVD. The absolute errors of the estimated mean total deviation (mTD) using optimal models with cpRNFLT and cpVD were also compared., Results: The AUROCs for discriminating glaucomatous eyes from normal eyes was significantly higher for cpRNFLT than the respective AUROCs for cpVD (0.969 [95% CI 0.939 to 0.998] vs. 0.872 [95% CI 0.806 to 0.938], p = 0.006), whereas cpVD had significantly higher AUROC for discriminating severe glaucoma eyes from moderate glaucoma eyes than cpRNFLT (0.771 [95% CI 0.655 to 0.886] vs. 0.578 [95% CI 0.420 to 0.736], p = 0.022). The mean absolute error in estimating mTD using both cpRNFLT and cpVD was significantly less than the error using cpRNFLT alone (4.56 ± 3.76 dB vs. 5.39 ± 4.00 dB, p = 0.027)., Conclusion: Our results suggest that cpVD is better for follow-ups after moderate stage. The combination of cpRNFLT and cpVD may improve VF estimation compared to cpRNFLT alone., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To investigate muscle volume changes in all body regions after total hip arthroplasty (THA) with dual-energy X-ray absorptiometry (DEXA), and determine the positive effects of THA for systemic muscle atrophy in patients with hip osteoarthritis (HOA)., Methods: In total, 116 patients with a mean age of 65.8 (45-84) years who had undergone THA for unilateral HOA were included in this study. DEXA scans were performed serially at 2 weeks, 3, 6, 12, 18, and 24 months after THA. The normalized height squared muscle volume (NMV) and the change ratio of NMV (ΔNMV) were calculated independently for operated lower extremity (LE), non-operated LE, both upper extremities (UEs), and trunk. Skeletal mass index, which is a sum of NMV of both LEs and UEs, was evaluated at 2 weeks and 24 months after THA to identify systemic muscle atrophy equivalent to the diagnostic criteria of sarcopenia., Results: ΔNMVs in non-operated LE, both UEs, and trunk increased gradually up to 6, 12, and 24 months after THA, although that in operated LE did not increase during a 24-month period. The ΔNMVs in operated LE, non-operated LE, both UEs, and trunk at 24 months after THA were +0.6%, +7.1%, +4.0%, and +4.0%, respectively (P = 0.993, P < 0.001, P < 0.001, P = 0.012). The proportion of systemic muscle atrophy significantly decreased from 2 weeks (38%) to 24 months (23%) after THA (P = 0.022)., Conclusions: THA can potentially have secondary positive effects for systemic muscle atrophy exception of operated LE., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Objectives　It is difficult for medical students to obtain information about public health physicians because there are very few public health physicians near them. To improve this situation, we surveyed the utilization of internet services to collect job information among medical students and produced six videos and conducted public relations activities for the recruitment of public health physicians based on the survey results.Methods　The subjects of the survey were medical students in their third year or above from 18 universities. Public health teachers in these 18 universities sent their students anonymous self-administered questionnaires created with Google Forms mainly by e-mail. The questionnaires included the following items "internet services used to collect job information," "desired length of each video for knowing job information," and "information you want to know about your future work." The responses were reflected in the length and the content of the videos and the settings for their distribution.Results　Responses were obtained from a total of 491 medical students, including 14 third-year students, 177 fifth-year students, and 300 sixth-year students. Homepages were the most frequently used online source for collecting job information (94.7%), followed by blogs (42.0%), Twitter (32.6%), and YouTube (18.9%). Medical students are less likely to use social networking services for collecting job information compared with non-medical job-hunting students. Regarding the length of the videos, 55.8% of the respondents preferred the length of one video to be less than 5 minutes, and 95.1% preferred it to be less than 10 minutes. Almost all of the respondents (93.1%) wanted to know the atmosphere of young public health physicians, and 74.1% also wanted to know the atmosphere of veteran physicians. Based on these results, we selected six public health physicians including young and veteran physicians and produced interview videos that conveyed the atmosphere of each doctor within 5 minutes per person. We refurbished the banner on the top page of the Japanese Association of Public Health Center Directors so that the videos uploaded to YouTube could be watched.Conclusion　We clarified the current situation of the utilization of internet services for job-hunting activities among medical students and were able to initiate video public relations activities for the recruitment of public health physicians in accordance with the needs. It is necessary to increase awareness of the video platform among medical students and clinicians by deepening cooperation with local governments, universities, and medical institutions and expanding the human network both online and in person.

Background: Femoral impaction bone grafting (IBG) was introduced in the late 1990s in Japan and has gradually become recognized as a useful option for femoral revision. The aim of the present study was to retrospectively analyze 10 to 15 years of clinical results of femoral revision arthroplasties of IBG using Exeter stem performed by experienced Japanese surgeons., Methods: We investigated radiographic and clinical records more than 2 years after surgery in 99 hips of 93 patients. The average age was 66.3 years (36-84 years) and the average follow-up period was 11 years (2-23 years and 8 months). Merle d'Aubigné and Postel hip score was used for clinical assessment, and re-operations for any reason were recorded. The survival curve was estimated using Kaplan-Meier method., Results: The mean Merle d'Aubigné and Postel hip score improved from 9.0 points to 14.5 points at the final follow-up. Re-operations were undertaken in 15 hips of 14 patients for aseptic acetabular component loosening (n = 1 hip), recurrent dislocation (n = 2 hips), infection (n = 4 hips), and periprosthetic femoral fracture (n = 8 hips). The survival rates at 10 and 15 years after operation were 87.1% and 81.1% with any type of re-operation as the endpoint, 92.2% and 92.2% with stem removal or exchange as the endpoint, 94.9% and 88.1% with re-operation for periprosthetic femoral fracture as the endpoint, and 99.0% and 99.0% with re-operation for aseptic stem loosening as the endpoint, respectively., Conclusions: The present study showed encouraging results of femoral IBG over 10 years by experienced surgeons in Japan. Although femoral IBG is recognized as a technically complex procedure, survivorship of the stem is excellent, with a 15-year stem survival rate of 99.0% at the end point of aseptic loosening., Competing Interests: Declaration of competing interest None of the authors has anything to declare regarding conflict of interest, nor does any author have a relationship with any funding companies., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Apoptotic cells' phosphoserine (PS) groups have a significant immunosuppressive effect. They inhibit proinflammatory signals by interacting with various immune cells, including macrophages, dendritic cells, and CD4 + cells. Previously, we synthesized PS-group-immobilized polymers and verified their immunomodulatory effects. Despite its confirmed immunomodulatory potential, the PS group has not been considered as a payload for antibody-drug conjugates (ADCs) in a targeted anti-inflammatory approach., Aim: We conducted this research to introduce an apoptotic-cell-inspired antibody-drug conjugate for effective immunomodulation., Method: Poly(2-hydroxyethyl methacrylate- co -2-methacryloyloxyethyl phosphorylserine) (p(HEMA- co -MPS)) was synthesized as a payload using RAFT polymerization, and goat anti-mouse IgG was selected as a model antibody, which was conjugated with the synthesized p(HEMA- co -MPS) via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/ N -Hydroxysuccinimide (EDC/NHS) reaction. The antibody-binding affinity, anti-inflammatory potential, and cytotoxicity measurements were evaluated., Results: We successfully synthesized ADCs with a significant anti-inflammatory effect and optimized the antibody-polymer ratio to achieve the highest antibody-binding affinity., Conclusion: We successfully introduced p(HEMA- co -MPS) to IgG without decreasing the anti-inflammatory potential of the polymer while maintaining its targeting ability. We suggest that the antibody-polymer ratio be appropriately adjusted for effective therapy. In the future, this technology can be applied to therapeutic antibodies, such as Tocilizumab or Abatacept.

Microbial pathogens, including bacteria, fungi and viruses, can develop resistance to clinically used drugs; therefore, finding new therapeutic agents is an ongoing challenge. Recently, we reported the photoimmuno-antimicrobial strategy (PIAS), a type of photoimmunotechnology, that enables molecularly targeted elimination of a wide range of microbes, including the viral pathogen severe acute respiratory syndrome coronavirus 2 and the multidrug-resistant bacterial pathogen methicillin-resistant Staphylococcus aureus (MRSA). PIAS works in the same way as photoimmunotherapy (PIT), which has been used to treat recurrent head and neck cancer in Japan since 2020. Both PIAS and PIT use a monoclonal antibody conjugated to a phthalocyanine derivative dye that undergoes a shape change when photoactivated. This shape change induces a structural change in the antibody-dye conjugate, resulting in physical stress within the binding sites of the conjugate and disrupting them. Therefore, targeting accuracy and flexibility can be determined based on the specificity of the antibody used. In this protocol, we describe how to design a treatment strategy, label monoclonal antibodies with the dye and characterize the products. We provide detailed examples of how to set up and perform PIAS and PIT applications in vitro and in vivo. These examples are PIAS against microbes using MRSA as a representative subject, PIAS against viruses using severe acute respiratory syndrome coronavirus 2 in VeroE6/TMPRSS2 cells, PIAS against MRSA-infected animals, and in vitro and in vivo PIT against cancer cells. The in vitro and in vivo protocols can be completed in ~3 h and 2 weeks, respectively., (© 2023. Springer Nature Limited.)

Aims: The clinical triad of idiopathic normal pressure hydrocephalus (iNPH) includes gait disturbance, dementia, and urinary incontinence. These symptoms are also frequently observed in patients with proximal femoral fracture (PFF). The aim of this study was to investigate the relationship between PFF and iNPH retrospectively., Patients and Methods: Of the130 patients over 80-years-old with PFF included in this study, 48 were assigned to the PFF group. Forty-eight patients with peripheral vertigo matched with the PFF group for age and sex were included in the control group. We compared the Evans' index (EI), which is a head computed tomography finding of iNPH, and the percentages of patients with EI>0.3 between the two groups. The PFF group was further divided into two subgroups depending on whether EI was higher or lower than 0.3 (the higher or lower subgroup, respectively). We compared the patient's gait abilities before PFF, causes of PFF, cognitive functions, and occurrence of urinary incontinence between both groups., Results: The mean value of EI in the PFF group was significantly higher than that in the control group (PFF group, 0.301; control group, 0.284; p=0.008). The percentages of patients with EI>0.3 in the PFF and control groups were 62.5% and 35.4%, respectively (p=0.014). In subgroup analyses, the gait ability before injury was worse in the higher subgroup than that in the lower subgroup and was prominent among individuals who could walk only with human assistance (p=0.018). There were no significant differences in other parameters., Conclusion: Elderly patients with PFF may have underlying idiopathic normal pressure hydrocephalus., Level of Evidence: III; case-control comparative study., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: This cross-sectional study aimed to clarify the differences in the retinal venous narrowing ratio (VNR) at retinal arteriovenous crossing by optical coherence tomography (OCT) among the eyes with branch retinal vein occlusion (BRVO), fellow eyes of patients with BRVO, and eyes of individuals without BRVO and to determine factors that influence the VNR., Methods: We studied 31 eyes of young participants, 54 eyes of an older control group, 56 fellow eyes of patients with BRVO, and 48 eyes with BRVO. Cross-sectional OCT images were used to determine the VNR at two arteriovenous crossings per eye., Results: Overall, 378 arteriovenous crossings were analyzed. The VNR of arterial overcrossings of fellow eyes (27.7% ± 11.1%) and BRVO eyes (27.3% ± 9.76%) were significantly higher than those in the young (16.0% ± 7.9%, all P < 0.001) and control (22.0% ± 8.81%, P < 0.001, P = 0.003, respectively) groups. The VNR of arterial overcrossings was significantly larger than that of venous overcrossings (24.0% ± 10.5% vs. 20.6% ± 13.0%, P = 0.021). A linear mixed-effects model showed that the VNR was significantly higher in arterial overcrossings, crossings with larger arterial internal diameters, smaller venous internal diameters, and participants with older age and a BRVO history., Conclusions: The VNR in arterial overcrossings was higher in BRVO eyes and even in the fellow eyes. Thus, a higher VNR in arterial overcrossings may contribute to BRVO development, and crossings with factors contributing to higher VNR might be associated with a risk of BRVO.

We evaluated the closure of full-thickness macular holes (MHs) the day after surgery in minimizing the burden and maximizing patient outcomes. Herein, 25-gauge pars plana vitrectomy, internal limiting membrane peeling, and fluid-gas (20% sulfur hexafluoride) were performed for the treatment. Patients were instructed to remain in the facedown position until the confirmation of MH closure, and the position was discontinued in cases where the closure was confirmed. In total, 43 eyes of 43 patients, whose average age was 69.7 ± 8.6 years, were enrolled in this study. We used swept source (SS)-optical coherence tomography (OCT) for the confirmation of MH closure for gas-filled eyes and used spectral domain (SD)-OCT for the reconfirmation of MH closure after the gas volume was reduced to less than half of the vitreous cavity. MH closure was confirmed in 40 eyes (93%, the closure group) on the next day after surgery. The time from surgery to SS-OCT imaging was 24.7 h. Although facedown positioning was terminated in cases where MH closure was confirmed, there were no cases in which the MH was re-opened afterward. The basal and minimum MH size was significantly larger in the non-closure group than that in the closure group ( p = 0.027, p = 0.043, respectively). Therefore, checking with SS-OCT the day after surgery and terminating facedown positioning in cases where MH closure was confirmed would be a useful method, removing a great burden for the elderly without sacrificing the MH closure rate.

Purpose: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS)., Patients and Methods: This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818)., Results: We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups., Conclusion: Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.

Background: Mfa1 fimbriae of the periodontal pathogen Porphyromonas gingivalis are responsible for biofilm formation and comprise five proteins: Mfa1-5. Two major genotypes, mfa1 70 and mfa1 53 , encode major fimbrillin. The mfa1 70 genotype is further divided into the mfa1 70A and mfa1 70B subtypes. The properties of the novel mfa1 70B remain unclear., Methods: Fimbriae were purified from P. gingivalis strains JI-1 (mfa1 70A ), 1439 (mfa1 70B ), and Ando (mfa1 53 ), and their components and their structures were analyzed. Protein expression and variability in the antigenic specificity of fimbrillins were compared using Coomassie staining and western blotting using polyclonal antibodies against Mfa1 70A , Mfa1 70B , and Mfa1 53 proteins. Cell surface expression levels of fimbriae were analyzed by filtration enzyme-linked immunosorbent assays., Results: The composition and structures of the purified Mfa1 fimbriae of 1439 was similar to that of JI-1. However, each Mfa1 protein of differential subtype/genotype was specifically detected by western blotting. Mfa1 70B fimbriae were expressed in several strains such as 1439, JKG9, B42, 1436, and Kyudai-3. Differential protein expression and antigenic heterogeneities were detected in Mfa2-5 between strains., Conclusion: Mfa1 fimbriae from the mfa170A and mfa170B genotypes indicated an antigenic difference suggesting the mfa170B, is to be utilized for the novel classification of P. gingivalis., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Purpose: To determine the factors significantly associated with the amplitudes and implicit times of the flicker electroretinograms (ERGs) recorded with the RETeval system by analyzing the comprehensive data obtained during a health checkup screening., Methods: Flicker ERGs were recorded with the RETeval system from 373 individuals who had a normal fundus and optical coherence tomography images. The sex, age, anthropometric, ophthalmologic, and hematologic data were collected from all participants who were 40- to 89-years-of-age. Univariable and multivariable linear mixed effects regression analyses were performed to identify factors that were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs., Results: Univariable linear mixed effects regression analysis showed significant correlations between the implicit times and the best-corrected visual acuity, the age, the axial length, the blood sugar level, and the blood urea nitrogen level. Analyses by multivariable linear mixed effects regression identified that the axial length (β = 0.28), the age (β = 0.24), and the blood sugar level (β = 0.092) were three independent factors that were significantly correlated with the implicit times of the RETeval flicker ERGs. Univariable linear mixed effects regression analysis also showed significant correlations between the amplitudes of the RETeval flicker ERGs and the age, the platelet count, and the creatinine level. Multivariable linear mixed effects regression models identified the age (β = -0.092), the platelet count (β = 0.099), and the creatinine level (β = -0.12) as three independent factors that were significantly correlated with the amplitudes of the RETeval flicker ERGs. However, the smoking habits, body mass index, and the blood pressure were not significantly correlated with either the implicit times or amplitudes of the RETeval flicker ERGs., Conclusions: Our results indicate that the age and some ophthalmologic and hematologic findings but not the anthropometric findings were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs. Thus, clinicians should remember these factors when analyzing the RETeval flicker ERGs., Competing Interests: The IOL master was on loan from Carl Zeiss Meditec and the color fundus camera was on loan from Canon. The automatic vision tester, TONOREF and spectral domain optical coherence tomography device, was on loan from Nidek. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Inooka 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.)

Introduction: Sensory dysfunctions and cognitive impairments are related to each other. Although a relationship between tinnitus and subjective olfactory dysfunction has been reported, there have been no reports investigating the relationship between tinnitus and olfactory test results., Methods: To investigate the relationship between tinnitus and olfactory test results, we conducted sensory tests, including hearing and visual examinations. The subjects included 510 community-dwelling individuals (295 women and 215 men) who attended a health checkup in Yakumo, Japan. The age of the subjects ranged from 40 to 91 years (mean ± standard deviation, 63.8 ± 9.9 years). The participants completed a self-reported questionnaire on subjective tinnitus, olfactory function, and hearing function, as well as their lifestyle. The health checkup included smell, hearing, vision, and blood examinations., Results: After adjusting for age and sex, the presence of tinnitus was significantly associated with subjective olfactory dysfunction, poor olfactory test results, hearing deterioration, vertigo, and headache. Additionally, high serum calcium levels and a low albumin/globulin ratio were significantly associated with low physical activity and nutrition. Women scored higher than men in olfactory and hearing examinations, but there was no gender difference in vision examinations., Conclusion: Subjective smell dysfunction and poor smell test results were significantly associated with tinnitus complaints. Hearing and vision were associated even after adjusting for age and sex. These findings suggest that evaluating the mutual relationships among sensory organs is important when evaluating the influence of sensory dysfunctions on cognitive function., Competing Interests: Nidek Co., Ltd. provided survey instruments for the vision test during the health checkup. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Katayama, Yoshida, Nakashima, Ito, Teranishi, Iwase, Sugiura, Goto, Uchida, Taki, Nakada, Tada, Suzuki, Nakano, Shimono, Saji, Kogure, Shimizu, Sone and Hamajima.)

A successful hepatic-to-azygos vein redirection was performed in a patient with absent inferior vena cava using a long vascular graft to address a pulmonary arterio-venous fistula after a failed Fontan conversion. No exacerbation was observed 5 years postoperatively., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer, and current treatments are only partially effective in disease control. More effective combination approaches are needed to improve the survival of TNBC patients. Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, is approved by the U.S. Food and Drug Administration to treat metastatic breast cancer after at least two previous chemotherapeutic regimens. However, eribulin as a single agent has limited therapeutic efficacy against TNBC., Methods: High-throughput kinome library RNAi screening, Ingenuity Pathway Analysis, and STRING analysis were performed to identify target kinases for combination with eribulin. The identified combinations were validated using in vivo and ex vivo proliferation assays., Results: We identified 135 potential kinase targets whose inhibition enhanced the antiproliferation effect of eribulin in TNBC cells, with the PI3K/Akt/mTOR and the MAPK/JNK pathways emerging as the top candidates. Indeed, copanlisib (pan-class I PI3K inhibitor), everolimus (mTOR inhibitor), trametinib (MEK inhibitor), and JNK-IN-8 (pan-JNK inhibitor) produced strong synergistic antiproliferative effects when combined with eribulin, and the PI3K and mTOR inhibitors had the most potent effects in vitro., Conclusions: Our data suggest a new strategy of combining eribulin with PI3K or mTOR inhibitors to treat TNBC.

Purpose: To evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with central retinal artery occlusion (CRAO)., Methods: Five eyes of five patients with CRAO underwent TdES (10-ms biphasic pulses, 20 Hz, 30 min) six times at 2-week intervals. Only the affected eye was stimulated with 1.0-mA pulses in all patients. The primary endpoint was the best-corrected logMAR visual acuity. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, mean deviation of the Humphrey field analyzer (HFA) 10-2, and HFA Esterman test score. We also evaluated its safety., Results: The logMAR visual acuity at 12 weeks was improved by 0.1 or more in two patients and was maintained in two patients compared to the baseline. No obvious changes in the mean logMAR visual acuity, ETDRS visual acuity, mean deviation, and HFA Esterman score were observed at 12 weeks compared to the baseline. All five enrolled patients completed the study according to the protocol. No treatment-related adverse events were observed during this study., Conclusion: In this study, logMAR visual acuity was slightly improved in two patients, confirming the safety of TdES. Since CRAO has no established treatment method, further research into the effects of TdES treatment in CRAO patients may be beneficial., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Miura 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.)