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PurposeIn patients with diabetic macular edema (DME) from YOSEMITE/RHINE, dual angiopoietin-2/vascular endothelial growth factor-A (VEGF-A) inhibition with faricimab resulted in visual/anatomic improvements with extended dosing. The SWAN trial (jRCTs031230213) will assess the efficacy, durability, and safety of faricimab during the treatment maintenance phase in patients with DME using a treat-and-extend (T&E)-based regimen adapted to clinical practice and the characteristics of patients achieving extended dosing intervals.MethodsSWAN is a 2-year, open-label, single-arm, interventional, multicenter trial enrolling adults with center-involving DME. All patients will receive three initial faricimab 6.0 mg doses every 4 weeks (Q4W). From week 12 onwards, in patients without active DME, dosing intervals will be extended in 8-week increments up to Q24W. In contrast, patients with active DME (central subfield thickness [CST] >325 μm and intraretinal fluid [IRF] or subretinal fluid [SRF] resulting in vision loss/disease aggravation) will receive a dose within a day and the dosing interval will be shortened by 4 weeks to a minimum of Q8W relative to the previous dosing interval. Recruitment commenced in August 2023 across a planned 16 sites in Japan.ResultsThe primary endpoint is change in best-corrected visual acuity (BCVA) from baseline at 1 year (averaged over weeks 52, 56, and 60). Key secondary endpoints include: change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire scores over time; proportion of patients with BCVA (decimal visual acuity) ≥0.5, ≥0.7, ≥1.0, or ≤0.1; proportion of patients with absence of DME, and IRF and/or SRF over time. Safety endpoints include incidence/severity of ocular/nonocular adverse events.ConclusionsThe SWAN trial is expected to provide evidence to support individualized faricimab dosing regimens, with the potential to reduce the burden of frequent treatments on patients, caregivers, and healthcare systems.

Objective structured clinical examinations (OSCEs) are a widely used performance assessment for medical and dental students. A common limitation of OSCEs is that the evaluation results depend on the characteristics of raters and a scoring rubric. To overcome this limitation, item response theory (IRT) models such as the many-facet Rasch model have been proposed to estimate examinee abilities while taking into account the characteristics of raters and evaluation items in a rubric. However, conventional IRT models have two impractical assumptions: constant rater severity across all evaluation items in a rubric and an equal interval rating scale among evaluation items, which can decrease model fitting and ability measurement accuracy. To resolve this problem, we propose a new IRT model that introduces two parameters: (1) a rater-item interaction parameter representing the rater severity for each evaluation item and (2) an item-specific step-difficulty parameter representing the difference in rating scales among evaluation items. We demonstrate the effectiveness of the proposed model by applying it to actual data collected from a medical interview test conducted at Tokyo Medical and Dental University as part of a post-clinical clerkship OSCE. The experimental results showed that the proposed model was well-fitted to our OSCE data and measured ability accurately. Furthermore, it provided abundant information on rater and item characteristics that conventional models cannot, helping us to better understand rater and item properties.

Background/aimAntiviral hepatitis and systemic therapies for hepatocellular carcinoma (HCC) remarkably progressed in the recent 10 years. This study aimed to reveal the actual transition and changes in the prognosis and background liver disease in non-advanced HCC in the past 20 years.MethodsThis retrospectively recruited 566 patients who were diagnosed with non-advanced HCC from February 2002 to February 2022. The prognosis was analyzed by subdividing according to the diagnosis date (period I: February 2002-April 2009 and period Ⅱ: May 2009-February 2022).ResultsPatients in period II (n = 351) were significantly older, with lower albumin-bilirubin (ALBI) scores and alpha-fetoprotein (AFP) and more anti-viral therapy, systemic therapy, and hepatic arterial infusion chemotherapy as compared with those in period I (n = 215). The etiology ratio of the background liver disease revealed decreased hepatitis C virus from 70.6% to 49.0% and increased non-B, non-C from 17.7% to 39.9% from periods I to Ⅱ. The multivariate analysis revealed older age and higher ALBI score in Barcelona Clinic Liver Cancer (BCLC) 0/A stage, AFP of >20 ng/mL, and higher ALBI score in BCLC B stage as independent prognosis factors. Fine-Gray competing risk model analysis revealed that liver-related deaths significantly decreased in period II as compared to period I, especially for BCLC stage 0/A (HR: 0.656; 95%CI: 0.442-0.972, P = 0.036).ConclusionThe characteristics of patients with non-advanced HCC have changed over time. Appropriate background liver management led to better liver-related prognoses in BCLC 0/A.

Background and objectiveA cytokine storm is caused by inflammatory cells, including pro-inflammatory macrophage phenotype (M1), and play a critical role in the pathogenesis of COVID-19, in which diffuse alveolar damage occurs in the lungs due to oxidative stress exposure. Heme oxygenase (HO)-1 is a stress-induced protein produced by the anti-inflammatory / anti-oxidative macrophage phenotype (M2), which also produces soluble CD163 (sCD163). In our study, we investigated and determined that serum HO-1 can be a predictive biomarker for assessing both the severity and the outcome of COVID-19 patients.MethodThe serum concentrations of HO-1 and sCD163 of COVID-19 patients were measured on admission. The relationship between these biomarkers and other clinical parameters and outcomes were evaluated.ResultsSixty-four COVID-19 patients (11 mild, 38 moderate, and 15 severe cases) were assessed. The serum HO-1 tended to increase (11.0 ng/mL vs. 24.3 ng/mL vs. 59.6 ng/mL with severity). Serum HO-1 correlated with serum lactate dehydrogenase (R = 0.422), C-reactive protein (R = 0.463), and the ground glass opacity (GGO) and consolidation score (R = 0.625) of chest computed tomography. The serum HO-1 showed a better area under the curve (AUC) for predicting ICU admission than the serum sCD163 (HO-1; 0.816 and sCD163; 0.743). In addition, composite parameters including serum HO-1 and the GGO and consolidation score showed a higher AUC for predicting ICU admission than the AUC of a single parameter.ConclusionClinically, serum HO-1, reflecting the activation of M2, could be a very useful marker for evaluating disease severity and predicting prognoses for COVID-19 patients. In addition, controlling activated M2 might be a preventative COVID-19 therapeutic target.

BackgroundInterprofessional education (IPE) is crucial in dentistry, medicine, and nursing. However, scant mixed methods studies have compared the IPE outcomes across these disciplines to develop evidence-based IPE. This study explored the differences in the readiness of dental, medical, and nursing students for interprofessional learning before and after IPE workshops and elucidated reasons for this disparity.MethodsData were obtained from dental, medical, and nursing students who participated in IPE workshops conducted at Tokyo Medical and Dental University in Japan in 2019 and 2020. The participants filled the validated Japanese version of the Readiness for Interprofessional Learning Scale (RIPLS) before and after attending the workshops (n = 378). Paired t-tests were performed to assess differences between the pre- and post- workshop RIPLS scores. Welch's t-tests were deployed to evaluate interdisciplinary differences in their scores. Qualitative analyses were conducted using an explanatory sequential design with focus group discussions (FGDs) held with 17 dental students to explain the quantitative results.ResultsTotal RIPLS scores increased significantly for every discipline after the workshops (p < 0.001). Dental students scored significantly lower pre- and post- workshop aggregates than medical and nursing students, respectively (p < 0.001). The FGDs yielded three principal themes in the explanations tendered by dental students on their lower scores: 1) dental students rarely felt the need for interprofessional collaborations, 2) dentists often worked without the need for interprofessional collaborations, and 3) dental students believed their contribution to the workshop was insufficient.ConclusionsThe results revealed divergences in the readiness of dental, medical, and nursing students for interprofessional learning, and the study illuminated possible reasons for these disparities. These outcomes will help develop evidence-based IPE by indicating approaches to place a higher value on interprofessional collaborations in educational environments, ameliorate the awareness of educators, and enhance the workshop facilitation style.

Over the course of evolution, the acquisition of novel structures has ultimately led to wide variation in morphology among extant multicellular organisms. Thus, the origins of genetic systems for new morphological structures are a subject of great interest in evolutionary biology. The larval skeleton is a novel structure acquired in some echinoderm lineages via the activation of the adult skeletogenic machinery. Previously, VEGF signaling was suggested to have played an important role in the acquisition of the larval skeleton. In the present study, we compared expression patterns of Alx genes among echinoderm classes to further explore the factors involved in the acquisition of a larval skeleton. We found that the alx1 gene, originally described as crucial for sea urchin skeletogenesis, may have also played an essential role in the evolution of the larval skeleton. Unlike those echinoderms that have a larval skeleton, we found that alx1 of starfish was barely expressed in early larvae that have no skeleton. When alx1 overexpression was induced via injection of alx1 mRNA into starfish eggs, the expression patterns of certain genes, including those possibly involved in skeletogenesis, were altered. This suggested that a portion of the skeletogenic program was induced solely by alx1. However, we observed no obvious external phenotype or skeleton. We concluded that alx1 was necessary but not sufficient for the acquisition of the larval skeleton, which, in fact, requires several genetic events. Based on these results, we discuss how the larval expression of alx1 contributed to the acquisition of the larval skeleton in the putative ancestral lineage of echinoderms.

New inhibitors of influenza viruses are needed to combat the potential emergence of novel human influenza viruses. We have identified a class of small molecules that inhibit replication of influenza virus at picomolar concentrations in plaque reduction assays. The compound also inhibits replication of vesicular stomatitis virus. Time of addition and dilution experiments with influenza virus indicated that an early time point of infection was blocked and that inhibitor 136 tightly bound to virions. Using fluorescently labeled influenza virus, inhibition of viral fusion to cellular membranes by blocked lipid mixing was established as the mechanism of action for this class of inhibitors. Stabilization of the neutral pH form of hemagglutinin (HA) was ruled out by trypsin digestion studies in vitro and with conformation specific HA antibodies within cells. Direct visualization of 136 treated influenza virions at pH 7.5 or acidified to pH 5.0 showed that virions remain intact and that glycoproteins become disorganized as expected when HA undergoes a conformational change. This suggests that exposure of the fusion peptide at low pH is not inhibited but lipid mixing is inhibited, a different mechanism than previously reported fusion inhibitors. We hypothesize that this new class of inhibitors intercalate into the virus envelope altering the structure of the viral envelope required for fusion to cellular membranes.

The WTC collapse exposed over 300,000 people to high concentrations of WTC-PM; particulates up to ∼50 mm were recovered from rescue workers' lungs. Elevated MDC and GM-CSF independently predicted subsequent lung injury in WTC-PM-exposed workers. Our hypotheses are that components of WTC dust strongly induce GM-CSF and MDC in AM; and that these two risk factors are in separate inflammatory pathways.Normal adherent AM from 15 subjects without WTC-exposure were incubated in media alone, LPS 40 ng/mL, or suspensions of WTC-PM(10-53) or WTC-PM(2.5) at concentrations of 10, 50 or 100 µg/mL for 24 hours; supernatants assayed for 39 chemokines/cytokines. In addition, sera from WTC-exposed subjects who developed lung injury were assayed for the same cytokines. In the in vitro studies, cytokines formed two clusters with GM-CSF and MDC as a result of PM(10-53) and PM(2.5). GM-CSF clustered with IL-6 and IL-12(p70) at baseline, after exposure to WTC-PM(10-53) and in sera of WTC dust-exposed subjects (n = 70) with WTC lung injury. Similarly, MDC clustered with GRO and MCP-1. WTC-PM(10-53) consistently induced more cytokine release than WTC-PM(2.5) at 100 µg/mL. Individual baseline expression correlated with WTC-PM-induced GM-CSF and MDC.WTC-PM(10-53) induced a stronger inflammatory response by human AM than WTC-PM(2.5). This large particle exposure may have contributed to the high incidence of lung injury in those exposed to particles at the WTC site. GM-CSF and MDC consistently cluster separately, suggesting a role for differential cytokine release in WTC-PM injury. Subject-specific response to WTC-PM may underlie individual susceptibility to lung injury after irritant dust exposure.