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Biologics are recommended in Japan to treat moderate to severe Crohn's Disease (CD). Although CD is associated with high direct costs in Japan, updated information after ustekinumab's approval is unavailable. We aimed to evaluate the healthcare resource utilization (HRU) and associated direct costs from the payer's perspective in Japan. Claims data (2010-2018) were retrospectively analyzed to identify patients with CD. HRU and associated costs were evaluated for 12 months before and after biologic initiation and followed-up till 36 months post-initiation. Outcomes were reported using descriptive statistics. Among the included patients (n = 3,496), 1,783 were on biologics and 1,713 were on non-biologics. Mean (SD) age was 36.4 (13.2) years and patients were predominantly male (76.1%). Patients aged 18-39 years were affected with CD the most (55.3%). Biologic initiation was associated with a reduction in inpatient stay, length of stay, outpatient visits, and associated costs; and an increase in pharmacy costs and total costs after 12 months. Extended follow-up showed a decreasing trend in HRU and costs till 24 months but an increase after 36 months. These findings demonstrated reduction in clinical burden and slight increase in economic burden with biologics. However, indirect costs also need to be evaluated.

Abstract We conducted a retrospective population-based, matched cohort study using the National Health Insurance Research Database to estimate healthcare resource utilisation (HRU) and costs in patients with newly diagnosed AL amyloidosis in Taiwan. Cases were matched 10:1 by age, sex, and area of residence to patients without AL amyloidosis (comparators) randomly selected from the database during the same time period. Annual all-cause HRU and costs for 3 years were quantified. AL amyloidosis-attributable costs were obtained by subtracting all-cause HRU costs incurred by comparators from cases. The mean age of all patients was 60.78 years and 59.07% were male. Co-morbidities were more frequent in cases than comparators. By 6 months after diagnosis, 12.1% of cases had died versus 0.9% of comparators. In the first year, cases had 103% more outpatient visits, 177% more emergency room visits, were hospitalised 4-times more frequently, and spent 5.5-times more days in hospital than comparators, and total healthcare costs were > sixfold higher. Costs incurred during the first year after diagnosis accounted for 55% of the 3-year cumulative cost. High HRU costs associated with delayed diagnosis and end-organ damage indicate a need for earlier diagnosis and more effective treatments for AL amyloidosis.

Background: Severe aortic regurgitation (AR) and mitral regurgitation (MR) can lead to left ventricular (LV) systolic dysfunction; however, there are limited data about recovery of LV after surgery for AR or MR. Little is known to guide the management of combined AR and MR (mixed valvular heart disease [VHD]). This study is sought to investigate the predictors of postoperative LV function recovery in left-sided regurgitant VHD with reduced left ventricular ejection fraction (LVEF), especially for mixed VHD. Methods: From 2010 to 2020, 2053 adult patients underwent aortic or mitral valve surgery at our center. The patients with valvular stenosis, infective endocarditis, concomitant revascularization, and preoperative LVEF ≥40 % were excluded. A total of 127 patients were included in this study: 22 patients with predominant AR (AR group), 64 with predominant MR (MR group), and 41 with combined AR and MR (AMR group). Results: The mean preoperative LVEF was 32.4 %, 30.7 %, and 30.2 % (p = 0.44) in the AR, MR, and AMR groups, respectively. The AR group was more likely to have postoperative LVEF recovery. The cut-point of left ventricular end-systolic diameter (LVESD) for better recovery was 49 mm for the MR group and 58 mm for the AMR group. Conclusion: LV dysfunction due to combined AR and MR has similar remodeling reserve as AR, and better recoverability than MR. Thus, double-valve surgery is recommended before the LVESD is > 58 mm.

A significant issue for traffic safety has been drowsy driving for decades. A number of studies have investigated the effects of acute fatigue on spectral power; and recent research has revealed that drowsy driving is associated with a variety of brain connections in a specific cortico-cortical pathway. In spite of this, it is still unclear how different brain regions are connected in drowsy driving at different levels of daily fatigue. This study identified the brain connectivity-behavior relationship among three different daily fatigue levels (low-, median- and high-fatigue) with the EEG data transfer entropy. According to the results, only low- and medium-fatigue groups demonstrated an inverted U-shaped change in connectivity from high performance to poor behavioral performance. In addition, from low- to high-fatigue groups, connectivity magnitude decreased in the frontal region and increased in the occipital region. These study results suggest that brain connectivity and driving behavior would be affected by different levels of daily fatigue.

Abstract Dermatomyositis and polymyositis are rare, idiopathic inflammatory myopathies. Interstitial lung disease is one of the most common and potentially severe extra-muscular manifestations of dermatomyositis and polymyositis and is strongly linked to poor prognosis and early mortality. We aimed to characterise the demographic and clinical characteristics, incidence, and treatment of interstitial lung disease in patients with dermatomyositis or polymyositis. We conducted a retrospective cohort study using the Japan Medical Data Center healthcare claims database. Patients in the database with dermatomyositis (International Classification of Disease version 10 M33.0, M33.1, M33.9) or polymyositis (M33.2) from 01-Jan-2011 until 31-Dec-2019 were identified and followed-up for interstitial lung disease (J84.x) until death, dis-enrolment, or study end (31 December 2020). Cumulative risk curves compared interstitial lung disease risk in dermatomyositis versus polymyositis. Risk factors were evaluated by Cox proportional hazard models. There were 886 patients with dermatomyositis and 745 patients with polymyositis included in the cohort analysis. Mean (standard deviation) age at dermatomyositis/polymyositis diagnosis was 46.0 (16.0)/49.7 (13.3) years and 300 (34%)/104 (14%) developed interstitial lung disease during follow-up. The incidence rate of interstitial lung disease per 100 person-years was 18.42 (95% CI 16.42–20.59) for dermatomyositis and 5.39 (95% CI 4.43–6.50) for polymyositis. In the analysis adjusted for sex, age, and comorbidity score, the risk of interstitial lung disease was significantly higher in patients with dermatomyositis than with polymyositis (hazard ratio 2.72, 95% CI 2.18–3.41). The rate diverged markedly between the groups in the first year after diagnosis. Risk factors for interstitial lung disease were older age in dermatomyositis, female sex and rheumatoid arthritis in polymyositis. Glucocorticoids with/without tacrolimus were the most common newly prescribed drugs after the interstitial lung disease diagnosis. In conclusion, the risk of developing interstitial lung disease was significantly higher in patients with dermatomyositis than with polymyositis, and risk factors were different in the 2 patient groups.

BackgroundThrombosis with thrombocytopenia syndrome (TTS) is a very rare prothrombotic disorder that is a safety concern for some COVID-19 vaccines. We aimed to devise a case definition to estimate the incidence of thrombosis with thrombocytopenia as a proxy for TTS in a national insurance claims database.MethodsWe conducted a retrospective observational study using the National Health Insurance Research Database (NHIRD) in Taiwan over the three-year period prior to the SARS-COV-2 pandemic (2017-2019). Our case definition was all patients with newly diagnosed thrombosis co-occurring with a diagnosis of thrombocytopenia within seven days before or after the thrombosis diagnosis. Cases were identified using International Classification of Disease-10 codes.FindingsWe identified 2010 patients with newly diagnosed thrombosis co-occurring with thrombocytopenia during the study period. The mean age was 64.71 years; female:male ratio 1:1.45. The most frequent thrombotic events were coronary artery disease (18.81%), cerebral infarction (16.87%), and disseminated intravascular coagulation (13.13%). Cerebral venous sinus thrombosis was rare (InterpretationWe observed that the demographic and clinical characteristics of thrombosis with co-occurring thrombocytopenia using our case definition is different from that of TTS. Further research is needed to refine the case definition of TTS in the post-COVID-19 vaccination period.

Background Although older patients with atrial fibrillation are at heightened risk of thromboembolic and bleeding events, their optimal treatment choice remains uncertain. Methods and Results This meta‐analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that compared thromboembolic or bleeding outcomes between a direct oral anticoagulant (DOAC) and a vitamin K antagonist (VKA) and reported outcomes for patients aged ≥75 years with atrial fibrillation. The efficacy outcome was the composite of stroke and systemic embolism. Safety outcomes included major bleeding, any clinically relevant bleeding, and intracranial hemorrhage. Each DOAC and VKA was compared pairwise in a network meta‐analysis. High‐ and low‐dose regimens and factor IIa and Xa inhibitors were also compared. Seven randomized controlled trials were included in the analysis. Stroke and systemic embolism risks did not differ significantly among DOACs. There were no significant differences in major bleeding between each DOAC and VKA. Intracranial hemorrhage risk was significantly lower with dabigatran, apixaban, and edoxaban than with VKA and rivaroxaban, which had similar risks. High‐dose regimens led to lower risks of stroke or systemic embolism compared with VKA and low‐dose regimens, with both doses having similar bleeding risks. Conclusions In patients aged ≥75 years with atrial fibrillation, DOACs were associated with fewer thromboembolic events compared with VKA, whereas dabigatran, apixaban, and edoxaban were associated with lower risks of intracranial hemorrhage compared with VKA and rivaroxaban. Registration URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42022329557.

Background Myocardial steatosis and fibrosis may play a role in the pathophysiology of heart failure with preserved ejection fraction. We therefore investigated the prognostic significance of epicardial fat (epicardial adipose tissue [EAT]) and myocardial diffuse fibrosis. Methods and Results Myocardial fibrosis, estimated as extracellular volume (ECV), and EAT were measured using cardiac magnetic resonance imaging in 163 subjects with heart failure with preserved ejection fraction. We also evaluated cardiac structure and diastolic and systolic function by echocardiography and cardiac magnetic resonance imaging. After 24 months' follow‐up, 39 (24%) subjects had experienced cardiovascular events, including hospitalization for heart failure, acute coronary syndrome, and cardiovascular death. Median EAT and mean ECV were significantly higher in subjects with cardiovascular events than survivors (EAT, 35 [25–45] versus 31 [21–38], P=0.006 and ECV, 28.9±3.16% versus 27.2±3.56%, P=0.04). Subjects with high EAT (≥42 g) had increased risk of cardiovascular events (hazard ratio [HR], 2.528 [95% CI, 1.704–4.981]; P=0.032). High ECV (>29%) was also significantly associated with poorer outcomes (HR, 1.647 [95% CI, 1.263–2.548]; P=0.013). With respect to secondary end points, high EAT and high ECV were associated with increased risk of the incident acute coronary syndrome (HR, 1.982 [95% CI, 1.008–4.123]; P=0.049) and hospitalization for heart failure (HR, 1.789 [95% CI, 1.102–6.987]; P=0.033), respectively. Conclusions Our study suggested that increased epicardial fat and ECV detected by cardiac magnetic resonance imaging have an impact on cardiovascular prognosis, in particular acute coronary syndrome and hospitalization for heart failure, respectively.

Abstract Background Although the powerful clinical effects of radiofrequency and microwave ablation have been established, such ablation is associated with several limitations, including a small ablation size, a long ablation time, the few treatment positioning, and biosafety risks. To overcome these limitations, biosafe and efficient magnetic ablation was achieved in this study by using biocompatible liquid gallium as an ablation medium and a contrast medium for imaging. Results Magnetic fields with a frequency (f) lower than 200 kHz and an amplitude (H) × f value lower than 5.0 × 109 Am−1 s−1 were generated using the proposed method. These fields could generate an ablation size of 3 cm in rat liver lobes under a temperature of approximately 300 °C and a time of 20 s. The results of this study indicate that biomedical gallium can be used as a contrast medium for the positioning of gallium injections and the evaluation of ablated tissue around a target site. Liquid gallium can be used as an ablation medium and imaging contrast medium because of its stable retention in normal tissue for at least 3 days. Besides, the high anticancer potential of gallium ions was inferred from the self-degradation of 100 µL of liquid gallium after around 21 days of immersion in acidic solutions. Conclusions The rapid wireless ablation of large or multiple lesions was achieved through the simple multi-injection of liquid gallium. This approach can replace the currently favoured procedure involving the use of multiple ablation probes, which is associated with limited benefits and several side effects. Methods Magnetic ablation was confirmed to be highly efficient by the consistent results obtained in the simulation and in vitro tests of gallium and iron oxide as well as the electromagnetic specifics and thermotherapy performance comparison detailed in this study Ultrasound imaging, X-ray imaging, and magnetic resonance imaging were found to be compatible with the proposed magnetic ablation method. Self-degradation analysis was conducted by mixing liquid gallium in acidic solutions with a pH of approximately 5–7 (to imitate a tumour-containing microenvironment). X-ray diffraction was used to identify the gallium oxides produced by degraded gallium ions.

Background Peripheral arterial disease (PAD) is a severe complication in patients with type 2 diabetes. Glycemic variability (GV) is associated with increased risks of developing microvascular and macrovascular diseases. However, few studies have focused on the association between GV and PAD. Methods and Results This cohort study used a database maintained by the National Taiwan University Hospital, a tertiary medical center in Taiwan. For each individual, GV parameters were calculated, including fasting glucose coefficient of variability (FGCV) and hemoglobin A1c variability score (HVS). Multivariate Cox regression models were constructed to estimate the relationships between GV parameters and composite scores for major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs). Between 2014 and 2019, a total of 45 436 adult patients with prevalent type 2 diabetes were enrolled for analysis, and GV was assessed during a median follow‐up of 64.4 months. The average number of visits and time periods were 13.38 and 157.87 days for the HVS group and 14.27 and 146.59 days for the FGCV group, respectively. The incidence rates for cardiac mortality, PAD, and critical limb ischemia (CLI) were 5.38, 20.11, and 2.41 per 1000 person‐years in the FGCV group and 5.35, 20.32, and 2.50 per 1000 person‐years in HVS group, respectively. In the Cox regression model with full adjustment, the highest FGCV quartile was associated with significantly increased risks of MALEs (hazard ratio [HR], 1.57 [95% CI, 1.40–1.76]; P

Background: The cardiac manifestations of late-onset hereditary transthyretin amyloidosis with p.A97S variant have not been extensively studied, and the prognostic factors remain unclear. Methods: The clinical profile, echocardiography, and ECG of patients diagnosed with ATTR p.A97S polyneuropathy between 2000 and 2016 were retrospectively collected. 67 patients with ATTR p.A97S were collected. Results: A total of 82% of patients met the criteria for left ventricular (LV) hypertrophy. Reduced global longitudinal strain (GLS) was noted in 42.1% of patients, and 14% of patients had a relative apical sparing pattern. A low voltage pattern in the ECG was observed in 31.3% of patients, while 64.2% presented with a pseudoinfarction pattern. End-systolic LV inner dimension (HR: 2.25 (95% CI: 1.01–5.01), p = 0.048), reduced GLS (HR: 5.26 (1.08–25.0), p = 0.039), relative apical longitudinal strain (RALS>1, HR: 8.57 (1.69–43.3), p = 0.009), increased E/A ratio (HR: 6.51 (1.17–36.4), p = 0.033), and increased QRS duration (HR: 1.02 (1.00–1.04), p = 0.05) were correlated with reduced survival in univariate analysis. Multivariate analysis revealed reduced RALS was significantly correlated with reduced survival (HR: 13.00 (1.81–93.45), p = 0.011). Conclusion: Our findings reveal that ATTR p.A97S is a cardiomyopathy as well as a polyneuropathic syndrome. Routine use of more contemporary echocardiographic techniques are recommended to identify cardiac amyloidosis and provide prognostic information. Keywords: Hereditary transthyretin amyloidosis, Familial amyloidotic polyneuropathy, p.A97S, Global longitudinal strain

Galectin-1 (Gal-1) is a pleiotropic homodimeric β-galactoside-binding protein with a single carbohydrate recognition domain. It has been implicated in several biological processes that are important during tumor progression. Several lines of evidence have indicated that Gal-1 is involved in cancer immune escape and induces T cell apoptosis. These observations all emphasized Gal-1 as a novel target for cancer immunotherapy. Here, we developed a novel Gal-1-targeting DNA aptamer (AP-74 M-545) and demonstrated its antitumor effect by restoring immune function. AP-74 M-545 binds to Gal-1 with high affinity. AP-74 M-545 targets tumors in murine tumor models but suppresses tumor growth only in immunocompetent C57BL/6 mice, not in immunocompromised non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice. Immunohistochemistry revealed increased CD4+ and CD8+ T cells in AP-74 M-545-treated tumor tissues. AP-74 M-545 suppresses T cell apoptosis by blocking the binding of Gal-1 to CD45, the main receptor and apoptosis mediator of Gal-1 on T cells. Collectively, our data suggest that the Gal-1 aptamer suppresses tumor growth by blocking the interaction between Gal-1 and CD45 to rescue T cells from apoptosis and restores T cell-mediated immunity. These results indicate that AP-74 M-545 may be a potential strategy for cancer immunotherapy. Keywords: immunotherapy, galectin-1, aptamer, lung cancer

Abstract Background In the past decade, fatigue has been regarded as one of the main factors impairing task performance and increasing behavioral lapses during driving, even leading to fatal car crashes. Although previous studies have explored the impact of acute fatigue through electroencephalography (EEG) signals, it is still unclear how different fatigue levels affect brain–behavior relationships. Methods A longitudinal study was performed to investigate the brain dynamics and behavioral changes in individuals under different fatigue levels by a sustained attention task. This study used questionnaires in combination with actigraphy, a noninvasive means of monitoring human physiological activity cycles, to conduct longitudinal assessment and tracking of the objective and subjective fatigue levels of recruited participants. In this study, degrees of effectiveness score (fatigue rating) are divided into three levels (normal, reduced, and high risk) by the SAFTE fatigue model. Results Results showed that those objective and subjective indicators were negatively correlated to behavioral performance. In addition, increased response times were accompanied by increased alpha and theta power in most brain regions, especially the posterior regions. In particular, the theta and alpha power dramatically increased in the high‐fatigue (high‐risk) group. Additionally, the alpha power of the occipital regions showed an inverted U‐shaped change. Conclusion Our results help to explain the inconsistent findings among existing studies, which considered the effects of only acute fatigue on driving performance while ignoring different levels of resident fatigue, and potentially lead to practical and precise biomathematical models to better predict the performance of human operators.