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Background: To address antibiotic overuse, the Japanese government implemented a novel financial incentive policy in 2018. The policy enables eligible healthcare facilities to claim 800 JPY (≈5.7 USD) per case wherein a rationale to not prescribe antibiotics is offered to children aged <3 years with acute upper respiratory tract infections or gastroenteritis. Although the short-term effect of this policy was observed in our previous study, its long-term effects have not been evaluated nationwide., Methods: We conducted a quasi-experimental study using a staggered difference-in-differences design with propensity score matching. Data from 165,113 children born between April 2017 and March 2019 were extracted from two nationwide administrative databases. The study tracked these children until May 2022, comparing those exposed to the policy with those who were not., Results: The introduction of financial incentives led to a 44.9% reduction (95%CI, 41.1% to 47.7%) in total antibiotic prescriptions within the first month and 19.5% reduction (95%CI, 8.7% to 29.1%) over 48 months. Broad-spectrum antibiotic use also decreased by 24.4% (95%CI, 14.0% to 33.6%) over the same period. The policy did not result in increased hospitalizations, after-hours visits, or healthcare costs, but was associated with a slight increase in the number of office visits. A dose-response relationship was observed, with reductions in antibiotic use leveling off after approximately five incentives., Conclusions: Financial incentives effectively reduced antibiotic prescriptions in children without adverse health outcomes, demonstrating sustained benefits over four years. This antimicrobial stewardship intervention offers a scalable model for other countries aiming to curb antibiotic overuse and combat antimicrobial resistance., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Lymph node (LN) metastasis is a poor prognostic factor in patients with prostate cancer. Elucidating the mechanisms underlying cancer progression in the metastatic microenvironment of LNs is crucial to establishing novel therapies. Adipocytes interact with cancer cells and regulate cancer progression. In this study, we aimed to clarify the clinicopathological significance of extranodal adipose tissue invasion in metastatic LNs and preoperative adipokine concentration in patients with prostate cancer exhibiting metastatic LNs., Methods: We examined the pathological findings of primary and metastatic nodes and clinical information of 66 specimens from 46 patients with prostate cancer. A sub-analysis was performed to assess the relationship between preoperative adiponectin/leptin concentrations and clinical/pathological findings in the blood samples of 56 patients with prostate cancer who either did or did not show LN metastasis., Results: The number of metastatic LNs in patients correlated with the involvement of adipose tissue and lymphovascular invasion (p = 0.039 and < 0.001, respectively). Preoperative adiponectin concentration was lower in patients with resected margin-positive and extraprostatic extension-positive primary cancers (p = 0.0071 and 0.02, respectively). Preoperative adiponectin concentrations were significantly lower in patients with metastatic LNs than in patients without LN metastasis (p < 0.001). Moreover, leptin concentrations were significantly higher in patients with metastatic LNs than in patients without LN metastasis (p < 0.001). In patients with metastatic LNs, preoperative adiponectin concentrations were significantly lower in patients with biochemical recurrence than in patients without biochemical recurrence (p = 0.031). There was no correlation between biochemical recurrence and pathological findings., Conclusions: This is the first report on the detailed histopathological characteristics of prostate cancer with LN metastases and the significance of preoperative adiponectin concentration in predicting the pathological features of primary cancers. Also, adipokines are a significant prediction factor of LN metastases for prostate cancer patients. Adipose tissue and adipose-secreting factors may be involved in the progression of metastatic and primary prostate cancer., (© 2024 Wiley Periodicals LLC.)

Formalin-fixed paraffin-embedded (FFPE) tissue samples are important for genomic analysis of thyroid carcinomas, particularly for various molecularly targeted therapies. Therefore, this study developed and validated a technique for preparing FFPE tissue samples that preserves nucleic acid quality, which is fundamental for precise genomic analysis, more effectively than conventional methods. We analyzed surgically resected thyroid gland tumors, lymph node metastases, and separately fixed tumor samples to optimize formalin fixation and assess the influence of specimen type and preparation methods on nucleic acid quality. We assessed several quality indicators, including the DNA integrity number, cycle threshold ratio, RNA integrity number, and DV200. Separately fixed tumor samples consistently exhibited higher DNA and RNA quality than conventionally processed samples. Additionally, lymph node metastases often exhibit nucleic acid quality matching or exceeding that of thyroid gland tumors, highlighting their potential reliability for genomic analysis. These findings suggest the utility of various specimen types for the comprehensive genetic profiling of thyroid carcinomas. In conclusion, this study demonstrated that preparing separately fixed tumor samples is an effective method for preserving DNA and RNA quality for genomic analyses. Biopsy punches enable specimen collection at various facilities, including those without the ability to handle frozen specimens. This contributes to the development of a method for obtaining high-quality pathological samples that can be widely used in general medical practice. Moreover, lymph node metastases often exhibit nucleic acid quality equal to or superior to that of thyroid gland tumors, highlighting their potential as acceptable sources for genomic analyses., Competing Interests: Declarations Ethics Approval and Consent to Participate Written informed consent was obtained from all patients for participation and publication of the study data. This study was performed in accordance with the tenets of the Declaration of Helsinki and approved by the Ethics Review Committee of Kanagawa Cancer Center (Approval No.: 2022-Eki-121). Competing Interests The authors declare no competing interests., (© 2024. The Author(s).)

Lipodystrophy and obesity are associated with insulin resistance and metabolic syndrome accompanied by fat tissue dysregulation. Here, we show that serine protease inhibitor A1 (SerpinA1) expression in the liver is increased during recovery from lipodystrophy caused by the adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces the proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to increased energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. SerpinA1 forms a complex with the Eph receptor B2 and regulates its downstream signaling in adipocytes. These results demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Cases of severe pectus excavatum presenting with worsening cardiopulmonary symptoms in the upright position have been reported. However, the underlying mechanism remains unclear. We evaluated posture-related morphological changes of the thorax in patients with pectus excavatum., Methods: Chest morphology was evaluated preoperatively using upright and supine computed tomography in 21 patients with pectus excavatum and 35 healthy volunteers. The minimum anterior-posterior thoracic diameter, depression depth, and Haller index on horizontal sections, as well as the T6-12 plumb line distance on sagittal sections, were compared between the two positions., Results: In patients with pectus excavatum (median age, 22 years; 18 males and 3 females), the minimum anterior-posterior diameter was smaller (4.5 vs 5.1 cm, P < 0.001) and the Haller index was greater (10.1 vs 6.4, P < 0.001) in the upright position than in the supine position. The T6-T12 plumb line distance was longer in the upright position (2.4 vs 0.8 cm, P < 0.001), while the depression depth showed no significant difference. Healthy volunteers exhibited similar changes. The degree of spinal curvature increased in the upright position due to the anterior shift of the lower thoracic vertebrae, resulting in a shorter anterior-posterior diameter, irrespective of chest wall deformity. One patient with dyspnoea only in the upright position exhibited compression of the right inferior pulmonary vein only on upright computed tomography., Conclusions: The minimum anterior-posterior diameter is shorter in the upright position. This may explain the worsening of cardiopulmonary symptoms in patients with severe pectus excavatum when in an upright position., Clinical Trial Number: UMIN000036438 https://center6.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000041519., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Respiratory syncytial virus (RSV) poses a global health challenge, particularly among younger children. While the disease burden in Japan has been preliminarily quantified in short-term or inpatient settings, a comprehensive understanding of outpatient settings at a national level is still lacking., Methods: In this retrospective cohort study, we followed 697,802 children until they reached 60 months of age, amounting to 25,680,468 million person-months, using two nationally representative databases from the fiscal years 2005-2021. We analyzed trends in the epidemiology of RSV infections and associated outpatient health resource use., Results: Incidence rates of RSV and associated hospitalizations among infants showed fluctuations of 50-100 cases and 20-30 hospitalizations per 1000 person-years, respectively, during the 2010s. These rates dropped to 8.7 cases and 2.2 hospitalizations per 1000 person-years in 2020, then returned to the same levels in the 2010s. Similar patterns were noted for RSV testing, outpatient visits, healthcare cost and the proportion of cases hospitalized (case-hospitalization risk). Whereas antibiotic use decreased from 56.4% in 2005 to 27.8% in 2021, palivizumab use increased from 95.2-195.9 days of therapy per 1000 person-years. Applying the calculated incidence rates to national data, annual outpatient healthcare costs for RSV infections were estimated to be 7-9 billion JPY (50-64 million USD) for children aged <60 months in the late 2010s., Conclusions: Our study highlights the changes in epidemiology and outpatient health resource utilization for children with RSV infections. These findings are valuable for policymakers and clinicians aiming to develop strategies, including newly developed maternal vaccines and single-dose long-acting monoclonal antibodies., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

[Purpose] This study aimed to determine the effectiveness of the Arthrokinematic Approach (AKA)-Hakata method for patients with low back pain (LBP). [Participants and Methods] The participants were 39 patients with LBP who visited a medical facility between June 1, 2022, and November 30, 2022. The intervention period was 8 weeks, with five treatment sessions, and the patient assessments were performed using patient self-reported measures of LBP and motor function assessment. [Results] The AKA-Hakata method showed significant differences in all of the items evaluated in the longitudinal comparison of patients. Additionally, an interaction was observed only in the Roland-Morris Disability Questionnaire between the two groups classified using the Subgrouping for Targeted Treatment Back Screening Tool. [Conclusion] The results of this study showed that treatment with the AKA-Hakata method may have an early therapeutic effect on the physical and psychosocial risks in daily life. The results of this study indicated that the AKA-Hakata method is effective for the treatment of LBP. However, this study only evaluated a relatively short treatment period of five sessions. Further research on the long-term treatment effect is needed in order to optimize the treatment duration in detail and investigate the effectiveness of the AKA-Hakata method., Competing Interests: None., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Inflammatory diseases that are driven by several pro-inflammatory cytokines has resulted in in the development of targeted therapies across different disease settings. Interleukin (IL)-36 cytokines have been implicated in several inflammatory diseases. In this review we describe the scientific evidence surrounding the use of the IL-36 receptor (IL-36R)-targeting antibody, spesolimab, in IL-36-mediated skin diseases: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), hidradenitis suppurativa, and Netherton syndrome (NS). Spesolimab, a high affinity, specific, humanized, antagonistic immunoglobulin G1 antibody, targets the IL-36R at a binding site distinct from its agonists, IL-36α/β/γ, and at least one endogenous antagonist, IL-36R antagonist. In vitro and in vivo data for spesolimab show effective inhibition of IL-36R-mediated signaling pathways, and six Phase I studies in healthy volunteers presented a favorable safety and pharmacokinetic (PK) profile, leading to the development of a clinical trial program to evaluate spesolimab in the treatment of IL-36R-mediated diseases. Six studies (including an expanded access program) have evaluated the efficacy, safety, PKs, and pharmacogenomics of spesolimab in patients with GPP flares. Spesolimab treatment of GPP flares resulted in rapid and sustained improvements in pustular and skin clearance, and clinically significant improvements in patient-reported symptoms and quality of life. Spesolimab also significantly reduces the risk of GPP flares and flare occurrence, preventing disease worsening and has a favorable safety profile. There have been three trials of spesolimab in PPP; further evaluation is needed to better define those patients who might benefit from the treatment. A trial of spesolimab in NS is ongoing, while other spesolimab trials suggest that IL-36 may only play a secondary role in the pathogenesis of atopic dermatitis. In conclusion, research into spesolimab has provided much needed insight into the role of IL-36 in the human immune system and the mechanism behind IL-36-mediated inflammatory diseases. Spesolimab provides an efficacious targeted treatment for GPP, a disease with a high unmet medical need., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Introduction: Physical activity (PA) is widely accepted as a therapeutic approach to age-related muscle mass loss. However, it is unclear whether all PA domains benefit muscle mass maintenance. This study investigated the association between low muscle mass and domain-specific-PA, including leisure-time and occupational moderate-to-vigorous-PA (MVPA)., Methods: This study included 27,357 middle-aged and older individuals (≥40 years) whose data were collected from 2014 to 2022 and analyzed in 2024. Low muscle mass was defined as a muscle mass index two standard deviations below the sex-specific average of 9426 young individuals (20-39 years). Leisure-time and occupational MVPA were assessed using the Global Physical Activity Questionnaire and categorized as 0 min/week, 1-149 min/week, and ≥150 min/week. Logistic regression analysis focused on all participants, and additional analyses stratified by sex, age, sedentary time, and transfer time were performed., Results: For leisure-time MVPA, participants with 1-149 min/week and ≥150 min/week had significantly lower odds of low muscle mass compared to those with no MVPA, with ORs of 0.795 (95% CI: 0.691, 0.914) and 0.740 (95% CI: 0.649, 0.843), respectively (p<0.01 for both). No significant association was found between occupational MVPA and low muscle mass. These findings were consistent across different strata of sex, age, sedentary time, and transfer time., Conclusions: Leisure-time MVPA is inversely associated with low muscle mass, whereas occupational MVPA shows no association, highlighting the importance of dynamic movements of sufficient intensity and recuperation time in maintaining muscle mass., (Copyright © 2024. Published by Elsevier Inc.)

Thymoma-associated multiorgan autoimmunity (TAMA) presents with skin symptoms similar to those of graft-versus-host disease (GVHD), liver dysfunction, and enteritis, in the absence of a history of hematopoietic stem cell or bone marrow transplantation. TAMA is a type of paraneoplastic syndrome associated with thymoma. Its etiology is unclear but is thought to be a result of breakdown of immune tolerance. Histopathologically, TAMA is characterized by epidermal acanthosis with parakeratosis, individual cell keratinization, liquefaction degeneration, and intraepidermal infiltration of CD8-positive lymphocytes. A 64-year-old female patient with a history of myasthenia gravis and thymoma treated with prednisolone (10 mg/day) and cyclosporine (150 mg/day) experienced erythema on her trunk after coronavirus disease 2019 (COVID-19) onset. A psoriatic drug eruption was suspected and the possible causative drug was discontinued, but the skin rash failed to improve. A skin biopsy demonstrated GVHD-like histopathological findings. Diarrhea, abdominal pain, and duodenal perforation occurred concurrently, leading to the diagnosis of TAMA. Thereafter, the patient continued prednisolone and cyclosporine in the same doses as the TAMA treatment and added topical steroids. During the disease course, candida fungemia and cytomegalovirus infection developed, resulting in the patient's death. The TAMA was considered to have been caused by the release of inflammatory cytokines, autoreactive T cell activation, and regulatory T cell dysfunction induced by COVID-19., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Competing Interests: Disclosures All authors report no disclosures or conflicts of interest.

Objectives: The Nuss procedure, a minimally invasive surgery for pectus excavatum, has undergone various improvements. However, the impact of using multiple bars on thoracic shape changes and surgical outcomes remains unclear., Methods: We retrospectively evaluated patients who underwent the Nuss procedure for pectus excavatum between August 2014 and September 2021. We divided the patients into 2 groups based on the number of bars placed and identified differences in surgical outcomes and morphological characteristics., Results: A total of 225 patients were evaluated, of whom 132 were classified into the ≤2 bar group (using 1 or 2 bars) and 93 into the ≥3 bar group (using 3 or more bars). There was no difference in the preoperative Haller index [median (interquartile range), 4.59 (3.67-6.16) vs 4.67 (4.12-6.14), P = 0.227], and asymmetric excavatum was more frequently observed in the ≥3 bar group (81% vs 51%, P < 0.001). The preoperative sternal torsion angle was larger in the ≥3 bar group, but no difference was found between the 2 groups postoperatively. The incidence of postoperative complications (≥grade 3) was comparable between groups (10% vs 17%, P = 0.105); however, postoperative pleurisy was more frequently observed in the ≥3 bar group (12% vs 4%, P = 0.021). In univariable and multivariable analyses, ≥3 bar placement was the only risk factor for postoperative pleurisy., Conclusions: The placement of multiple bars (≥3 bars) is useful for the correction of asymmetric pectus excavatum, but attention should be paid to the potential risk of postoperative pleurisy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Aim: To examine if a novel reactive balance training program (ReacStep) designed for clinical settings is acceptable to clinicians prescribing balance and mobility training., Methods: ReacStep consists of tether-release reactive step training, volitional trip and slip training, and functional strength training. An open survey comprising 11-point visual analog scale items (0 = strongly disagree to 10 = strongly agree) based on the Theoretical Framework of Acceptability was sent to clinicians working in balance and mobility training. Items evaluated the acceptability of ReacStep across seven domains (intervention coherence, perceived efficacy, self-efficacy, ethicality, affective attitude, burden and opportunity cost)., Results: Two hundred and seven clinicians (169 Physiotherapists, 22 Exercise Physiologists, 11 Occupational Therapists and five others) completed the survey. Respondents considered ReacStep to have good overall acceptability, intervention coherence, effectiveness, ethicality and self-efficacy (mean acceptability scores >7). However, respondent's ratings of ReacStep's affective attitude, burden and opportunity cost were more variable (mean acceptability scores 2-8) due to concerns about client anxiety, the need for a safety harness and staffing and training requirements. Respondents considered that ReacStep would be more effective and safer to conduct in geriatrics clients compared with neurological clients, and that it would be more appropriate for rehabilitation and private practice settings compared to home settings., Conclusions: ReacStep was generally acceptable from the perspective of clinicians who prescribe balance and mobility training in various clinical settings, and was deemed more effective and safer for older clients without neurological conditions, and beneficial in outpatient rehabilitation and private practice settings., (© 2024 The Author(s). Physiotherapy Research International published by John Wiley & Sons Ltd.)

Psoriatic disease (PsD) is a chronic disease affecting skin (psoriasis) and joints (psoriatic arthritis, PsA) that has a significant impact on patients' quality of life (QOL). We report findings from the Japanese subgroup of patients included in Psoriasis and Beyond: The Global Psoriatic Disease Survey, a cross-sectional, quantitative online survey of patients with self-reported, healthcare professional (HCP)-diagnosed, moderate-to-severe plaque psoriasis, with or without PsA. Eligible patients who were recruited online completed a 25-min internet-based survey in Japanese. We assessed patients' understanding of the systemic nature of PsD, disease burden, perception towards their HCPs, treatment expectations, and satisfaction with care. Of the 148 patients, 74% were females. In total, 65% of patients were aware of the systemic nature of their disease. A minority of patients (27%) were aware that PsA was related to their psoriasis, and 30% and 42% of patients were unaware of any manifestations and comorbidities, respectively, related to PsD. Overall, 21% of patients reported that their disease has a "very large" to "extremely large" impact on their QOL (assessed by Dermatology Life Quality Index score), while the majority (61%) reported a "small" effect or "no effect" at all on QOL. Patients experienced stigma and discrimination and had a negative impact on relationships due to PsD. More patients with psoriasis and concomitant PsA (66%) were satisfied with their current treatment than those with psoriasis alone (46%). Overall, 41% of patients were not involved in deciding their treatment goals. These results suggest that Japanese patients may not be fully aware of the systemic nature of PsD, its manifestations and comorbidities. While these patients were somewhat satisfied with their current treatment, they were only occasionally consulted in deciding treatment goals. Policy measures are required to address the stigma and discrimination experienced by patients. Increased patient participation in their care supports shared decision-making and enhanced treatment outcomes., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Background: This study examined (i) adaptations in muscle activity following perturbation-based balance training (PBT) using treadmill belt-accelerations or PBT using walkway trips and (ii) whether adaptations during treadmill PBT transfer to a walkway trip., Methods: Thirty-eight older people (65+ years) undertook two PBT sessions, including 11 treadmill belt-accelerations and 11 walkway trips. Surface electromyography (EMG) was measured bilaterally on the rectus femoris (RF), tibialis anterior (TA), semitendinosus (ST) and gastrocnemius medial head (GM) during the first (T1) and eleventh (T11) perturbations. Adaptations (within-subjects - 1st vs 11th perturbations for treadmill and walkway PBT) and their transfer (between-subjects - 1st walkway trip after treadmill PBT vs 1st walkway trip with no prior training) effects were examined for the EMG parameters., Results: Treadmill PBT reduced post-perturbation peak muscle activation magnitude (left RF, TA, ST, right RF, ST, GM), onset latency (right TA), time to peak (right RF) and co-contraction index (knee muscles) (P < 0.05). Walkway PBT reduced post-trip onset latencies (right TA, ST), peak magnitude (left ST, right GM), time to peak (right RF, ST) and pre-perturbation muscle activity (right TA) (P < 0.05). Those who undertook treadmill PBT were not different to those without prior training during the first walkway trip (P > 0.05)., Conclusions: Both treadmill and walkway PBT induced earlier initiation and peak activation of right limb muscles responsible for the first recovery step. Treadmill PBT also reduced co-contraction of the knee muscles. Adaptations in muscle activity following treadmill PBT did not transfer to a walkway trip., 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 B.V.)

Introduction: The early detection of gastric neoplasms (GNs) leads to favorable treatment outcomes. The latest endoscopic system, EVIS X1, includes third-generation narrow-band imaging (3G-NBI), texture and color enhancement imaging (TXI), and high-definition white-light imaging (WLI). Therefore, this randomized phase II trial aimed to identify the most promising imaging modality for GN detection using 3G-NBI and TXI., Methods: Patients with scheduled surveillance endoscopy after a history of esophageal cancer or GN or preoperative endoscopy for known esophageal cancer or GN were randomly assigned to the 3G-NBI, TXI, or WLI groups. Endoscopic observations were performed to detect new GN lesions, and all suspected lesions were biopsied. The primary endpoint was the GN detection rate during primary observation. Secondary endpoints were the rate of missed GNs, early gastric cancer detection rate, and positive predictive value for a GN diagnosis. The decision rule had a higher GN detection rate between 3G-NBI and TXI, outperforming WLI by >1.0%., Results: Finally, 901 patients were enrolled and assigned to the 3G-NBI, TXI, and WLI groups (300, 300, and 301 patients, respectively). GN detection rates in the 3G-NBI, TXI, and WLI groups were 7.3, 5.0, and 5.6%, respectively. The rates of missed GNs were 1.0, 0.7, and 1.0%, the detection rates of early gastric cancer were 5.7, 4.0, and 5.6%, and the positive predictive values for the diagnosis of GN were 36.5, 21.3, and 36.8% in the 3G-NBI, TXI, and WLI groups, respectively., Discussion: Compared with TXI and WLI, 3G-NBI is a more promising modality for GN detection., (Copyright © 2024 by The American College of Gastroenterology.)

The effectiveness of a hybrid closed-loop (HCL) system in improving glycemic control is unclear in Japanese individuals. Therefore, we assessed the effect impact of the MiniMed 770G HCL system on glycemic control in this population. This prospective, single-center, 24-week observational study (registration number: UMIN000047394) enrolled 23 individuals with type 1 diabetes mellitus using the Medtronic MiniMed 640G system. The primary endpoint was the improvement in time in the range of 70-180 mg/dL after transitioning to the MiniMed 770G HCL system. We observed an increase in time in range (from 64.1 [55.8-69.5] to 70.9 [67.1-74.4] %, interquartile range 25-75%, p < 0.001) and a decrease in glycated hemoglobin level (from 7.4 [7.0-7.9] to 7.1 [6.8-7.4] %, p = 0.003). There was a significant reduction in time above the range (181-250 mg/dL: 25.8 [20.9-28.6] to 19.5 [17.1-22.1] %, p < 0.001; >251 mg/dL: 8.7 [4.0-13.0] to 4.7 [3.6-9.1] %, p < 0.001). Time below the range remained unchanged (54-69 mg/dL: 1.8 [0.4-2.4] to 2.1 [0.4-3.9] %, p = 0.24; <54 mg/dL: 0.2 [0.0-1.0] to 0.5 [0.1-1.3] %, p = 0.14). In a subgroup of 12 patients with a high HCL implementation rate, the basal insulin infusion decreased immediately after mealtime insulin administration and increased after approximately 120 minutes. The ratings from questionnaires assessing treatment burden, satisfaction, and quality of life remained unchanged. The MiniMed 770G HCL system improved glycemic control and optimized insulin delivery, particularly in patients with high implementation rates.

Objectives: Digital gait biomarkers collected from body-worn devices can remotely and continuously collect movement types, quantity, and quality in real life. This study assessed whether digital gait biomarkers from a wrist-worn device could identify people with frailty in a large sample of middle-aged and older adults., Design: Cross-sectional study., Setting and Participants: A total of 5822 middle-aged (43-64 years) and 4344 older adults (65-81 years) who participated in the UK Biobank study., Measures: Frailty was assessed using a modified Fried's frailty assessment and was defined as having ≥3 of the 5 frailty criteria (weakness, low activity levels, slowness, exhaustion, and weight loss). Fourteen digital gait biomarkers were extracted from accelerometry data collected from wrist-worn sensors worn continuously by participants for up to 7 days., Results: A total of 238 (4.1%) of the middle-aged group and 196 (4.5%) of the older group were categorized as frail. Multivariable logistic regression analysis revealed that less daily walking (as assessed by step counts), slower maximum walking speed, and increased step time variability best-identified people with frailty in the middle-aged group [area under the curve (95% CI): 0.70 (0.66-0.73)]. Less daily walking, slower maximum walking speed, increased step time variability, and a lower proportion of walks undertaken with a manual task best-identified people with frailty in the older group [0.73 (0.69-0.76)]., Conclusions and Implications: Our findings indicate that measures obtained from wrist-worn wearable devices worn in everyday life can identify individuals with frailty in both middle-aged and older people. These digital gait biomarkers may facilitate screening programs and the timely implementation of frailty-prevention interventions., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4-44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype-genotype correlation., (© 2024 Wiley Periodicals LLC.)

Background: The COVID-19 pandemic posed substantial challenges to healthcare systems. Understanding the responses of pediatric health services is crucial for future pandemic planning and preparedness, yet such data remains limited., Methods: In this retrospective cohort study, we analyzed data from administrative databases developed by Japan Medical Data Center and DeSC Healthcare Inc. The dataset comprised records of 2,612,511 children, totaling 60,224,888 person-months, from January 2020 to May 2022. Multivariate generalized estimation equations were used to examine the incidence rates of COVID-19 and associated health resource use., Results: Our analysis revealed that the incidence rates of COVID-19 gradually increased from Wave I (2.2 cases per 100,000 person-months) to Wave V (177.8cases per 100,000 person-months), with a notable elevation during Wave VI (2367.7 cases per 100,000 person-months). While nucleic acid amplification tests were primarily used during Waves I-V, the use of rapid antigen tests markedly increased in Wave VI. The hospitalization rates increased gradually from 0.2 in Wave I to 10.2 events per 100,000 person-months in Wave VI, and the case-hospitalization risk decreased from 14.9% in Wave II to 0.7% in Wave VI. Additionally, we observed decreasing trends in the use of antibiotics (Wave I, 31.8%; Wave VI, 9.0%), whereas antipyretic use rose from Wave I (56.1%) to Wave VI (86.6%)., Conclusions: Our study highlighted essential changes in the nationwide pediatric healthcare system's response to the COVID-19 pandemic. These findings provide valuable insights into the future pandemic planning and preparedness., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: The risk of fungal infection in patients with psoriasis receiving biologics is not fully understood in clinical practice., Objective: To assess the incidence and the risk of fungal infection onset in patients with psoriasis receiving biologics., Methods: A retrospective cohort study of 592 psoriasis cases treated with biologics at a single center., Results: Seventy-three (12.3%) of the 592 cases involved a fungal infection. Fungal infection occurrence was more frequently associated with the use of interleukin (IL) 17 inhibitors than of other biologics. The risk factors of fungal infection were the type of biologic agent (P = .004), age at the start of biologic therapy (odds ratio, 1.04; 95% CI, 1.02-1.06), and diabetes mellitus (odds ratio, 2.40; 95% CI, 1.20-4.79)., Limitations: The present, retrospective study did not include patients who did not receive biologic therapy. Moreover, the type of biologic agent used was changed in many cases., Conclusions: Patients with psoriasis treated with IL-17 inhibitors were more likely to cause fungal infections, especially candidiasis, than other biologics. Moreover, the age at the start of biologic therapy and diabetes mellitus onset were also independent risk factors of fungal infection., Competing Interests: Conflicts of interest Dr Minami has been a speaker for AbbVie∗, Taiho Pharmaceutical∗, Janssen Pharmaceuticals∗, and Maruho∗. Dr Mori has received honoraria from Kyowa Kirin∗, Maruho∗, and Taiho Pharmaceutical∗. Dr Abe has received honoraria from Boehringer Ingelheim∗, Maruho∗, Kyowa Kirin∗, Taiho Pharmaceutical∗, GRAFA Laboratories, Sun Pharma∗, UCB Pharma∗, Janssen Pharmaceuticals∗, Japan Tissue Engineering, Amgen, Bristol Myers Squibb, AbbVie∗, and Syneos Health Commercial. Dr Kazutoshi Harada received research grants from Maruho∗, Taiho Pharmaceutical∗, Kaken Pharmaceutical, AbbVie∗, Sun Pharma∗, Eli Lilly∗, and Pfizer and has been a speaker for Sato Pharmaceutical, Eisai∗, Eli Lilly∗, Pfizer, Sun Pharma∗, and Kaken Pharmaceutical. Dr Okubo has received honoraria from AbbVie∗, Amgen, Boehringer Ingelheim∗, Bristol Myers Squibb, Eli Lilly∗, Janssen Pharmaceuticals∗, Kyowa Kirin∗, Leo Pharma, Maruho∗, Otsuka Pharmaceutical, Pfizer, Sanofi, Sun Pharma∗, Taiho Pharmaceutical∗, Tanabe-Mitsubishi∗, and UCB Pharma∗. Drs Hiruma, Kazuharu Harada, Fujimori, Suzuki, and Okura have no conflicts of interest to disclose. Asterisks indicate manufacturers of biologics used for psoriasis in Japan., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Salvage surgery for primary lung cancer is expected to become increasingly common. This study aimed to clarify the survival impact of pathologic characteristics after salvage surgery., Methods: Consecutive patients who underwent salvage surgery following definitive chemoradiotherapy or systemic therapy for initially unresectable lung cancer from 2010 to 2020 were enrolled in this study. The tumor slides were reviewed to determine the size of the tumor bed and the proportions of viable tumor, necrosis, and stroma., Results: A total of 23 patients were evaluated, and 18 had clinical stage IIIB-IV disease. Six received chemoradiotherapy and 17 received systemic therapy alone. A major pathologic response (MPR, ≤ 10% of viable tumor) was observed in 6 patients, and 4 patients achieved a pathological complete response. The 3-year overall and recurrence-free survival rates (OS and RFS) were 78.6% and 59.2%, respectively. There was no significant difference in OS between patients with and without MPR, and even non-MPR patients achieved a favorable 3-year OS of 70.2%. Meanwhile, patients with high (≥ 30%) stroma showed significantly better OS than those with low (< 30%) stroma (3-year OS: 100% vs. 23.3%, p < 0.001)., Conclusions: This study showed that the proportion of stroma can be useful for predicting long-term survival after salvage surgery. Further large-scale studies are warranted to confirm the current findings., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Toll-like receptors (TLRs) form a key bridge between the innate and adaptive immune systems. The lipopeptide based TLR2 agonists such as Pam 2 CSK 4 are promising vaccine adjuvants but drawbacks include its surfactant like nature and cumbersome synthesis. Although the TLR2 activity of Pam 2 CS-OMe is commensurate with Pam 2 CSK 4 , its water solubility is much less, rendering it ineffective for clinical use. In the present investigation, we designed a synthesis pathway for a novel water-soluble TLR2-active analogue, Pam 2 CS-DMAPA (13), which enhanced the immunogenicity of recombinant SARS-CoV2 and hepatitis B antigens in mice. Co-formulation of compound 13 with 2 % aluminium hydroxide gel led to a further significant improvement in vaccine immunogenicity. This synthetically simpler compound 13 was water soluble and equally potent to Pam 2 CSK 4 adjuvant, but was superior in terms of manufacturing simplicity and scalability. This makes compound 13 a promising TLR2 targeted adjuvant for further development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Deepak B. Salunke reports financial support and administrative support were provided by Panjab University. Prof. Nikolai Petrovsky reports financial support was provided by National Institute of Allergy and Infectious Diseases. Prof. Nikolai Petrovsky and Dr. Deepak B. Salunke reports financial support was provided by Global Connections Fund. Dr. Deepak B. Salunke reports financial support was provided by Ministry of Human Resources, Government of India. If there are other authors, they 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 Elsevier Inc. All rights reserved.)

Objective Atrial fibrillation (AF) is the most common cause of tachycardia-induced cardiomyopathy (TIC). However, which patients with AF are prone to developing TIC remains unclear. In this study, we investigated the clinical features of AF patients with TIC. Methods This single-center study included 722 patients with AF (average age, 63.1±10.2 years old; 191 women) who underwent radiofrequency catheter ablation. We defined TIC as an initial left ventricular ejection fraction (LVEF) of <40% and a >20% recovery of the LVEF after successful AF ablation and compared the clinical characteristics between the TIC and control groups. Results The proportions of type 2 diabetes (30.5% vs. 14.7%), renal dysfunction (34.2% vs. 23.8%), hypertension (67.1% vs. 54.8%), and persistent AF (62.2% vs. 32.2%) were significantly higher in the TIC group (n=82) than in the control group (n=640). The atrioventricular nodal effective refractory period (AVNERP) (303±72 ms vs. 332±86 ms; p=0.017) was significantly shorter in the TIC group than in the control group. A multivariable analysis found that persistent AF [odds ratio (OR), 3.19; 95% confidence interval (CI), 1.94-5.24], renal dysfunction (OR, 1.87; 95% CI, 1.06-3.32), and type 2 diabetes (OR, 2.30; 95% CI, 1.31-4.05) were significantly associated with TIC. Conclusion Comorbid renal dysfunction and type 2 diabetes were clinical features of AF patients with TIC. Persistent AF, and short AVNERP may be involved in the development of TIC.

Study Design: Single institution observational study., Objectives: To investigate the ceiling and floor effects of the Berg Balance Scale (BBS), Mini-Balance Evaluation Systems Test (BESTest), and Brief-BESTest, as well as to determine the intra- and inter-rater reliabilities and minimal detectable change (MDC) of the Mini-BESTest and Brief-BESTest in patients with acute and subacute incomplete cervical spinal cord injury (SCI) classified as AIS D., Setting: Advanced critical care center of our university hospital., Methods: Twenty patients with incomplete cervical SCI who could stand without assistance were recruited. The floor and ceiling effects were evaluated by plotting histograms from the distribution of scores on the BBS, Mini-BESTest and Brief-BESTest, and calculating skewness. The Mini-BESTest and Brief-BESTest were evaluated and videotaped simultaneously, and intra- and inter-rater reliabilities were assessed. The MDC was also calculated., Results: The skewness of the BBS was -1.57, and the full score was 35%, indicating a ceiling effect. However, no ceiling or floor effect was observed for the Mini-BESTest and the Brief-BESTest. Intraclass correlation coefficients for intra-rater and inter-rater reliabilities were 0.98 and 0.97 for the Mini-BESTest and Brief-BESTest, respectively. Individual item reliability was moderate or better for the Mini-BESTest and excellent or better for the Brief-BESTest. The MDC of total scores ranged 3.14-3.84 and 2.92-3.60 for the Mini-BESTest and Brief-BESTest, respectively., Conclusions: The Mini-BESTest and Brief-BESTest are reliable assessment tools for patients with acute and subacute incomplete SCI classified as AIS D. Clarified error ranges aid in estimating the treatment effect on balance abilities., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.)

Our objective was to establish consensus on (1) which patients with plaque psoriasis and limited skin involvement (body surface area [BSA] <10%) are suitable for systemic treatment, and (2) a definition of 'topical therapy failure'. A steering committee refined 13 statements drawn from literature related to the study objectives. An independent panel of 45 clinical experts from Japan indicated their agreement to each statement using a 10-point Likert scale (Round 1; strong consensus, ≥70% of responses = 7-10 and median value ≥8). The steering committee reviewed Round 1 results and refined the statements for Round 2, as necessary. In Round 2, the panel indicated their agreement to each statement using a 3-point scale (strong consensus, ≥70% of responses and median value of 3) and were shown Round 1 responses before voting. Forty-five clinicians participated in Round 1 and 41 of those (91%) participated in Round 2. Consensus was achieved on the criteria of eligibility for systemic treatment among patients with limited skin involvement as disease involvement at special or difficult to treat areas, psoriasis-induced psychological distress, uncontrolled symptoms (e.g., scaling, bleeding, pruritus, insomnia) affecting their social life, psoriatic arthritis, or failure of topical therapy. Consensus on criteria for topical failure were persistent symptoms (e.g., itchiness, pain) and plaques, poor patient satisfaction with treatment, a need to increase medication quantity or application time after treatment with two topicals for 4 weeks; or if the Psoriasis Area Severity Index score of >3 or Physician Global Assessment Score of ≥2 after 8 weeks treatment. Our Delphi panel proposes criteria to help physicians identify patients with psoriasis and limited skin involvement who would benefit from systemic therapy and suggests a definition for topical therapy 'failure' which could indicate a move to systemic treatment is warranted., (© 2024 Japanese Dermatological Association.)

Background: The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days., Methods: Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets., Results: Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options., Conclusions: We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs., (© 2024. The Author(s).)

The present case series examined five instances of psoriasiform drug eruption diagnosed between 2014 and 2022 at the study site and 23 cases of drug eruption manifesting psoriasiform lesions which had been reported between 1986 and 2022. The causative drug, distribution of the skin eruptions, clinical latency to eruption, treatment course, and histopathological findings were investigated. The most common causative agents were calcium channel blockers (CCB) (64.5%). Of the 28 cases of psoriasiform drug eruption for which details of the eruption sites were reported, 46.4% occurred on the face, which was slightly higher than the usual distribution of psoriasis. CCB were responsible for 80.0% of the cases of facial skin rash. The mean time from the administration of the suspected drug to eruption onset was 25.0 months (range: 0.5-120 months; median: 13.0 months). In all the cases, the skin rash improved after the causative drug was discontinued. CCB were the most common causative agent, and the eruptions more commonly occurred on the face than in normal psoriasis, suggesting that it is especially important to confirm whether there is a history of CCB administration in psoriasis patients with extensive, facial skin eruptions., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: Palmoplantar pustulosis (PPP), a refractory skin disease characterized by repeated eruptions of sterile pustules and vesicles on palms and/or soles, involves interleukin-17 pathway activation. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, is being investigated for use in PPP treatment., Objective: The aim was to assess the efficacy and safety of brodalumab in Japanese PPP patients with moderate or severe pustules/vesicles., Methods: A phase 3, randomized, double-blind, placebo-controlled trial was conducted between July 2019 and August 2022, at 41 centers in Japan. Patients aged 18-70 years with a diagnosis of PPP for ≥ 24 weeks, a PPP Area Severity Index (PPPASI) score of ≥ 12, a PPPASI subscore of pustules/vesicles of ≥ 2, and inadequate response to therapy were included. Participants were randomized 1:1 to receive brodalumab 210 mg or placebo, subcutaneously (SC) at baseline, weeks 1 and 2, and every 2 weeks (Q2W) thereafter until week 16. Changes from baseline to week 16 in the PPPASI total score (primary endpoint) and other secondary skin-related endpoints and safety endpoints were assessed., Results: Of the 126 randomized patients, 50 of 63 in the brodalumab group and 62 of 63 in the placebo group completed the 16-week period. Reasons for discontinuation were adverse event (n = 6), withdrawal by patient/parent/guardian (n = 3), progressive disease (n = 3), and lost to follow-up (n = 1) in the brodalumab group and Good Clinical Practice deviation (n = 1) in the placebo group. Change from baseline in the PPPASI total score at week 16 was significantly higher (p = 0.0049) with brodalumab (least-squares mean [95% confidence interval {CI}] 13.73 [10.91-16.56]) versus placebo (8.45 [5.76-11.13]; difference [95% CI] 5.29 [1.64-8.94]). At week 16, brodalumab showed a trend of rapid improvement versus placebo for PPPASI-50/75/90 response (≥ 50%/75%/90% improvement from baseline) and Physician's Global Assessment 0/1 score: 54% versus 24.2%, 36.0% versus 8.1%, 16.0% versus 0.0%, and 32.0% versus 9.7%, respectively. Infection was the dominant treatment-emergent adverse event (TEAE); the commonly reported TEAEs were otitis externa (25.4%/1.6%), folliculitis (15.9%/3.2%), nasopharyngitis (14.3%/4.8%), and eczema (14.3%/12.9%) in the brodalumab/placebo groups, respectively. The severity of most TEAEs reported was Grade 1 or 2 and less frequently Grade ≥ 3., Conclusions: Brodalumab SC 210 mg Q2W demonstrated efficacy in Japanese PPP patients. The most common TEAEs were mild infectious events., Trial Registration: NCT04061252 (Date of Trial Registration: August 19, 2019)., (© 2024. The Author(s).)

Thyroid carcinomas exhibit various genetic alterations, including the RET and NTRK fusion genes that are targets for molecular therapies. Thus, detecting fusion genes is crucial for devising effective treatment plans. This study characterized the pathological findings associated with these genes to identify the specimens suitable for genetic analysis. Thyroid carcinoma cases positive for the fusion genes were analyzed using the Oncomine Dx Target Test. Clinicopathological data were collected and assessed. Among the 74 patients tested, 8 had RET and 1 had NTRK3 fusion gene. Specifically, of the RET fusion gene cases, 6 exhibited "BRAF-like" atypia and 2 showed "RAS-like" atypia, while the single case with an NTRK3 fusion gene presented "RAS-like" atypia. Apart from one poorly differentiated thyroid carcinoma, most cases involved papillary thyroid carcinomas (PTCs). Primary tumors showed varied structural patterns and exhibited a high proportion of non-papillary structures. Dysmorphic clear cells were frequently observed. BRAF V600E immunoreactivity was negative in all cases. Interestingly, some cases exhibited similarities to diffuse sclerosing variant of PTC characteristics. While calcification in lymph node metastases was mild, primary tumors typically required hydrochloric acid-based decalcification for tissue preparation. This study highlights the benefits of combining morphological and immunohistochemical analyses for gene detection and posits that lymph node metastases are more suitable for genetic analysis owing to their mild calcification. Our results emphasize the importance of accurate sample processing in diagnosing and treating thyroid carcinomas., (© 2024. The Author(s).)

Background: TactiFlex is a next-generation catheter that is being used increasingly in ablation-treatment strategies. The purpose of this study was to investigate the differences in ablation lesions when the ablation power, time, and perfusion flow are varied with TactiFlex and TactiCath catheters., Methods: The TactiFlex and TactiCath catheters were contacted perpendicularly/obliquely/parallel to the swine myocardium at varying powers (30, 40, and 50 W), time points (10, 15, 20, 25, 30, and 40 s), and forces (5, 10, 15, 20, and 30 g); the depth, width, and area of each lesion were measured, and the number of steam pops that occurred was counted., Results: A total of 672 (336 lesions for each catheter) radiofrequency (RF) energy applications were delivered and 648 lesions were analyzed, excluding steam pops. The surface area and volume increased significantly with an increasing contact force for the TactiCath. The TactiCath lesions were significantly deeper than those for TactiFlex in most groups with the same power and seconds. The surface area was significantly larger when the catheters were contacted obliquely/parallel to the myocardium than perpendicularly using TactiCath, whereas the difference was less significant in the case of TactiFlex. In a 10-g contact force ablation experiment, TactiFlex did not cause pops, but TactiCath caused pops in 9.8% of cases., Conclusion: The TactiFlex lesions were shallower than those of TactiCath. However, TactiFlex catheters reduced the steam pops during RF applications. Those data should help clinicians understand the characteristics of the catheters and develop adequate strategies., (© 2024. The Author(s).)

The concept of pustulotic arthro-osteitis (PAO) was first reported by Sonozaki et al. in 1979, with diagnostic criteria (Sonozaki criteria) proposed in 1981. These criteria have served as the gold standard for PAO diagnosis for over 40 years. In recent years, there has been an increasing emphasis on maximizing the quality of life of patients with PAO. This is achieved by striving for clinical remission, structural remission, and functional remission through early diagnosis and appropriate therapeutic intervention from an early stage. This article is an English translation of a summary of the 'Modified PAO Diagnostic Guidance 2022', edited by the Japan Ministry of Health, Labour and Welfare's Research Group on improvement of medical standard and quality of life of patients with spondyloarthritis and related diseases represented by ankylosing spondylitis and the Japan Spondyloarthritis Society. This guidance is intended to be helpful to both Japanese and global communities in rheumatology and spondyloarthritis., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: The aim of the current study was to determine the safety and immunogenicity of trivalent inactivated influenza vaccine (TIV) alone or formulated with Advax delta inulin adjuvant in those who were older (aged >60 years) or had chronic disease., Methods: Over 4 consecutive years from 2008 through 2011, adult participants with chronic disease or >60 years of age were recruited into a randomized controlled study to assess the safety, tolerability and immunogenicity of Advax-adjuvanted TIV (TIV + Adj) versus standard TIV. The per-protocol population with ≥1 postbaseline measurement of influenza antibodies comprised 1297 participants, 447 in the TIV and 850 in the TIV + Adj) group., Results: No safety issues were identified. Variables negatively affecting vaccine responses included obesity and diabetes mellitus. Advax adjuvant had a positive impact on anti-influenza immunoglobulin M responses and on H3N2 and B strain seropositivity as assessed by hemagglutination inhibition., Conclusions: TIV + Adj was safe and well tolerated in individuals with chronic disease. There is an ongoing need for research into improved influenza vaccines for high-risk populations., Clinical Trials Registration: Australia New Zealand Clinical Trial Registry: ACTRN 12608000364370., Competing Interests: Potential conflicts of interest. Y. H. O. and N. P. are affiliated with Vaxine, which holds proprietary rights over Advax adjuvant. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Doege-Potter syndrome, characterized by solitary fibrous tumors and non-islet cell tumor hypoglycemia, is rare. Here, we report a case of Doege-Potter syndrome in which retroperitoneal tumor resection was performed with continuous intraoperative blood glucose monitoring., Case Presentation: A 37-year-old man presented with hypoglycemia-related symptoms, and a 10 × 12 × 9 cm tumor was found in his right kidney. Following tumor resection, insulin secretory abnormalities improved, and intraoperative blood glucose monitoring showed no hypoglycemic events. High levels of insulin-like growth factor-II confirmed the diagnosis of an insulin-like growth factor-II-producing tumor with non-islet cell tumor hypoglycemia. Postoperative serum insulin-like growth factor-II levels normalized, with no recurrence observed over 3 years., Conclusions: This case highlights the rarity of primary retroperitoneal Doege-Potter syndrome, emphasizes the safety of intraoperative blood glucose levels during surgery, and suggests rapid recovery of insulin secretion postoperatively., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca 2+ buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca 2+ -buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca 2+ facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca 2+ dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Background: Although left bundle branch area pacing (LBBAP) reportedly results in fewer adverse outcomes after implantation than conventional stylet-guided right ventricular septal pacing (RVSP), previous studies have not compared LBBAP with accurate RVSP using a delivery catheter. The aim of this study was to compare clinical outcomes between LBBAP and accurate RVSP among patients with atrioventricular block (AVB)., Methods: This single-center observational study enrolled 160 patients requiring RV pacing due to symptomatic AVB between September 2018 and December 2021. Primary composite outcomes included all-cause death, hospitalization due to heart failure (HF), and upgrading to biventricular pacing. Secondary composite outcomes included any procedural and postprocedural complications., Results: Overall, 160 patients were analyzed (LBBAP, n = 81; RVSP, n = 79). No significant differences in baseline characteristics were observed between the two groups. The RV pacing burden at 1 year after implantation was 90.8% ± 20.4% and 86.2% ± 22.6%, respectively (p = 0.21). During a mean follow-up of 840 ± 369 days, the incidence of the primary outcome was significantly lower with LBBAP (4.9%) compared to RVSP (22.8%) (Log-rank p = 0.02). There was no significant difference in the incidence of the secondary outcome between the two groups (3.7% vs. 5.1%, p = 0.65). In the multivariate analysis, baseline QRS duration, RV pacing burden, and LBBAP were independently associated with the primary outcome (baseline QRS duration: hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.00-1.02; p < 0.001; RV pacing burden: HR, 1.01; 95% CI, 1.00-1.02; p < 0.001; LBBAP: HR, 0.45; 95% CI, 0.31-0.64; p < 0.001)., Conclusion: In patients requiring frequent RV pacing, LBBAP was associated with reduced adverse clinical outcome compared to accurate RVSP using a delivery catheter., (© 2024. The Author(s).)

Toll-like receptor (TLR)-7/8 agonists are promising candidates for the development of new-generation vaccine adjuvants. Adsorption of TLR7/8 agonists on aluminum salts (alum) may further enhance vaccine immunogenicity. Evaluation of the adjuvanticity of the most active dual TLR7/8 agonists, 1-(3-(aminomethyl)benzyl)-2-butyl-1 H -imidazo[4,5- c ]quinolin-4-amine ( m -AM-BBIQ, 10 ) and its para derivative p -AM-BBIQ ( 11 ), along with their gallic acid and protocatechuic acid amides in a recombinant-protein-based COVID-19 vaccine platform confirmed the importance of vic -polyphenolic functionality in TLR7/8 agonists for the alum adsorption, thereby resulting in a balanced Th1/Th2 immune response. A novel 7,8-dihydroxy-IMDQ derivative (dh- p -AM-BBIQ, 21 ) was designed wherein the vic -diphenolic functionality was introduced in the quinoline ring of the imidazo[4,5- c ]quinoline scaffold. Compound 21 not only retained the TLR7 agonistic activity (EC 50 = 3.72 μM) but also showed high adsorption to alum and induced a potent antibody response to SARS-CoV-2 spike protein and hepatitis B surface antigen immunized mice. The combination adjuvant comprising compound 21 adsorbed to alum represents a promising candidate for further development as a human and veterinary vaccine adjuvant., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Background and Aims: There is a high incidence of stricture after endoscopic submucosal dissection (ESD) for cervical esophageal cancer. We aimed to elucidate the risk factors for stricture and to evaluate the efficacy of steroid injection for stricture prevention in the cervical esophagus., Methods: We retrospectively analyzed 100 patients who underwent ESD for cervical esophageal cancer to (1) identify the factors associated with stricture among patients who did not receive steroid injection, and (2) compare the incidence of stricture between patients with and without steroid injection., Results: Among 48 patients who did not receive steroid injection, there were significant differences in tumor size (P = .026), resection time (P = .028), and circumferential extent of the mucosal defect (P = .005) between patients with stricture (n = 5) and without stricture (n = 43). Compared with patients without steroid injection, patients with steroid injection had a significantly lower incidence of stricture when the post-ESD mucosal defect was <3/4 and ≥1/2 (40% versus 8%; P = .039). For the patients with a post-ESD mucosal defect of ≥3/4 (n = 13), local steroid injection was performed for all of them, and 6 (46%) developed stricture., Conclusions: Patients who underwent ≥1/2 circumferential resection were at high risk of cervical esophageal stricture. Steroid injection had a stricture prevention effect in patients with <3/4 and ≥1/2 circumferential resection, but seemed to be insufficient in preventing stricture in patients with ≥3/4 circumferential resection., Competing Interests: Disclosure The following authors disclosed financial relationships: S. Shichijo: honoraria from Olympus, EA Pharma, AstraZeneca, AI Medical Service, Janssen Pharmaceutical, and Fujifilm Medical; T. Kanesaka: honoraria from Olympus, AstraZeneca, and AI Medical Service; S. Yamamoto: honoraria from Ono Pharmaceutical, and MSD; N. Uedo: honoraria from Olympus, Fujifilm Medical, Boston Scientific, Daiichi-Sankyo, Takeda Pharmaceutical, EA Pharma, Otsuka Pharmaceutical, AstraZeneca, Miyarisan Pharmaceutical, and AI Medical Service; R. Ishihara: honoraria from Olympus, Fujifilm Medical, Daiichi-Sankyo, Miyarisan Pharmaceutical, AI Medical Service, AstraZeneca, MSD, and Ono Pharmaceutical. The other authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

The safety and efficacy of apremilast in psoriatic disease has been demonstrated in clinical trials, including in Japanese patients. This post-marketing surveillance study was conducted after approval of apremalast in Japan in 2016 to evaluate the safety and effectiveness of the drug in Japanese patients with plaque psoriasis (PsO) and psoriatic arthritis (PsA) in routine clinical practice. Patients (enrolled between September 1, 2017, and August 31, 2019), were observed for 12 months after apremilast treatment initiation or until discontinuation or withdrawal. Safety was assessed by evaluating adverse reactions (ARs) and serious ARs. Effectiveness measures in PsO included the proportion of patients who achieved global improvement and Physician's Global Assessment (PGA) scores of 0/1 and the change from baseline in the Dermatology Life Quality Index (DLQI) after 6 and 12 months treatment. The safety analysis set included 1063 patients (PsO, n = 992; PsA, n = 127). ARs and serious ARs were reported in 29.4% and 0.7% of patients, respectively; most occurred <1 month after apremilast initiation. There were no reports of fatal ARs, serious infections, hypersensitivity, or vasculitis. No new safety signals were identified. Among the key survey items, gastrointestinal disorders were the most common ARs (21.3%). In patients with PsO, after 6 and 12 months of treatment, effectiveness rates of achieving highly effective or effective global improvement of were 90.9% and 93.8%; PGA 0/1 was achieved by 42.7% and 58.1% of patients; mean decrease from baseline in total DLQI score was 4.2 (p < 0.0001) and 5.7 (p < 0.0001), respectively. Effectiveness was evaluated in a small number of patients with PsA for some measures; after 6 and 12 months of treatment, improvements were observed in global improvement effectiveness rates, Disease Activity Score in 28 Joints score, Visual Analog Scale score, and DLQI score. We conclude that orally administered apremilast was well tolerated and effective in Japanese patients with PsO and/or PsA enrolled in this post-marketing surveillance study., (© 2024 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Importance: Generalized pustular psoriasis (GPP) lacks internationally accepted definitions and diagnostic criteria, impeding timely diagnosis and treatment and hindering cross-regional clinical and epidemiological study comparisons., Objective: To develop an international consensus definition and diagnostic criteria for GPP using the modified Delphi method., Evidence Review: The rarity of GPP presents a challenge in acquiring comprehensive published clinical data necessary for developing standardized definition and criteria. Instead of relying on a literature search, 43 statements that comprehensively addressed the fundamental aspects of the definitions and diagnostic criteria for GPP were formulated based on expert reviews of 64 challenging GPP cases. These statements were presented to a panel of 33 global GPP experts for voting, discussion, and refinements in 2 virtual consensus meetings. Consensus during voting was defined as at least 80% agreement; the definition and diagnostic criteria were accepted by all panelists after voting and in-depth discussion., Findings: In the first and second modified Delphi round, 30 (91%) and 25 (76%) experts participated. In the initial Delphi round, consensus was achieved for 53% of the statements, leading to the approval of 23 statements that were utilized to develop the proposed definitions and diagnostic criteria for GPP. During the second Delphi round, the final definition established was, "Generalized Pustular Psoriasis is a systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules." It can occur with or without systemic symptoms, other psoriasis types, and laboratory abnormalities. GPP may manifest as an acute form with widespread pustules or a subacute variant with an annular phenotype. The identified essential criterion was, "Macroscopically visible sterile pustules on erythematous base and not restricted to the acral region or within psoriatic plaques.", Conclusions and Relevance: The achievement of international consensus on the definition and diagnostic criteria for GPP underscores the importance of collaboration, innovative methodology, and expert engagement to address rare diseases. Although further validation is needed, these criteria can serve as a reference point for clinicians, researchers, and patients, which may contribute to more accurate diagnosis and improved management of GPP.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect a broad range of animal species and has been associated with severe disease in some taxa. Few studies have evaluated optimal strategies to mitigate the risk to susceptible zoo animals. This study evaluated the safety and immunogenicity of a protein-based veterinary SARS-CoV-2 vaccine (SpikeVet™) in zoo animals. Two to three doses of SpikeVet™ were administered intramuscularly or subcutaneously 3-4 weeks apart to 354 zoo animals representing 38 species. SpikeVet™ was very well tolerated across all species. Minor adverse effects were observed in 1.69% of animals vaccinated, or 1.04% of vaccine doses administered. Preliminary immunogenicity analyses in representative carnivores (meerkats, lions) and an artiodactylid (domestic goat) showed SpikeVet™-immunized animals developed serum antibodies able to neutralize a range of SARS-CoV-2 variants, including the vaccine-homologous Wuhan and Mu variants, as well as vaccine-heterologous Omicron BA.2 and XBB.1 strains. Prior to vaccination, all eight lions were seropositive for Wuhan strain by surrogate viral neutralization testing, suggesting past infection with SARS-CoV-2 or cross-reactive antibodies generated by another closely related coronavirus. These results from a range of zoo species support the ongoing development of SpikeVet™ as a safe and effective veterinary SARS-CoV-2 vaccine., (© 2024 John Wiley & Sons Ltd.)

Background/aim: BRAF and TERT promoter mutations are associated with the poor prognosis of papillary thyroid carcinoma. This single-center retrospective study investigated the influence of these genes on advanced cases., Patients and Methods: Advanced cases who underwent gene panel testing and cases who underwent complete resection were classified as groups A and C, respectively. The gene mutations were determined using gene panel testing or Sanger sequencing using tumor DNA., Results: The study included 51 cases in group A and 44 cases in group C. In group A, all cases had unresectable lesions or distant metastasis; 82.4% of cases showed no accumulation of radioactive iodine in metastasis and 47.1% of cases were administered drug therapy. Meanwhile, all cases of group C did not have distant metastasis. The prevalence of TERT promoter mutations was significantly higher in group A compared to group C (70.6% vs. 18.2%, p<0.001). However, there was no significant difference in the prevalence of BRAF mutations between the two groups (86.3% vs. 90.9%). In Group C, disease-free survival was significantly shorter in patients harboring the TERT promoter mutations (p<0.001), despite no significant difference in that according to the BRAF mutation status. In addition, there was no significant difference in overall survival in group A according to the TERT promoter mutation status., Conclusion: Advanced papillary thyroid carcinoma was associated with the TERT promoter mutations, but not with BRAF mutation. Meanwhile, TERT promoter mutations did not affect overall survival among the advanced cases., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)