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The relationship between renal impairment and diabetic peripheral neuropathy (DPN) remains inconclusive. We aim to investigate the risk factors for the occurrence of DPN in Taiwanese adults with type 2 diabetes mellitus (T2DM) and focus on renal impairment. A hospital-based study was conducted from 2013 to 2019 and 552 Taiwanese people who had T2DM without DPN at baseline were enrolled. DPN was diagnosed using the Michigan Neuropathy Screening Instrument. Potential risk factors were recorded, including patient's sociodemographic factors, current medication usage and biochemical markers. As of 2019, 73 developed DPN and 479 had no DPN. The cumulative incidence during the 6-year period was 13.22%. Multivariable logistic regression analysis revealed that lower estimated glomerular filtration rate (eGFR) (odds ratio [OR] 0.98, p = 0.005), advanced age (OR 1.06, p = 0.001), increased body weight (OR 1.04, p = 0.018), duration of DM (OR 1.05, p = 0.036) and male gender (OR 3.69, p = 0.011) were significantly associated with future DPN. In addition, patients with T2DM under the age of 65 with higher serum creatinine concentration (OR 8.91, p = 0.005) and higher baseline HbA1C (OR 1.71, p < 0.001) revealed significantly associated with future DPN. In conclusion, this is the first large scaled hospital-based study with long term follow-up to investigate risk factors for DPN in Taiwanese. Lower eGFR and higher serum creatinine concentration, particularly in people under the age of 65, are predictors of future DPN in Taiwanese people with T2DM. Other predictors included advanced age, increased body weight, duration of DM, male gender for all ages and HbA1c in enrolled patients under the age of 65. Our study not only confirms the association between renal impairment and future DPN but also provides a commonly available assessment to predict the future DPN., (© 2022. The Author(s).)

In this study, we separately used a laboratory Hollander beater, a pilot scale 12″ single-disc refiner and an expanded trial with a commercial paper mold mill to investigate the feasibility of using thermal-alkali/enzyme pretreated rice straw semi-chemical mechanical pulp to substitute portions of old corrugated carton board (OCC) pulp in the paper industry. In the laboratory plan, sequential treatments of NaOH at a 5-10% dosage and enzymes at a 0.2-4% dosage were applied to rice straw, followed by beating using a Hollander beater for 1-2 h to complete the rice straw semi-chemical mechanical pulping process. When the NaOH dosage, enzyme dosage and refining time were 10%, 0.2% and 1 h, the best quality rice straw pulp was obtained. Along with the increase in NaOH dosage, the pulp freeness decreased significantly, and the pulp accepted rate increased. Enzymatic treatment enhanced rice straw quality only after NaOH dosage treatment, which then reacted with rice straw to increase the quality of pulp. In the expanded trial, the rice straw semi-chemical mechanical pulp was blended with OCC pulp (0%, 25%, 50%, 75% and 100%) to form handsheets. Along with an increase in rice straw proportions, the tensile index, burst index, and ring-crush index increased by 109-200%, 13-196%, and 124-187%, respectively. In an online commercial paper mold mill trial, blending rice straw pulp with OCC could successfully make paper-mold egg cartons, with both mill operation and product smoothness appearance being highly acceptable., (© 2022. The Author(s).)

Internal tandem duplication of the Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 ( FLT3 -ITD) is one of the most clinically relevant mutations in acute myeloid leukemia (AML), with a high FLT3 -ITD allelic ratio (AR) (≥0.5) being strongly associated with poor prognosis. FLT3 -ITDs are heterogeneous, varying in size and location, with some patients having multiple FLT3 -ITDs. Bulk cell-based approaches are limited in their ability to reveal the clonal structure in such cases. Using single-cell proteogenomic sequencing (ScPGseq), we attempted to identify a relapse-fated subclone in an AML case with mutations in WT1 , NPM1 , and FLT3 tyrosine kinase domain and two FLT3 -ITDs (21 bp and 39 bp) (low AR) at presentation, then relapsed only with WT1 and NPM1 mutations and one FLT3 -ITD (high AR). This relapse-fated subclone at presentation (∼2.1% of sequenced cells) was characterized by the presence of a homozygous 21 bp FLT3 -ITD resulting from copy neutral loss of heterozygosity (CN-LOH) of chr13q and an aberrant, immature myeloid cell surface signature, contrast to the cell surface phenotype at presentation. In contrast to results from multicolor flow-cytometry, ScPGseq not only enabled the early detection of rare relapse-fated subclone showing immature myeloid signature but also highlighted the presence of homozygous 21 bp FLT3 -ITDs in the clone at presentation., Competing Interests: The authors declare no competing financial interests., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent mother-to-infant transmission in highly viremic HBV-infected women. Data on hepatitis B surface antigen (HBsAg) levels in pregnant women are lacking. We aimed to investigate prepartum and postpartum HBsAg kinetics and its correlation with HBV DNA in pregnant women. HBV-infected mothers with HBV DNA ≥7.5 log 10  IU/ml were tested for HBsAg and HBV DNA from baseline to 6 months postpartum. Of the 186 pregnant women with comparable baseline HBsAg and HBV DNA, 101 received TDF from the third trimester until 1 month postpartum. At delivery, TDF group had mildly lower HBsAg (4.32 ± 0.47 vs. 4.54 ± 0.35 log 10  IU/ml, p = .0004) and markedly lower HBV DNA (4.26 ± 0.97 vs. 8.11 ± 0.70 log 10  IU/ml, p < .0001) than the control group. In the TDF group, mean reduction of HBsAg and HBV DNA from baseline to delivery were 0.22 ± 0.38 and 3.96 ± 0.93 log 10  IU/ml. HBsAg reduction had a positive correlation (r = .309; p = .0017) with HBV DNA reduction, and was predictive of HBV DNA reduction ≥3 log 10  IU/ml (area under the receiver operating characteristic curve, 0.67; 95% confidence interval, 0.50-0.82). At 6 months postpartum, TDF and control group had comparable HBsAg and HBV DNA. In conclusion, HBsAg decreased slightly at delivery in pregnant women receiving TDF. For monitoring the effect of antiviral therapy during pregnancy, HBV DNA is a better marker than HBsAg. Our data provided valuable information regarding monitoring HBV-infected pregnant women using antiviral therapy., (© 2021 John Wiley & Sons Ltd.)

A universal hepatitis B virus (HBV) vaccination program has been implemented in Taiwan since 1984. A total of 1611 individuals in Taipei were enrolled to monitor long-term efficacy. The prevalences of hepatitis B surface antigen (HBsAg) and hepatitis B core antibody in the vaccinated birth cohort were lower than in those born before 1984 (0.4% vs 7.7%, and 2.2% vs 50.8%, respectively; P < .0001). Three vaccine-failure carriers all were born to HBsAg-carrier mothers, probably due to no antiviral intervention during pregnancy. Occult HBV infection was rare in the postvaccination era. High vaccination coverage, comprehensive HBV screening, and antiviral agents for pregnant mothers will be essential to eliminate HBV transmission., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: We assessed the association between hospitalization for illness from COVID-19 infection and chronic conditions among Medicare beneficiaries (MBs) with fee-for-service (FFS) claims by race and ethnicity for January 1-September 30, 2020., Methods: We used 2020 monthly Medicare data from January 1-September 30, 2020, reported to the Centers for Medicare and Medicaid Services to compute hospitalization rates per 100 COVID-19 MBs with FFS claims who were hospitalized (ICD-10-CM codes: B97.29 before April 1, 2020; ICD-10-CM codes: U07.1 from April 1, 2020, onward) with or without selected chronic conditions. We used logistic regression to estimate adjusted odds ratios with 95% confidence intervals for association of person-level rate of being hospitalized with COVID-19 and each of 27 chronic conditions by race/ethnicity, controlling for age, sex, and urban-rural residence among MBs., Results: COVID-19-related hospitalizations were associated with all selected chronic conditions, except osteoporosis and Alzheimer disease/dementia among COVID-19 MBs. The top five conditions with the highest odds for hospitalization among COVID-19 MBs were end-stage renal disease (adjusted odds ratios (aOR): 2.15; 95% CI: 2.10-2.21), chronic kidney disease (aOR: 1.54; 95% CI: 1.52-1.56), acute myocardial infarction (aOR: 1.45; 95% CI: 1.39-1.53), heart failure (aOR: 1.43; 95% CI: 1.41-1.44), and diabetes (aOR: 1.37; 95% CI: 1.36-1.39)., Conclusions: Racial/ethnic disparities in hospitalization rate persist among MBs with COVID-19, and associations of COVID-19 hospitalization with chronic conditions differ among racial/ethnic groups in the USA. These findings indicate the need for interventions in racial/ethnic populations at the highest risk of being hospitalized with COVID-19., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Introduction: Juvenile idiopathic arthritis (JIA) is a cluster of autoimmune rheumatic diseases occurring in children 16 years of age or less. While it is well-known that pain may be experienced during inflammatory and non-inflammatory states, much remains ambiguous regarding the molecular mechanisms that may drive JIA pain. Thus, in this pilot study, we explored the variability of the serum proteomes in relation to pain severity in a cohort of JIA patients., Methods: Serum samples from 15 JIA patients (male and female, 12.7 ± 2.8 years of age) were assessed using liquid chromatography/mass spectrometry (LC/MS). Correlation analyses were performed to determine the relationships among protein levels and self-reported clinical pain severity. Additionally, how the expression of pain-associated proteins related to markers of inflammation (Erythrocyte Sedimentation Rate (ESR)) or morphological properties of the central nervous system (subcortical volume and cortical thickness) implicated in JIA were also evaluated., Results: 306 proteins were identified in the JIA cohort of which 14 were significantly (p < 0.05) associated with clinical pain severity. Functional properties of the identified pain-associated proteins included but were not limited to humoral immunity (IGLV3.9), inflammatory response (PRG4) and angiogenesis (ANG). Associations among pain-associated proteins and ESR (IGHV3.9, PRG4, CST3, VWF, ALB), as well as caudate nucleus volume (BTD, AGT, IGHV3.74) and insular cortex thickness (BTD, LGALS3BP) were also observed., Conclusions: The current proteomic findings suggest both inflammatory- and non-inflammatory mediated mechanisms as potential factors associated with JIA pain. Validation of these preliminary observations using larger patient cohorts and a longitudinal study design may further point to novel serologic markers of pain in JIA., (© 2022. The Author(s).)

Competing Interests: The authors declare no conflict of interest. J.E.R. was supported by NIH grant 5T32AI007512-34. P.A.N. was supported by NIH grant P30AR070253. M.H.C. was supported by a Rheumatology Research Foundation Scientist Development Award, NIH/NIAID T32AI007512, NIH/NICHD K12HD052896, a Joint Biology Consortium microgrant off parent grant NIH/NIAMS P30AR070253, and a Translation Accelerator Grant from the Human Skin Disease Research NIH/NIAMS P30AR069625.

Published research provides minimal insights into variation by urban or rural residence of HIV infection risk and injection drug use. We used the 2020 Medicare claims data to assess the association of urban-rural residence and concurrent HIV infection and opioid use disorder (OUD), adjusted for demographic risk factors, among Medicare beneficiaries (MBs) with fee-for-service claims paid during 2020. Medicare beneficiaries with both HIV infection and OUD were more likely than those without to be aged ≤64 years, male, Black, residing in the U.S. Northeast, residing in an urban county, and to have one or more comorbid condition. Medicare beneficiaries who lived in urban counties had higher odds (adjusted odds ratio 4.04; 95% confidence interval 3.72, 4.39) of having HIV and OUD than those who lived in rural counties. Urban-rural residence was associated with concurrent HIV infection and OUD, independent of age, sex, race/ethnicity, and comorbidity among MBs with claims paid during 2020.

Background/purpose: The status of nonalcoholic fatty liver disease (NAFLD) can wax and wane over time in children. However, the factors affecting its incidence and remission remain elusive. We aimed to investigate NAFLD incidence, remission and predicting factors in obese children., Methods: Obese children aged 9-10 and 12-13 years were recruited from schools and followed up for 2 years. Liver ultrasonography was performed at baseline and Year 1. Alanine aminotransferase (ALT) concentrations were measured at baseline, Year 1 and Year 2. Elevated ALT was defined as above 26 U/L for boys and 22 U/L for girls. Four NAFLD susceptible genes, including PNPLA3, GCKR, TM6SF2 and MBOAT7, were genotyped. We analyzed the effects of these risk factors on the incidence and remission of NAFLD and elevated ALT., Results: At baseline, 86 of 440 (19.5%) subjects had ultrasonography-diagnosed NAFLD. At Year 1, of 264 subjects without NAFLD at baseline, 20 (7.6%) developed NAFLD. The baseline BMI z-score and increment in BMI z-score independently predicted incident NAFLD. Of the 68 subjects with NAFLD at baseline, 36 (52.9%) had NAFLD remission. Decrement in BMI z-score independently predicted NAFLD remission. The four studied NAFLD susceptible genes were not significantly associated with either the incidence or remission of NAFLD. In addition, changes in BMI z-score predicted the incidence and remission of elevated ALT from Year 1 to Year 2., Conclusion: Obese children with increasing BMI are more likely to develop NAFLD and those with decreasing BMI are more likely to have NAFLD remission., Competing Interests: Declaration of conflicts of interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/purpose: Helicobacter pylori infection is one of the most common causes of peptic ulcer disease among children. This study is aimed to investigate the eradication rate of 14-day sequential therapy and the antibiotic resistance of H. pylori in children., Methods: Eighty-seven treatment-naïve children (55 males; median age, 13.5 years) with H. pylori infection from January 2009 to August 2019 were recruited in this study. The status of H. pylori infection was confirmed by culture or histology with the aid of urea rapid test or C-13 urea breathe test. Patients treated with either triple therapy for 7 days or 14 days, or sequential therapy for 14 days was analyzed retrospectively., Results: Thirty-eight (43.7%) patients received 14-day sequential therapy, 24 (27.6%) patients received 14-day triple therapy and the remaining 25 (28.7%) patients received 7-day triple therapy. The eradication rate of 14-day sequential therapy was significantly superior to 7-day triple therapy (97.4% vs. 80%, p = 0.032), and tended to be better than 14-day triple therapy (83%, p = 0.07). Of the 54 patients with available antibiotic resistance data, the resistant rate of clarithromycin, metronidazole, levofloxacin, and amoxicillin were 22.2%, 16.7%, 9.1% and 2.2%, respectively. Clarithromycin resistance demonstrated an inverse association with eradication success (Odds ratio = 0.017, p < 0.001)., Conclusion: In treatment-naïve children with H. pylori infection, 14-day sequential therapy is superior to triple therapy, and achieve a high eradication rate (above 90%) in an area of high clarithromycin resistance., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Virtual labs provide space for students to iteratively test, observe, and revise their understanding so as to improve their scientific literacy. However, one of the challenges that students face is that they need to think and act like scientists so as to be sensitively alert to methodological flaws and various sources of error. This study thus compared the effect of two instructional approaches using a virtual lab to enhance students' scientific literacy. Before students were given the opportunity to conduct science inquiries with the virtual lab, they were required to critique problematic inquiry cases (the critique group) or watch teachers' demonstrations (the teacher demonstration group) before taking part in the inquiry. By analyzing data from 50 middle school students, this study found that the effect of applying virtual labs can be augmented by an instructional design that engages students in critiquing experiments prior to their inquiry with the virtual lab. This study also found a limitation of the use of virtual labs in helping students transfer what they have learned from the teacher's demonstration to new inquiry contexts. A close relation among scientific literacy post-test scores, critiquing performance, and inquiry performance in the inquiry activity was detected, suggesting that student critiquing prior to inquiry is in alignment with the goal of developing students' inquiry skills and scientific literacy with virtual labs., Competing Interests: Conflict of interestAll authors of this manuscript declare that we have no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022.)

Context: During the COVID-19 pandemic, demand for telehealth services increased to reduce disease exposure for patients and providers and to meet preexisting demand for physician services in health resource shortage areas., Objective: To estimate self-reported telehealth availability, equipment for accessing telehealth, and telehealth usage among Medicare beneficiaries during the COVID-19 pandemic., Design: We used data from the 2020 Medicare Current Beneficiary Survey (MCBS) COVID-19 Fall Supplement Public Use File to estimate the weighted percentages of beneficiaries who had (a) access to telehealth before or during COVID-19; (b) equipment for accessing telehealth; and (c) telehealth visits during COVID-19. We used logistic regression to examine sociodemographic factors associated with telehealth usage., Participants: Beneficiaries who participated in the MCBS COVID-19 Fall Supplements., Results: During October and November 2020, telehealth appointments offered by providers were available to 63.8% (95% confidence interval [CI], 61.8-65.9) of Medicare beneficiaries who had accessed medical care by telephone or video. Among those, only 18.0% (95% CI, 16.1-19.9) had been offered telehealth before the pandemic. The majority of beneficiaries (92.2%; 95% CI, 91.2-93.1) had 1 or more types of equipment available for accessing telehealth, but only 44.9% (95% CI, 43.0-46.9) had had a telehealth visit since July 1, 2020. Older adults, minorities, those with a lower income, and non-English speakers had less availability of telehealth equipment. Patient characteristics were significantly (P < .05) associated with telehealth use, including age, sex, race/ethnicity, and equipment availability., Conclusion: Telehealth availability for Medicare beneficiaries increased substantially during the COVID-19 pandemic. Even with the improvement in telehealth offerings and use hastened by the pandemic, gaps in access and use still exist. Effectiveness and implementation research can find ways to close gaps in telehealth services between vulnerable and underrepresented populations and counterparts., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Parkinson's disease (PD) manifests with dominant motor symptoms and a wide range of non-motor symptoms (NMS). Dementia is one of the most disabling and exhausting NMS throughout the clinical course. We conducted a population-based, age-stratified, retrospective cohort study to investigate the incidence rate and risk of dementia of patients with newly diagnosed PD, and linked to the clinicopathological PD subtypes. Methods: Patients with newly diagnosed PD (PD group, n = 760) and control subjects (non-PD group, n = 3,034) were selected from the Taiwan's National Health Insurance Research Database from January 2001 to December 2005. The dementia incidence rate and dementia-free survival rate were calculated. Results: The overall dementia incidence rate was 17.5 and 5.7 per 1,000 person-years in PD and non-PD groups, respectively. The PD group had a significantly higher overall risk of dementia than controls ( p < 0.001). The younger PD patients had a lower dementia incidence rate than the older PD patients, but a higher dementia risk compared to the same age of controls (<60 years, adjusted HR 6.55, 95% CI 1.56-27.48, p = 0.010). The dementia-free survival rate was significantly lower in the PD group compared to the non-PD group during follow-up ( p < 0.001). Conclusion: In our study, the older age of onset in PD patients resulted in a higher incidence rate of dementia. In the young age of PD patients, the incidence rate of dementia was lower than the older PD patients, but the dementia risk was higher than controls of the same age. These findings possibly implied that there were different pathogenesis and pathologies causing dementia in younger and older PD patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chang, Yang, Chen, Lin and Chang.)

Background: Blepharospasm (BSP) and hemifacial spasm (HFS) are both facial hyperkinesia however BSP is thought to be caused by maladaptation in multiple brain regions in contrast to the peripherally induced cause in HFS. Plausible coexisting pathophysiologies between these two distinct diseases have been proposed. Objectives: In this study, we compared brain resting state functional connectivity (rsFC) and quantitative thermal test (QTT) results between patients with BSP, HFS and heathy controls (HCs). Methods: This study enrolled 12 patients with BSP, 11 patients with HFS, and 15 HCs. All subjects received serial neuropsychiatric evaluations, questionnaires determining disease severity and functional impairment, QTT, and resting state functional MRI. Image data were acquired using seed-based analyses using the CONN toolbox. Results: A higher cold detection threshold was found in the BSP and HFS patients compared to the HCs. The BSP and HFS patients had higher rsFC between the anterior cerebellum network and left occipital regions compared to the HCs. In all subjects, impaired cold detection threshold in the QTT of lower extremities had a correlation with higher rsFC between the anterior cerebellar network and left lingual gyrus. Compared to the HCs, increased rsFC in right postcentral gyrus in the BSP patients and decreased rsFC in the right amygdala and frontal orbital cortex in the HFS subjects were revealed when the anterior cerebellar network was used as seed. Conclusions: Dysfunction of sensory processing detected by the QTT is found in the BSP and HSP patients. Altered functional connectivity between the anterior cerebellar network and left occipital region, especially the Brodmann area 19, may indicate the possibility of shared pathophysiology among BSP, HFS, and impaired cold detection threshold. Further large-scale longitudinal study is needed for testing this theory in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fang, Chen, Chang, Wu and Guo.)

Background: Non-motor subtypes of Parkinson's disease (PD) include the limbic, cognitive, and brainstem phenotype, which may have different pathological pathways with olfaction. In this work, we aim to clarify the association between olfactory dysfunction, depression, cognition, and disease severity in PD. Methods: A total of 105 PD subjects were included and divided into anosmia and non-anosmic groups, using the University of Pennsylvania Smell Identification Test (UPSIT). All patients were evaluated with the movement disorder society unified Parkinson's disease rating scale (MDS-UPDRS), the Beck depression inventory (BDI)-II, and the Montreal cognitive assessment (MoCA). Results: The BDI-II and UPSIT scores had a trend of reverse correlation without statistical significance (β-coefficient -0.12, p = 0.232). However, the odds ratio (OR) in anosmia was 2.74 (95% CI 1.01-7.46) for depression and 2.58 (95% CI 1.06-6.29) for cognitive impairment. For the MDS-UPDRS total and Part 3 score, the anosmia had a β-coefficient of 12.26 (95% CI 5.69-18.82) and 8.07 (95% CI 3.46-12.67), respectively. Neither depression nor cognitive impairment is associated with motor symptoms. Conclusion: More severe olfactory dysfunction in PD is associated with cognitive impairment and greater disease severity. Depression in PD may involve complex pathways, causing relatively weak association with olfactory dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fang, Chang, Yang, Chen and Lin.)

Childhood noninfectious uveitis leads to sight-threatening complications. Idiopathic chronic anterior uveitis and juvenile idiopathic arthritis-associated uveitis are most common. Inflammation arises from an immune response against antigens within the eye. Ophthalmic work-up evaluates anatomic involvement, disease activity, ocular complications, and disease course. Local and/or systemic glucocorticoids are initial treatment, but not as long-term sole therapy to avoid glucocorticoids-induced toxicity or persistent ocular inflammation. Children with recurrent, refractory, or severe disease require systemic immunosuppression with methotrexate and/or anti-tumor necrosis factor monoclonal antibody medications (adalimumab, infliximab). Goals of early detection and treatment are to optimize vision in childhood uveitis., Competing Interests: Disclosure Dr M.H. Chang is supported by a Rheumatology Research Foundation Scientist Development Award, NIH/NICHDK12HD052896, and a Joint Biology Consortium microgrant off parent grant NIH/NIAMSP30AR070253. Dr J.G. Shantha is supported by the National Eye Institute of the National Institutes of Health under award number K23 EY030158. Dr S.T. Angeles-Han is supported by the NIH National Eye Institute under Award Number R01EY030521., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rheumatoid arthritis is a systemic autoimmune disease, but disease flares typically affect only a subset of joints, distributed in a distinctive pattern for each patient. Pursuing this intriguing pattern, we show that arthritis recurrence is mediated by long-lived synovial resident memory T cells (T RM ). In three murine models, CD8+ cells bearing T RM markers remain in previously inflamed joints during remission. These cells are bona fide T RM , exhibiting a failure to migrate between joints, preferential uptake of fatty acids, and long-term residency. Disease flares result from T RM activation by antigen, leading to CCL5-mediated recruitment of circulating effector cells. Correspondingly, T RM depletion ameliorates recurrence in a site-specific manner. Human rheumatoid arthritis joint tissues contain a comparable CD8+-predominant T RM population, which is most evident in late-stage leukocyte-poor synovium, exhibiting limited T cell receptor diversity and a pro-inflammatory transcriptomic signature. Together, these findings establish synovial T RM as a targetable mediator of disease chronicity in autoimmune arthritis., Competing Interests: Declaration of interests R.A.C. has a pending patent application describing depletion of T(RM) as a strategy to treat autoimmune and inflammatory diseases. The other authors declare no relevant competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Osteosarcoma is the most frequent primary malignant bone tumor, composed of mesenchymal cells producing osteoid and immature bone. The sensitive detection of telomerase plays a pivotal role in the early diagnosis and therapeutic treatment of osteosarcoma. We report here an in vitro strategy for sensitive telomerase activity detection through the integration of rolling circle amplification (RCA) and a clustered regularly spaced short palindrome repeats (CRISPR)-Cas12a system. In the proposed strategy, telomerase substrate (TS) primers are easily controlled to extend five bases (GGGTT) to give short telomerase extension products (TEP) with definite lengths without adding dATP. The resulting short TEPs can then cyclize the padlock through hybridizing with its two terminals and thus initiate the following RCA. To obtain an improved sensitivity, the CRISPR-Cas12a system is attached to collaterally cut surrounding DNA reporter probes after recognizing the target single strand DNA sequence in the RCA products. The highlights of this strategy are as follows: (i) the short TEP triggered strategy is excellent at detecting low telomerase activity and thus contributes to the early diagnosis of malignant tumors; (ii) highly sensitive telomerase activity detection which is easy to operate from RCA initiated CRISPR-Cas12a; (iii) opening up of a new avenue for telomerase activity detection with a CRISPR-Cas12a system. Finally, the proposed strategy exhibited sensitive telomerase activity detection under optimized experimental parameters and has great application potential for the clinical diagnosis of malignant tumors and the development of anti-cancer drugs.

Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children, yet the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq), DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4+, CD8+, and γδ T cells expressed Th1-related markers, whereas Th17 cells were not enriched. Th1 skewing was prominent in CD4+ T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4+ T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg-specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. Although synovial fluid CD4+ T cells displayed an overall Th1 phenotype, scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced Tregs, peripheral helper T cells, and cytotoxic CD4+ T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.

Background: Primary sclerosing cholangitis (PSC) is often associated with ulcerative colitis (UC). We investigated the clinical characteristics of pediatric UC patients with and without PSC., Methods: We retrospectively recruited children with UC, with and without PSC, from 2006 to 2017 in a tertiary center in Taiwan. The clinical data of the patients, including clinical and endoscopic UC severity scores, medications, and laboratory parameters, were analyzed., Results: We recruited five children with PSC-UC (PSC-UC group), and 26 with UC alone (non-PSC UC group) in this retrospective analysis. Among the patients with PSC-UC, four (80%) were compatible with definite or probable autoimmune sclerosing cholangitis (ASC). The UC Endoscopic Index of Severity (5.00 vs. 9.00, P = 0.003) and Mayo score (4.00 vs. 8.00, P = 0.014) were significantly lower in the PSC-UC group than the non-PSC UC group. The prevalence of immunomodulator use was significantly higher in the PSC-UC than the non-PSC UC group (100% vs. 42.3%, P = 0.043), but there was no difference regarding steroids, mesalamine, or biologics. At the end of the study, significantly fewer patients were steroid-free in the PSC-UC than the non-PSC UC group (20.0% vs. 84.6%, P = 0.010)., Conclusions: Pediatric patients with PSC-UC had less severe colitis than those with UC alone in terms of the clinical activity index and endoscopic severity index, but they were more likely to need an immunomodulator and less likely to be steroid-free in the long term, for the control of liver disease., Competing Interests: Declaration of competing interest The authors declared no potential, perceived, or real conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Earthquakes occur thousands of times every day around the world. They are naturally destructive seismic events and often result in soil liquefaction. Soil microbiota plays a vital role in soil environments and may serve as an effective indicator to assess soil liquefaction after earthquakes. This study aimed to detect the microbial community abundance and composition in soil samples of different depths. Soil samples were collected in Southern Taiwan immediately after the 2010 earthquake. Their physical characteristics were determined, and their microbial communities were analyzed through 16S amplicon sequencing. The results revealed that Nitrospirae phylum dominated in the liquefied layer. In particular, the genus HB118 , dominant in the liquefied layer, was not detected at other soil depths or in the expelled liquefied soil. This finding not only provides valuable insights into changes in microbial community composition at different soil depths after earthquakes but also suggests a useful indicator for monitoring liquefied soil., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Biliary stricture is an important biliary complication after liver transplant in children. We aimed to investigate the utility of serum bile acid levels for prediction of biliary stricture in children after liver transplant. This study enrolled 60 children who underwent liver transplantation at a mean age of 2.04±0.30 years; serum bile acid levels were surveyed in a cross-sectional design. These patients were followed regularly at our institute, and the clinical data were collected prospectively. The major indication of liver transplant in this pediatric cohort was biliary atresia (78.33%). During the follow-up period (3.08±0.30 years), nine patients (15%) developed biliary stricture after the check of serum bile acid. A receiver operating characteristic curve analysis yielded a serum bile acid cutoff of >40 μM for the prediction of biliary stricture (P = 0.002). A serum bile acid level >40 is the most important predictor of a biliary stricture after liver transplant (odds ratio=65.65, P = 0.003) after adjusting for gender and GGT levels. The phenomenon remained on Cox's proportional hazard survival analysis (hazard ratio =15.42, P = 0.001). The mortality risk after liver transplant was significantly higher in subjects with serum bile acid levels >40 μM than in those with levels ≤40 μM (log-rank test, P = 0.004).Conclusion: Serum bile acid levels can be used for non-invasive screening and prediction of biliary stricture and mortality in children after liver transplantation. What is Known: • Biliary stricture is a major biliary complication after pediatric liver transplantation, and we showed the serum bile acid level significantly associates with biliary stricture. What is New: • In this study, we demonstrated the serum bile acid level may assist in the early detection of biliary stricture and mortality non-invasively., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Introduction: Pain is prevalent in juvenile idiopathic arthritis (JIA). Unknowns regarding the biological drivers of pain complicate therapeutic targeting. We employed neuroimaging to define pain-related neurobiological features altered in JIA., Methods: 16 male and female JIA patients (12.7 ± 2.8 years of age) on active treatment were enrolled, together with age- and sex-matched controls. Patients were assessed using physical examination, clinical questionnaires, musculoskeletal MRI, and structural neuroimaging. In addition, functional magnetic resonance imaging (fMRI) data were collected during the resting-state, hand-motor task performance, and cold stimulation of the hand and knee., Results: Patients with and without pain and with and without inflammation (joint and systemic) were evaluated.  Pain severity was associated with more physical stress and poorer cognitive function. Corrected for multiple comparisons, morphological analysis revealed decreased cortical thickness within the insula cortex and a negative correlation between caudate nucleus volume and pain severity. Functional neuroimaging findings suggested alteration within neurocircuitry structures regulating emotional pain processing (anterior insula) in addition to the default-mode and sensorimotor networks., Conclusions: Patients with JIA may exhibit changes in neurobiological circuits related to pain. These preliminary findings suggest mechanisms by which pain could potentially become dissociated from detectable joint pathology and persist independently of inflammation or treatment status., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Amphibian species are highly vulnerable to climate change with significant species decline and extinction predicted worldwide. However, there are very limited studies on amphibians in South Korea. Here, we assessed the potential impacts of climate change on different habitat groups (wetland amphibians, Group 1; migrating amphibians, Group 2; and forest-dwelling amphibians, Group 3) under future climate change and land cover change in South Korea using a maximum entropy modelling approach. Our study revealed that all amphibians would suffer substantial loss of suitable habitats in the future, except Lithobates catesbeianus , Kaloula borealis , and Karsenia koreana . Similarly, species richness for Groups 2 and 3 will decline by 2030, 2050, and 2080. Currently, amphibian species are widely distributed across the country; however, in future, suitable habitats for amphibians would be concentrated along the Baekdudaegan Mountain Range and the southeastern region. Among the three groups, Group 3 amphibians are predicted to be the most vulnerable to climate change; therefore, immediate conservation action is needed to protect them. We expect this study could provide crucial baseline information required for the government to design climate change mitigation strategies for indigenous amphibians.

Context: Approximately 80% of US tuberculosis (TB) cases verified during 2015-2016 were attributed to untreated latent TB infection (LTBI). Identifying factors associated with LTBI treatment failure might improve treatment effectiveness., Objective: To identify patients with indicators of isoniazid (INH) LTBI treatment initiation, completion, and failure., Methods: We searched inpatient and outpatient claims for International Classification of Diseases (Ninth and Tenth Revisions), National Drug, and Current Procedural Terminology codes. We defined treatment completion as 180 days or more of INH therapy during a 9-month period. We defined LTBI treatment failure as an active TB disease diagnosis more than 1 year after starting LTBI treatment among completers and used exact logistic regression to model possible differences between groups. Among treatment completers, we matched 1 patient who failed treatment with 2 control subjects and fit regression models with covariates documented on medical claims paid 6 months or less before INH treatment initiation., Participants: Commercially insured US patients in a large commercial database with insurance claims paid during 2005-2016., Main Outcome Measures: (1) Trends in treatment completion; (2) odds ratios (ORs) for factors associated with treatment completion and treatment failure., Results: Of 21 510 persons who began LTBI therapy during 2005-2016, 10 725 (49.9%) completed therapy. Treatment noncompletion is associated with those younger than 45 years, living in the Northeast or South Census regions, and women. Among persons who completed treatment, 30 (0.3%) progressed to TB disease. Diagnoses of rheumatoid arthritis during the 6 months before treatment initiation and being aged 65 years or older (reference: ages 0-24 years) were significantly associated with INH LTBI treatment failure (adjusted exact OR = 5.1; 95% CI, 1.2-28.2; and adjusted exact OR = 5.1; 95% CI, 1.2-25.3, respectively)., Conclusion: Approximately 50% of persons completed INH LTBI therapy, and of those, treatment failure was associated with rheumatoid arthritis and persons 65 years or older among a cohort of US LTBI patients with commercial health insurance., Competing Interests: The authors have no nongovernmental sources of funding or conflicts of interest to declare for this research., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Tenofovir disoproxil fumurate (TDF) therapy during late pregnancy in highly viremic mothers can reduce residual overt hepatitis B virus (HBV) infections of their infants that occur despite immunoprophylaxis. 1 , 2 Occult HBV infection (OBI) has been defined as the presence of HBV DNA in liver or sera in subjects seronegative for hepatitis B surface antigen (HBsAg). 3 OBI has been found in varying proportions of immunized infants born to HBsAg-positive mothers. 4-6 We aimed to investigate the impact of maternal TDF therapy during pregnancy on vertically acquired OBI., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The South China Sea (SCS) is a high biodiversity region in the world ocean, supports abundant marine resources to the peripheral nations, and affects weather/climate in southeast Asia. A better understanding of its circulation is important to better prediction and management of the SCS. Here we reveal sizable intraseasonal oscillations at period ~ 50 days between May and November 2017 in the acoustic Doppler current profiler observed velocity in the central SCS. Satellite observed wind and sea level data together with a process-oriented numerical experiment suggest that the oscillations were caused by locally-generated and remotely-penetrated westward-propagating Rossby waves. The summer southwesterly monsoon strengthening/weakening and the resultant Ekman pumping velocity and shoreward Ekman transport increase/decrease and consequent coastal sea level rise/fall off the west coast of Palawan create westward-propagating Rossby waves causing velocity oscillations in the central SCS. Besides the local generation, Rossby waves with sea level anomaly > 0.2 m propagating from the Pacific through the Sulu Sea into the SCS could contribute to the intraseasonal velocity oscillations in the central SCS.

Background: To estimate real-world outcomes in East Asian populations, we conducted a nationwide retrospective analysis of the efficacy and safety of lenalidomide for del(5q) myelodysplastic syndrome (MDS) patients with transfusion-dependent anemia in Korea., Methods: Patients aged ≥19 years who had received lenalidomide for the treatment of lower-risk, red blood cell (RBC) transfusion-dependent del(5q) MDS were selected. A filled case report form (CRF) with information from electronic medical records was requested from members of the acute myeloid leukemia (AML)/MDS Working Party of the Korean Society of Hematology. All the CRFs were gathered and analyzed., Results: A total of 31 patients were included in this study. Of 28 evaluable patients, 19 (67.9%) achieved RBC transfusion independence (RBC-TI). Female sex and the development of thrombocytopenia during treatment were associated with achieving RBC-TI. The most common non-hematologic toxicities were pruritus, fatigue, and rashes. All non-hematologic toxicities of grades ≥3 were limited to rash (12.9%) and pruritus (6.5%). Dose reduction was required in 15 of the 19 responders (78.9%). The most common final stable dosing schedule for the responders was 5 mg once every other day (31.6%)., Conclusion: Lenalidomide efficacy and tolerability were similar in the Asian del(5q) MDS patients and western patients. Dose reduction during treatment was common, but it was not associated with inferior outcomes.

Background: Peripheral nerve injuries result in muscle denervation and apoptosis of the involved muscle, which subsequently reduces mitochondrial content and causes muscle atrophy. The local injection of mitochondria has been suggested as a useful tool for restoring the function of injured nerves or the brain., Objective: To determine outcomes following the administration of isolated mitochondria into denervated muscle after nerve injury that have not been investigated., Methods: Muscle denervation was conducted in a sciatic nerve crushed by a vessel clamp and the denervated gastrocnemius muscle was subjected to 195 μg hamster green fluorescent protein (GFP)-mitochondria intramuscular infusion for 10 min., Results: The mitochondria were homogeneously distributed throughout the denervated muscle after intramuscular infusion. The increases in caspase 3, 8-oxo-dG, Bad, Bax, and ratio of Bax/Bcl-2 levels in the denervated muscle were attenuated by mitochondrial infusion, and the downregulation of Bcl-2 expression was prevented by mitochondrial infusion. In addition, the decrease in the expression of desmin and the acetylcholine receptor was counteracted by mitochondrial infusion; this effect paralleled the amount of distributed mitochondria. The restoration of the morphology of injured muscles and nerves was augmented by the local infusion of mitochondria. Mitochondrial infusion also led to improvements in sciatic functional indexes, compound muscle action potential amplitudes, and conduction latencies as well as the parameters of CatWalk (Noldus) gait analysis., Conclusion: The local infusion of mitochondria can successfully prevent denervated muscle atrophy and augment nerve regeneration by reducing oxidative stress in denervated muscle., (© Congress of Neurological Surgeons 2021.)

Objective: To clarify the association of anosmia or constipation with cognitive dysfunction and disease severity in patients with Parkinson's disease (PD)., Methods: Newly diagnosed patients with PD (less than 5 years) without a clinical diagnosis of dementia were included from February 2017 to August 2018. The subjects were further divided into subgroups based on whether anosmia occurred and the grade of constipation. The severity of PD motor symptoms was rated using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and cognitive functions were evaluated by Montreal Cognitive Assessment (MoCA). Statistical analyses including t-tests, chi-square tests, multiple linear regression, and binary logistic regression were used to determine statistical significance., Results: A total of 107 newly diagnosed PD patients were included in this study. The MoCA score was significantly lower in the anosmia group (p < 0.001). Constipation was associated with impaired olfaction in a post-hoc test. The correlation coefficient between MoCA and UPSIT score was 0.41 (p < 0.001). Total anosmia and age were associated with cognitive dysfunction (MoCA < 26) (odds ratio, 2.63, p = 0.003; 1.10, p < 0.001, respectively). The anosmia group had a higher MDS-UPDRS part 3 score with β coefficient of 7.30 (p = 0.02). Furthermore, grade 3 constipation was associated with a higher MDS-UPDRS total score with β coefficient of 14.88 (p = 0.02)., Conclusions: Anosmia but not constipation was associated with cognitive impairment in PD patients. Nevertheless, severe constipation was associated with impaired olfaction and PD disease severity. We suggest that the propagation of α-synuclein from the olfactory route is distinct from the enteric nervous system, but the intercommunication between these two routes is complex., Competing Interests: The authors have declared that no competing interests exist.

Background: We investigated the relationships among the percentage of hepatitis B virus (HBV) mutations and liver fibrosis after hepatitis B e antigen (HBeAg) seroconversion., Methods: We quantified the percentage of HBV mutants by pyrosequencing using serum samples obtained at inflammatory phase and after HBeAg seroconversion in 160 initially HBeAg-positive chronic HBV-infected patients. The relationships between antiviral agents, percentages of HBV mutations, and liver stiffness measurements (LSMs) were analyzed., Results: We demonstrated that the percentages of A1762T/G1764A mutation are significantly higher in subjects with an LSM >7 kPa than in those with an LSM ≤7 kPa after HBeAg seroconversion. Hepatitis B e antigen seroconversion age is positively correlated with the percentages of A1762T/G1764A mutation at inflammatory phase before HBeAg seroconversion. Subjects who underwent interferon, entecavir, or tenofovir disoproxil fumarate therapy before HBeAg seroconversion possessed a lower percentage of A1762T/G1764A mutation after HBeAg seroconversion. The percentage of A1762T/G1764A ≥20% after HBeAg seroconversion was predictive of an LSM >7 kPa (hazard ratio = 6.37, P = .001). The presence of A1762T/G1764A led to downregulated messenger ribonucleic acid and protein levels of programmed-death ligand-1 (PD-L1) in hepatocytes., Conclusions: The percentage of A1762T/G1764A mutations after HBeAg seroconversion was associated with liver fibrosis. The A1762T/G1764A mutation may evoke hepatic inflammation by suppressing PD-L1 in hepatocytes., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The complex isolation and purification process of hepatocytes for transplantation is labor intensive and with great contamination risk. Here, as a pilot and feasibility study, we examined in vitro and in vivo hepatocyte isolation feasibility and cell function of Cell Saver ® Elite ® , an intraoperative blood-cell-recovery system., Methods: Rat and pig liver cells were collected using this system and then cultured in vitro, and their hepatocyte-specific enzymes were characterized. We then transplanted the hepatocytes in an established acute liver-injured (retrorsine+D-galactosamine-treated) rat model for engraftment. Recipient rats were sacrificed 1, 2, and 4 weeks after transplantation, followed by donor-cell identification and histological, serologic, and immunohistopathological examination. To demonstrate this Cell Saver ® strategy is workable in the first place, traditional (classical) strategy, in our study, behaved as certainty during the cell manufacturing process for monitoring quality assurance throughout the course, from the start of cell isolation to post-transplantation., Results: We noted that in situ collagenase perfusion was followed by filtration, centrifugation, and collection in the Cell Saver ® until the process ended. Most (>85%) isolated cells were hepatocytes (>80% viability) freshly demonstrating hepatocyte nuclear factor 4α and carbamoyl-phosphate synthase 1 (a key enzyme in the urea cycle), and proliferating through intercellular contact in culture, with expression of albumin and CYP3A4. After hepatocyte transplantation in dipeptidyl peptidase IV (-/-) rat liver, wild-type donor hepatocytes engrafted and repopulated progressively in 4 weeks with liver functional improvement. Proliferating donor hepatocyte-native biliary ductular cell interaction was identified. Post-transplantation global liver functional recovery after Cell Saver and traditional methods was comparable., Conclusions: Cell Saver ® requires reduced manual manipulation for isolating transplantable hepatocytes.

Aim: To explore the effect of home-based exercise on motor symptoms (MS), non-motor symptoms (NMS), and health-related quality of life (HRQOL) in Parkinson's disease (PD) patients., Methods: This study was a randomized control trial with a convenience sample of 98 PD patients. Data were collected at baseline and interventions after 4 and 8 weeks. The exercise group was instructed to perform 150 min/week of exercise at home; the control group maintained their regular lifestyle. Questionnaires measured MS, NMS, and HRQOL. We also compare compliance and non-compliance subgroups of the exercise group. The generalized estimating equation (GEE) was used to determine the exercise effect of 120 and 150 min per week after testing for exercise times was at six time points (90-140 min)., Results: The exercise (n = 49) and control groups (n = 49) were homogeneous except for disease stage at baseline. Significant differences were found for depression, HRQOL, motor ability, activity of daily living, and fatigue (p < .000) between the exercise and control groups, and also between the compliance and non-compliance subgroups (p < .05). The GEE revealed that exercising 150 min/week significantly improved HRQOL, depression, motor ability, ADL, fatigue, and sleep quality (p < .05), though not anxiety, and exercising 120 min/week was also effective., Conclusions: This home-based exercise was effective in improving MS, NMS, and HRQOL. We recommend PD patients to exercise 30-50 min at least three times a week, or 10-15 min per session daily, to accumulate 120-150 min per week., (© 2021 Japan Academy of Nursing Science.)

The gold-spotted pond frog ( Pelophylax chosenicus ) is an endangered amphibian species in South Korea. In order to obtain ecological information regarding the gold-spotted pond frog's habitat environment and biological interactions, we applied stable isotope analysis to quantify the ecological niche space (ENS) of frogs including black-spotted pond frogs ( P. nigromaculatus ) and bullfrogs ( Lithobates catesbeianus ) within the food web of two different habitats-an ecological wetland park and a rice paddy. The gold-spotted pond frog population exhibited a broader ENS in the ecological wetland park than in the rice paddy. According to the carbon stable isotope ratios, gold-spotted pond frogs mainly fed on insects, regardless of habitat type. However, the results comparing the range of both carbon and nitrogen stable isotopes showed that gold-spotted pond frogs living in the rice paddy showed limited feeding behavior, while those living in the ecological wetland park fed on various food sources located in more varied trophic positions. Although the ENS of the gold-spotted pond frog was generally less likely to be overlapped by that of other frog species, it was predicted to overlap with a high probability of 87.3% in the ecological wetland park. Nevertheless, gold-spotted pond frogs in the ecological wetland park were not significantly affected by the prey competition with competitive species by feeding on other prey for which other species' preference was low. Since these results show that a habitats' food diversity has an effect on securing the ENS of gold-spotted pond frogs and prey competition, we recommend that the establishment of a food environment that considers the feeding behavior of gold-spotted pond frogs is important for the sustainable preservation of gold-spotted pond frogs and their settlement in alternative habitats.

Background: Despite timely administration of IVIG, some patients with Kawasaki disease (KD) develop rapidly progressive or giant coronary artery aneurysms (CAA)., Case Presentation: We describe our experience using cyclophosphamide (CYC) for the treatment of such cases as well as a review of the literature on the use of CYC in KD. Through a retrospective chart review of our KD population, we identified ten children treated for KD with intravenous CYC (10 mg/kg/dose) for one or two doses. Seven patients were male, the median age was 2.0 years (range 4 months - 5 years). All patients received initial IVIG between day 4-10 of illness. Other anti-inflammatory treatments administered before CYC included second IVIG (n = 9), corticosteroids (n = 10), infliximab (n = 4), cyclosporine (n = 2), and anakinra (n = 1). Median illness day at administration of the first CYC dose was 22.5 days (range:10-36 days). The primary indication for treatment with CYC for all patients was large or giant CAA and/or rapid progression of CAA. Three patients received a second dose of CYC (10 mg/kg) for progressively enlarging CAA. CAA did not progress after final CYC treatment. One patient with a history of neutropenia in infancy developed severe neutropenia 9 days after treatment with CYC, which recovered without intervention or complications. No patient developed infections or other serious toxicity from CYC., Conclusion: In KD patients with severe and progressive enlargement of CAA despite anti-inflammatory therapy, CYC seemed to arrest further dilation and was well-tolerated. Future multicenter studies are needed to confirm our findings in this subgroup of KD patients.

Background: The bile salt export pump (BSEP) is a pivotal apical/canalicular bile salt transporter in hepatocytes that drives the bile flow. Defects in BSEP function and canalicular expression could lead to a spectrum of cholestatic liver diseases. One prominent manifestation of BSEP-associated cholestasis is the defective canalicular localization and cytoplasmic retention of BSEP. However, the etiology of impaired BSEP targeting to the canalicular membrane is not fully understood. Our goal was to discover what molecule could interact with BSEP and affect its post-Golgi sorting., Methods: The human BSEP amino acids (a.a.) 491-630 was used as bait to screen a human fetal liver cDNA library through yeast two-hybrid system. We identified a BSEP-interacting candidate and showed the interaction and colocalization in the co-immunoprecipitation in hepatoma cell lines and histological staining in human liver samples. Temperature shift assays were used to study the post-Golgi trafficking of BSEP. We further determine the functional impacts of the BSEP-interacting candidate on BSEP in vitro. A hydrodynamically injected mouse model was established for in vivo characterizing the long-term impacts on BSEP., Results: We identified that charged multivesicular body protein 5 (CHMP5), a molecule of the endosomal protein complex required for transport subcomplex-III (ESCRT-III), interacted and co-localized with BSEP in the subapical compartments (SACs) in developing human livers. Cholestatic BSEP mutations in the CHMP5-interaction region have defects in canalicular targeting and aberrant retention at the SACs. Post-Golgi delivery of BSEP and bile acid secretion were impaired in ESCRT-III perturbation or CHMP5-knockdown hepatic cellular and mouse models. This ESCRT-III-mediated BSEP sorting preceded Rab11A-regulated apical cycling of BSEP., Conclusions: Our results showed the first example that ESCRT-III is essential for canalicular trafficking of apical membrane proteins, and provide new targets for therapeutic approaches in BSEP associated cholestasis.

Biliary atresia (BA) is a challenging liver disease in infancy. Early diagnosis of BA is important for timely hepatoportoenterostomy. We evaluated the age-specific diagnostic performance of transient elastography (TE) with a liver stiffness measurement (LSM) greater than 7.7 kPa in BA among infants with cholestasis. A total of 61 infants with cholestasis (5-121 days of age) were enrolled in this prospective follow-up study; 15 infants were BA. Four age groups were defined (≤30, 31-60, 61-90, and 91-180 days). Picrosirius red staining was performed to quantify the percentage of collagen fibers in liver specimens. The utility of an LSM greater than 7.7 kPa for diagnosis of BA among infants with cholestasis was compared among age groups. In all four groups, TE showed high diagnostic power for BA using the criterion of an LSM greater than 7.7 kPa. Positive predictive values were 100%, 100%, and 100% in the groups aged 30 days or younger, 31 to 60 days, and 61 to 90 days, respectively. Respective negative predictive values were 90.9%, 94.7%, and 100%, and respective diagnostic accuracies were 92.9%, 95.2%, and 100%. The positive predictive value, negative predictive value, and diagnostic accuracy were 100%, 100%, and 100%, respectively, for LSM greater than 8.8 kPa in the group aged 91 to 180 days. The LSM was positively correlated with the percentage of collagen fibers stained by picrosirius red ( P  = 0.03). Conclusion: In this prospective follow-up study, TE had good diagnostic accuracy for differentiation of BA from non-BA cholestasis in infants with cholestasis who were 90 days of age or younger. The LSM was significantly positive correlated with the liver fibrosis status stained by picrosirius red in infants with cholestasis., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background: The relationship between postprandial hyperglycaemia and diabetic peripheral neuropathy (DPN), whether painful or painless, has yet to be determined. Thus, the aim of this study was to investigate the relationship in patients with type 2 diabetes (T2D)., Methods: This cross-sectional study was conducted in adults with T2D between January and October 2013. Blood samples were collected after overnight fasting every 3 months prior to enrolment. For this study, increased postprandial glycaemic exposure was defined as high glycated haemoglobin (HbA 1c ) and near-normal mean fasting plasma glucose (FPG) levels. Both painless and painful DPN were evaluated using two validated tools, the Michigan Neuropathy Screening Instrument (MNSI) and Douleur Neuropathique 4 (DN4) questionnaire., Results: This study included 1040 participants with mean FPG levels<140mg/dL, 535 of which were<126mg/dL. Of these patients, 200/1040 (19.2%) and 105/535 (19.6%) had DPN. Multivariate analysis demonstrated that higher HbA 1c levels (≥7%) did not increase risk of painless DPN, but did significantly increase risk of painful DPN in T2D patients with FPG<140mg/dL and<126mg/dL, with corresponding odds ratios of 2.49 and 3.77 (95% confidence intervals: 1.09-5.71 and 1.20-11.79), respectively, after adjusting for demographic factors, diabetes-related variables and comorbidities., Conclusion: This study is the first to reveal that increased postprandial glycaemic exposure, as assessed by high HbA1c and near-normal FPG levels, is associated with an increased risk of painful DPN in adults with T2D., (Copyright © 2020. Published by Elsevier Masson SAS.)

The C-reactive protein-to-albumin ratio (CAR) has not been assessed in diffuse large B cell lymphoma (DLBCL, the most common non-Hodgkin lymphoma). This retrospective study evaluated the prognostic value of CAR in 186 DLBCL patients. A CAR value of 0.158 was selected as the most discriminative cut-off for identifying patients with high CAR values (73/141 patients, 51.8%). During a median follow-up of 32.5 months, the high CAR group had significantly poorer complete response to induction therapy (64.4% vs. 92.6%; p < 0.001), 3-year overall survival (OS) (68.3% vs. 96.2%; p < 0.0001), and 3-year progression-free survival (PFS) (53.5% vs. 88.0%; p < 0.0001). After adjusting for the International Prognostic Index components, a high CAR value independently predicted poor OS (HR: 6.02, 95% CI 1.19-30.38; p = 0.030) and PFS (HR: 3.62, 95% CI 1.40-9.36; p = 0.008). In an independent validation cohort (n = 50), patients with CAR > 0.158 also showed worse 3-year OS (47.9% vs. 87.2%, p = 0.0035) and 3-year PFS (36.1% vs. 82.1%, p = 0.0011). A high CAR remained significantly associated with poor outcomes for > 60-year-old patients (OS: p = 0.0038, PFS: p = 0.0015) and younger patients (OS: p = 0.0041, PFS: p = 0.0044). Among older patients, a high CAR value also predicted non-relapse mortality (p = 0.035). Therefore, the CAR might complement the International Prognostic Index in DLBCL cases.

Background/purpose: Anastomotic stricture (AS) is a major morbidity of patients with esophageal atresia (EA) after surgical reconstruction. Our study determined the risk factors of AS after EA reconstruction. The therapeutic efficacy and complications of esophageal dilatation for children with AS were also evaluated., Methods: Forty children treated for EA between January 2008 and December 2018 were included in this retrospective analysis. Esophageal dilatation was performed when AS was diagnosed. The therapeutic effect of esophageal dilatation was determined based on nutritional status, as assessed by the weight-for-age z-score., Results: Sixteen EA patients developed AS. A gap >1.5 cm between the esophageal pouches (P = 0.02) in patients with EA and type A EA was a risk factor for developing AS. A mean of 7.7 sessions of esophageal dilatation were performed per patient, and no complications occurred. The nutritional status of EA children with AS after dilatation was not inferior to that of the children without AS at the 6-month follow-up., Conclusion: A gap >1.5 cm between the esophageal pouches and type A EA are risk factors for AS after esophageal reconstruction. Esophageal dilatation is both safe and effective for managing strictures and improves nutritional status in EA children with AS., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population starting from birth dose, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective, the cancer preventive efficacy support it as the first successful example of cancer preventive vaccine in human. Addition of hepatitis B immunoglobulin immediately after birth and antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are existing or possible emerging strategies to enhance the prevention efficacy of HBV infection and its related liver cancer. Secondary prevention with current antiviral agents may reduce the risk or delay the onset of HCC development, but could not eradicate HBV infection and HCC. Better antiviral therapeutic agents are needed for better secondary prevention.

Various stresses derived from both internal and external oxidative environments lead to the excessive production of reactive oxygen species (ROS) causing progressive intracellular oxidative damage and ultimately cell death. The objective of this study was to evaluate the protective effects of Citrus junos Tanaka peel extract (CE) against oxidative-stress induced the apoptosis of lung cells and the associated mechanisms of action using in vitro and in vivo models. The protective effect of CE was evaluated in vitro in NCI-H460 human lung cells exposed to pro-oxidant H 2 O 2 . The preventive effect of CE (200 mg/kg/day, 10 days) against pulmonary injuries following acrolein inhalation (10 ppm for 12 h) was investigated using an in vivo mouse model. Herein, we demonstrated the inhibitory effect of CE against the oxidative stress-induced apoptosis of lung cells under a highly oxidative environment. The function of CE is linked with its ability to suppress ROS-dependent, p53-mediated apoptotic signaling. Furthermore, we evaluated the protective role of CE against apoptotic pulmonary injuries associated with the inhalation of acrolein, a ubiquitous and highly oxidizing environmental respiratory pollutant, through the attenuation of oxidative stress. The results indicated that CE exhibits a protective effect against the oxidative stress-induced apoptosis of lung cells in both in vitro and in vivo models.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

Background: Community onset K. pneumoniae bacteremia (KPB) is a major problem in Taiwan for decades. We aimed to revisit the role of virulent genotype K1/K2 and possible predisposing factors, compared to our published 2007 cohort., Methods: All adult patients with monomicrobial KPB during 2017 at a medical center in Taiwan were prospectively enrolled. We genotyped the major K types of K. pneumoniae strains, and analyzed the role of prior use of antibiotic or proton pump inhibitor (PPI)., Results: A total of 213 cases were enrolled. Compared to our previous 2007 study (n = 231), there was a higher percentage of patients with community onset bacteremia (75% vs. 60%, p = 0.003). The overall mortality rate was lower in 2017 (23% vs. 32%, p = 0.02), while the rates of antimicrobial resistance (all classes) were higher in 2017. There were 40 cases of liver abscesses in 2017 (19%), with an overall mortality rate of 7.5%. The prevalence of K1 was similar (16% in 2017 vs. 19% in 2007), but the prevalence of K2 decreased significantly (7% in 2017 vs. 17% in 2007, p = 0.001). After excluding 39 cases without data of recent medication use, 48 of 174 (28%) of patients had received a PPI within 90 days. Patients with recent PPI use had more complicated underlying illnesses, higher antimicrobial resistance, and higher in-hospital mortality, but was negatively associated with liver abscess (4% vs. 24%, p = 0.002). Of patients with community-acquired bacteremia, 51% used antibiotics within 90 days. After excluding 37 patients received antibiotics within 14 days before the detection of bacteremia, patient with antibiotic use within 15-90 days had higher Pittsburgh bacteremia scores (4.5 vs. 2.7, p = 0.04), creatinine levels, and frequency of recent surgery, but was not associated with liver abscess (21% vs. 31%, p = 0.33)., Discussion: In summary, after a decade, community onset KPB is still prevalent (1.3 case per 1000 emergency department visit). K1 remains to be the dominant genotype. The association of prior ampicillin/amoxicillin or PPIs use for liver abscess is not confirmed., Competing Interests: Declaration of Competing Interest All authors report no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Background: This study aimed to clarify whether Parkinson's disease (PD) and depression were independent risk factors or with synergic effects in dementia., Methods: Newly diagnosed PD ( n  = 1213) patients and control subjects ( n  = 4852) were selected from the Taiwan National Health Insurance Research Database from January 2001 through December 2008. Follow-up ended in 2011 with an outcome of dementia occurring or not. This cohort was divided into controls with or without depression, PD only, and PD with depression. The incident rate of dementia and hazard ratio (HR) using Cox's regression analysis were calculated for each group., Results: When compared with controls without depression as HR 1.00, the adjusted HR for dementia was 3.29 ( p < 0.001) in the PD only group, 2.77 ( p < 0.001) in the PD with depression group, and 1.55 ( p =0.024) in the depression only group. The incident rate of dementia was 29.2 (per 1000 person-years) in the PD only group and 13.2 in the PD with depression group. The effect of PD on dementia in the depression group produced a HR of 0.97 ( p =0.905)., Conclusions: Parkinson's disease served as a risk factor for dementia. By comparison, depression was not a risk factor for dementia in PD patients, although it did act as a risk factor for dementia., Competing Interests: All authors declare that they have no conflicts of interest., (Copyright © 2020 Ting-Chun Fang et al.)

Generation of a safe, economical, and effective vaccine capable of inducing mucosal immunity is critical for the development of vaccines against enteric viral diseases. In the current study, virus-like particles (VLPs) containing the spike (S), membrane (M), and envelope (E) structural proteins of porcine epidemic diarrhea virus (PEDV) expressed by the novel polycistronic baculovirus expression vector were generated. The immunogenicity and protective efficacy of the PEDV VLPs formulated with or without mucosal adjuvants of CCL25 and CCL28 (CCL25/28) were evaluated in post-weaning pigs. While pigs intramuscularly immunized with VLPs alone were capable of eliciting systemic anti-PEDV S-specific IgG and cellular immunity, co-administration of PEDV VLPs with CCL25/28 could further modulate the immune responses by enhancing systemic anti-PEDV S-specific IgG, mucosal IgA, and cellular immunity. Upon challenge with PEDV, both VLP-immunized groups showed milder clinical signs with reduced fecal viral shedding as compared to the control group. Furthermore, pigs immunized with VLPs adjuvanted with CCL25/28 showed superior immune protection against PEDV. Our results suggest that VLPs formulated with CCL25/28 may serve as a potential PEDV vaccine candidate and the same strategy may serve as a platform for the development of other enteric viral vaccines.