In vivo adenine base editing rescues adrenoleukodystrophy in a humanized mouse model.

X-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the brain, spinal cord, adrenal glands, and testes. In ALD patients, very-long-chain fatty acids (VLCFAs) fail to enter the peroxisome and undergo subsequent ß-oxidation, resulting in their accumulation in the body. It has not been tested whether in vivo base editing or prime editing can be harnessed to ameliorate ALD. We developed a humanized mouse model of ALD by inserting a human cDNA containing the pathogenic variant into the mouse Abcd1 locus. The humanized ALD model showed increased levels of VLCFAs. To correct the mutation, we tested both base editing and prime editing and found that base editing using ABE8e(V106W) could correct the mutation in patient-derived fibroblasts at an efficiency of 7.4%. Adeno-associated virus (AAV)-mediated systemic delivery of NG-ABE8e(V106W) enabled robust correction of the pathogenic variant in the mouse brain (correction efficiency: ∼5.5%), spinal cord (∼5.1%), and adrenal gland (∼2%), leading to a significant reduction in the plasma levels of C26:0/C22:0. This established humanized mouse model and the successful correction of the pathogenic variant using a base editor serve as a significant step toward treating human ALD disease.

RFX4 is an intrinsic factor for neuronal differentiation through induction of proneural genes POU3F2 and NEUROD1.

Proneural genes play a crucial role in neuronal differentiation. However, our understanding of the regulatory mechanisms governing proneural genes during neuronal differentiation remains limited. RFX4, identified as a candidate regulator of proneural genes, has been reported to be associated with the development of neuropsychiatric disorders. To uncover the regulatory relationship, we utilized a combination of multi-omics data, including ATAC-seq, ChIP-seq, Hi-C, and RNA-seq, to identify RFX4 as an upstream regulator of proneural genes. We further validated the role of RFX4 using an in vitro model of neuronal differentiation with RFX4 knock-in and a CRISPR-Cas9 knock-out system. As a result, we found that RFX4 directly interacts with the promoters of POU3F2 and NEUROD1. Transcriptomic analysis revealed a set of genes associated with neuronal development, which are highly implicated in the development of neuropsychiatric disorders, including schizophrenia. Notably, ectopic expression of RFX4 can drive human embryonic stem cells toward a neuronal fate. Our results strongly indicate that RFX4 serves as a direct upstream regulator of proneural genes, a role that is essential for normal neuronal development. Impairments in RFX4 function could potentially be related to the development of various neuropsychiatric disorders. However, understanding the precise mechanisms by which the RFX4 gene influences the onset of neuropsychiatric disorders requires further investigation through human genetic studies.

Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06).

BACKGROUND: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC. METHODS: We retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan). RESULTS: A total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy. CONCLUSIONS: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression. TRIAL REGISTRATION: This study was registered in the Clinical Trial Registry of Korea ( https://cris.nih.go.kr : KCT 0007732).

Inhibition of Phagocytosis by Silibinin in Mouse Macrophages.

This study investigated the effects of silibinin, derived from milk thistle (Silybum marianum), on lipopolysaccharide (LPS)-induced morphological changes in mouse macrophages. Silibinin was treated at various doses and time points to assess its effects on macrophage activation, including morphological changes and phagocytosis. Silibinin effectively inhibited LPS-induced pseudopodia formation and size increase, while unstimulated cells remained round. Silibinin's impact on phagocytosis was dose- and time-dependent, showing a decrease. We explored its mechanism of action on kinases using a MAPK array. Among the three MAPK family members tested, silibinin had a limited effect on JNK and p38 but significantly inhibited ERK1/2 and related RSK1/2. Silibinin also inhibited MKK6, AKT3, MSK2, p70S6K, and GSK-3ß. These findings highlight silibinin's potent inhibitory effects on phagocytosis and morphological changes in macrophages. We suggest its potential as an anti-inflammatory agent due to its ability to target key inflammatory pathways involving ERK1/2 and related kinases. Overall, this study demonstrates the promising therapeutic properties of silibinin in modulating macrophage function and inflammation.

A GLP-1/GLP-2 receptor dual agonist to treat NASH: Targeting the gut-liver axis and microbiome.

BACKGROUND AND AIMS: Currently there is no Food and Drug Administration-approved drug to treat NAFLD and NASH, the rates of which are increasing worldwide. Although NAFLD/NASH are highly complex and heterogeneous conditions, most pharmacotherapy pipelines focus on a single mechanistic target. Considering the importance of the gut-liver axis in their pathogenesis, we investigated the therapeutic effect of a long-acting dual agonist of glucagon-like peptide (GLP)-1 and GLP-2 receptors in mice with NAFLD/NASH. APPROACH AND RESULTS: C57BL/6J mice were fed a choline-deficient high-fat diet/high fructose and sucrose solution. After 16 weeks, mice were randomly allocated to receive vehicle, GLP1-Fc, GLP2-Fc, or GLP1/2-Fc fusion (GLP1/2-Fc) subcutaneously every 2 days for 4 weeks. Body weight was monitored, insulin/glucose tolerance tests were performed, feces were collected, and microbiome profiles were analyzed. Immobilized cell systems were used to evaluate direct peptide effect. Immunohistochemistry, quantitative PCR, immunoblot analysis, tunnel assay, and biochemical assays were performed to assess drug effects on inflammation, hepatic fibrosis, cell death, and intestinal structures. The mice had well-developed NASH phenotypes. GLP1/2-Fc reduced body weight, glucose levels, hepatic triglyceride levels, and cellular apoptosis. It improved liver fibrosis, insulin sensitivity, and intestinal tight junctions, and increased microvillus height, crypt depth, and goblet cells of intestine compared with a vehicle group. Similar effects of GLP1/2-Fc were found in in vitro cell systems. GLP1/2-Fc also changed microbiome profiles. We applied fecal microbiota transplantation (FMT) gain further insight into the mechanism of GLP1/2-Fc-mediated protection. We confirmed that FMT exerted an additive effect on GLP1-Fc group, including the body weight change, liver weight, hepatic fat accumulation, inflammation, and hepatic fibrosis. CONCLUSIONS: A long-acting dual agonist of GLP-1 and GLP-2 receptors is a promising therapeutic strategy to treat NAFLD/NASH.

Digital Health Equity and Tailored Health Care Service for People With Disability: User-Centered Design and Usability Study.

BACKGROUND: As digital health services advance, digital health equity has become a significant concern. However, people with disability and older adults still face health management limitations, particularly in the COVID-19 pandemic. An essential area of investigation is proposing a patient-centered design strategy that uses patient-generated health data (PGHD) to facilitate optimal communication with caregivers and health care service providers. OBJECTIVE: This study aims to conceptualize, develop, and validate a digitally integrated health care service platform for people with disability, caregivers, and health care professionals, using Internet of Things devices and PGHD to contribute to improving digital health equity. METHODS: The methodology consists of 5 stages. First, a collaborative review of the previous app, Daily Healthcare 1.0, was conducted with individuals with disabilities, caregivers, and health care professionals. Secondly, user needs were identified via personas, scenarios, and user interface sketches to shape a user-centered service design. The third stage created an enhanced app that integrated these specifications. In the fourth stage, heuristic evaluations by clinical and app experts paved the way for Daily Healthcare 2.0, now featuring Internet of Things device integration. Conclusively, in the fifth stage, an extensive 2-month usability evaluation was executed with user groups comprising individuals with disabilities using the app and their caregivers. RESULTS: Among the participants, "disability welfare information and related institutional linkage" was the highest priority. Three of the 14 user interface sketches the participants created were related to "providing educational content." The 11 heuristic evaluation experts identified "focusing on a single task" as a crucial issue and advocated redesigning the home menu to simplify it and integrate detailed menus. Subsequently, the app Daily Healthcare 2.0 was developed, incorporating wearable devices for collecting PGHD and connecting individuals with disabilities, caregivers, and health care professionals. After the 2-month usability evaluation with 27 participants, all participants showed an increase in eHealth literacy, particularly those who used the caregiver app. Relatively older users demonstrated improved scores in health IT usability and smartphone self-efficacy. All users' satisfaction and willingness to recommend increased, although their willingness to pay decreased. CONCLUSIONS: In this study, we underscore the significance of incorporating the distinct needs of individuals with disabilities, caregivers, and health care professionals from the design phase of a digital health care service, highlighting its potential to advance digital health equity. Our findings also elucidate the potential benefits of fostering partnerships between health consumers and providers, thereby attenuating the vulnerability of marginalized groups, even amid crises such as the COVID-19 pandemic. Emphasizing this imperative, we advocate for sustained endeavors to bolster the digital literacy of individuals with disabilities and champion collaborative cocreation, aiming to uphold the collective ethos of health and digital health equity.

Identifying serum miRNA biomarkers for radiation exposure in hematopoietic humanized NSG-SGM3 mice.

BACKGROUND: Humans are commonly exposed to ionizing radiation. The conventional approach for estimating radiation exposure is to integrate physical and clinical measurements for optimizing the dose calculation. However, these methods have several limitations. The present study attempted to identify candidate microRNA (miRNA) biomarkers for radiation exposure in a hematopoietic humanized NSGS (hu-NSGS) mouse model. METHODS: We grafted human CD34+ hematopoietic stem cells into NSG-SGM3 (NSGS) mice. The hu-NSGS mice underwent total body irradiation at doses of 2, 3, and 4 Gy. Tissues from the spleen, thymus, and lymph nodes of hu-NSGS mice were prepared to analyze levels of CD45+ and CD3+ T cells and CD 20+ B cells using flow cytometry and immunohistochemistry. Serum miRNAs were profiled using a digital multiplexed NanoString n-Counter. RESULTS: The expression of 45 miRNAs was upregulated/downregulated hu-NSGS mice. The miRNAs hsa-mir-188-5p, hsa-let-7a-5p, hsa-mir-612, hsa-mir-671-5p, and hsa-mir-675-5p were highly radiation-responsive in irradiated hu-NSGS mice. When compared with control mice, radiation-exposed mice exhibited significant upregulated of hsa-let-7a-5p expression and significant downregulation of hsa-mir-188-5p expression. CONCLUSIONS: Single miRNAs or combinations of hsa-mir-188-5p, hsa-let-7a-5p, hsa-mir-675-5p, hsa-mir-612, and hsa-mir-671-5p can be used as biomarkers for predicting the impact of radiation exposure. The current findings suggest the usefulness of hu-NSGS models for investigating radiation biomarkers.

Increased EAT volume after anthracycline chemotherapy is associated with a low risk of cardiotoxicity in breast cancer.

PURPOSE: Chemotherapy-induced cardiotoxicity is a critical issue for patients with breast cancer. Change of epicardial adipose tissue (EAT) is associated with cardiac dysfunction. The objective of this study was to investigate the relationship between EAT and chemotherapy-induced cardiotoxicity. METHODS: This retrospective study analyzed EAT on chest computed tomography (CT) of patients with early breast cancer using automatic, quantitative measurement software between November 2015 and January 2020. Changes in EAT before and after initiation of chemotherapy were compared according to the type of anticancer drug. Subclinical cardiotoxicity was defined as worsening ≥ 10% in left ventricular ejection fraction to an absolute value > 50% with a lower limit of normal measured with standard echocardiography. RESULTS: Among 234 patients with breast cancer, 85 were treated with adjuvant anthracycline-based (AC) and 149 were treated with non-anthracycline-based (non-AC) chemotherapy. There was a significant increase in EAT volume index (mL/kg/m2) at the end of chemotherapy compared to that at the baseline in the AC group (3.33 ± 1.53 vs. 2.90 ± 1.52, p < 0.001), but not in the non-AC group. During the follow-up period, subclinical cardiotoxicity developed in 20/234 (8.6%) patients in the total population [13/85 (15.3%) in the AC group and 7/149 (4.8%) in the non-AC group]. In the multivariable analysis, EAT volume index increment after chemotherapy was associated with a lower risk of subclinical cardiotoxicity in the AC group (Odds ratio: 0.364, 95% CI 0.136-0.971, p = 0.044). CONCLUSIONS: Measurement of EAT during anthracycline-based chemotherapy might help identify subgroups who are vulnerable to chemotherapy-induced cardiotoxicity. Early detection of EAT volume change could enable tailored chemotherapy with cardiotoxicity prevention strategies.

Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study).

BACKGROUND: The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change. RESULTS: Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104). CONCLUSIONS: Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 ).

Effectiveness and safety of teneligliptin added to patients with type 2 diabetes inadequately controlled by oral triple combination therapy: A multicentre, randomized, double-blind, and placebo-controlled study.

AIM: To investigate the effectiveness and safety of teneligliptin over placebo in patients with type 2 diabetes (T2D) inadequately controlled by triple therapy. MATERIALS AND METHODS: This trial was a prospective, multicentre, randomized, double-blind, placebo-controlled study. The 12-week double-blind period was followed by a 12-week, open-label clinical trial. One hundred patients with T2D who failed to achieve the glycaemic target (7.1% ≤ HbA1c ≤ 9.0%) with conventional triple oral antidiabetic drugs (OADs) of metformin, sulphonylurea, and sodium-glucose co-transporter-2 inhibitor were assigned randomly 1:1 into teneligliptin and placebo-teneligliptin groups. The primary endpoint was mean change in HbA1c level from baseline in each group at 12 weeks. RESULTS: For a total of 99 patients (n = 51 for the teneligliptin group, and n = 48 for the placebo-teneligliptin group), the mean age and duration of diabetes were 60.7 and 13.6 years, respectively, and HbA1c was 7.8% at baseline. At 12 weeks, the teneligliptin group achieved a significant reduction in HbA1c from baseline (-0.9% ± 0.6%, P < .001), with an intergroup difference of -0.75% compared with the placebo group (95% CI [-0.99%, -0.51%], P < .001). At the end of the 24-week treatment period, both groups showed significant reductions in HbA1c level from baseline (placebo-teneligliptin group, -0.8% ± 0.6% [P < .001], teneligliptin group, -0.9% ± 0.6% [P < .001]), without significant intergroup difference (-0.17%, 95% CI [-0.41%, 0.07%], P = .156). There was no significant difference between the groups in the rate of adverse events (placebo-teneligliptin group, n = 3 [6.3%]; teneligliptin group, n = 11 [11.1%]; P = .550), and the safety profiles were favourable in both groups. CONCLUSIONS: The current study shows that teneligliptin could be a valid option as a fourth OAD for the treatment of patients with T2D inadequately controlled with a triple combination of OADs.

Neutrophil-lymphocyte ratio and carotid plaque burden in patients with essential thrombocythemia and polycythemia vera.

BACKGROUND AND AIMS: Chronic inflammation plays a critical role in the pathogenesis of myeloproliferative neoplasm (MPN), and inflammatory conditions are closely related to the development and exacerbation of atherosclerosis. This study aimed to compare carotid plaque burden and neutrophil-lymphocyte ratio (NLR) in the essential thrombocythemia (ET)/polycythemia vera (PV) and control groups. METHODS AND RESULTS: We retrospectively assessed carotid plaque burden and NLR in patients with ET/PV between January 2010 and September 2021 and propensity-score matched these patients to control subjects from the general population. All patients underwent carotid imaging using carotid ultrasonography for atherosclerosis screening. After 3:1 propensity-score matching, 140 patients in the control group were matched to 51 patients in ET/PV group. The mean NLR was significantly higher in the MPN group than in the control group (4.77 ± 3.96 vs. 1.93 ± 1.03, p < 0.001). The carotid plaque score was also higher in MPN group than in the control group (2.37 ± 1.47 vs. 1.94 ± 1.17, p = 0.038). CONCLUSION: Patients with PV/ET show a higher NLR and carotid plaque burden than the normal population. This reflected that PV/ET was a highly inflammatory and atherosclerotic condition expressing potentially increased cardiovascular risk.

Successful Treatment of Thrombotic Thrombocytopenic Purpura in a Patient with Mixed Connective Tissue Disease.

BACKGROUND: Although the survival rate of thrombocytopenic purpura (TTP) has increased significantly due to the introduction of therapeutic plasma exchange (TPE). TTP in patients with mixed connective tissue disease (MCTD) has a very high mortality rate and a very small number of reported cases. In TTP, daily TPE is administered until a treatment response is achieved; however, in practice, TPE is often not performed for such long durations. METHODS: We report a case of TTP with MCTD in a female patient. She had developed thrombocytopenia and hemolytic anemia 9 months after delivery. She had status epilepticus and lapsed into a coma. RESULTS: The patient was successfully treated with extended sessions of TPE with corticosteroids and rituximab. CONCLUSIONS: Although the TTP regimen has not yet been established and remains controversial, this report demonstrates the importance of continuing daily TPE until achieving a treatment response.

Establishing Reference Range and Assessing Precision Performance of the TEG6s System; Verification of TEG6s to Introduce to Clinical Laboratory.

BACKGROUND: Thromboelastography (TEG) provides assessment of global coagulation. The TEG6s (Haemonetics Corporation) is a newly developed cartridge-based system, fully automated and the first true point-of-care TEG. In this study, we evaluated the precision and established the reference intervals (RIs) for TEG6s. METHODS: TEG assays were performed on the blood of healthy donors to determine RIs and on the QC materials for precision testing. The study design was developed in accordance with Clinical and Laboratory Standards Institute Guidelines. RESULTS: TEG6s precision testing yielded low variability except R, due to a low value for the mean. The newly established RIs of R, MA, and LY30 were similar to the manufacturer's RIs. Some were different, showing short K and increased α. CONCLUSIONS: This study has shown that TEG6s has high precision and each institution should verify the manufacturer's RIs before adopting TEG6s and establish RIs if necessary.

Developing a Loop-Mediated Isothermal Amplification Assay for the Rapid Detection of Seven Respiratory Viruses including SARS-CoV-2.

Background and Objectives: The coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a pandemic even in 2022. As the initial symptoms of COVID-19 overlap with those of infections from other respiratory viruses, an accurate and rapid diagnosis of COVID-19 is essential for administering appropriate treatment to patients. Currently, the most widely used method for detecting respiratory viruses is based on real-time polymerase chain reaction (PCR) and includes reverse-transcription real-time quantitative PCR (RT-qPCR). However, RT-qPCR assays require sophisticated facilities and are time-consuming. This study aimed to develop a real-time quantitative loop-mediated isothermal amplification (RT-qLAMP) assay and compare its analytical performance with RT-qPCR. Materials and Methods: A total of 315 nasopharyngeal swabs from patients with symptoms of respiratory infections were included in this study. A primary screening of the specimens was performed using RT-qPCR. RNA/DNA from standard strains for respiratory viruses and heat-inactivated preparations of standard strains for SARS-CoV-2 were used to evaluate the accuracy and target specificity of the RT-qLAMP assay. Results: We successfully developed an RT-qLAMP assay for seven respiratory viruses: respiratory syncytial virus (RSV) A, RSV B, adenovirus, influenza (Flu) A (H1N1 and H3N2), Flu B, and SARS-CoV-2. RT-qLAMP was performed in a final reaction volume of 9.6 µL. No cross-reactivity was observed. Compared with the RT-PCR results, the sensitivity and specificity of the RT-qLAMP assay were 95.1% and 100%, respectively. The agreement between the two methods was 97.1%. The median amplification time to RT-qLAMP positivity was 22:34 min (range: 6:80-47:98 min). Conclusions: The RT-qLAMP assay requires a small number of reagents and samples and is performed with an isothermal reaction. This study established a fast, simple, and sensitive test that can be applied to point-of-care testing devices to facilitate the detection of respiratory viruses, including SARS-CoV-2.

Learning experience design of an mHealth self-management intervention for adolescents with type 1 diabetes.

Type 1 diabetes (T1D) is a lifelong and chronic condition that can cause severely compromised health. The T1D treatment regimen is complex, and is a particular challenge for adolescents, who frequently experience a number of treatment adherence barriers (e.g., forgetfulness, planning and organizational challenges, stress). Diabetes Journey is a gamified mHealth program designed to improve T1D self-management through a specific focus on decreasing adherence barriers and improving executive functioning skills for adolescents. Grounded in situativity theory and guided by a sociotechnical-pedagogical usability framework, Diabetes Journey was designed, developed, and evaluated using a learning experience design approach. This approach applied design thinking methods within a Successive Approximation Model design process. Iterative design and formative evaluation were conducted across three design phases, and improvements were implemented following each phase. Findings from the user testing phase indicate Diabetes Journey is a user-friendly mHealth program with high usability that holds promise for enhancing adolescents' T1D self-management. Implications for future designers and researchers are discussed regarding the social dimension of the sociotechnical-pedagogical usability framework. An extension to the framework is proposed to extend the social dimension to include socio-cultural and contextual considerations when designing mHealth applications. Consideration of the pedagogical and sociocultural dimensions of learning is imperative when developing psychoeducational interventions.

Label-Free SERS Analysis of Urine Using a 3D-Stacked AgNW-Glass Fiber Filter Sensor for the Diagnosis of Pancreatic Cancer and Prostate Cancer.

Metabolomics shows tremendous potential for the early diagnosis and screening of cancer. For clinical application as an effective diagnostic tool, however, improved analytical methods for complex biological fluids are required. Here, we developed a reliable rapid urine analysis system based on surface-enhanced Raman spectroscopy (SERS) using 3D-stacked silver nanowires (AgNWs) on a glass fiber filter (GFF) sensor and applied it to the diagnosis of pancreatic cancer and prostate cancer. Urine samples were pretreated with centrifugation to remove large debris and with calcium ion addition to improve the binding of metabolites to AgNWs. The label-free urine-SERS detection using the AgNW-GFF SERS sensor showed different spectral patterns and distinguishable specific peaks in three groups: normal control (n = 30), pancreatic cancer (n = 22), and prostate cancer (n = 22). Multivariate analyses of SERS spectra using unsupervised principal component analysis and supervised orthogonal partial least-squares discriminant analysis showed excellent discrimination between the pancreatic cancer group and the prostate cancer group as well as between the normal control group and the combined cancer groups. The results demonstrate the great potential of the urine-SERS analysis system using the AgNW-GFF SERS sensor for the noninvasive diagnosis and screening of cancers.

Structuring Pickering Emulsion Interfaces with Bilayered Coacervates of Cellulose Nanofibers and Hectorite Nanoplatelets.

In this study, we present a water-in-silicone oil (W/S) Pickering emulsion system stabilized via in situ interfacial coacervation of attractive hectorite nanoplatelets (AHNPs) and bacterial cellulose nanofibrils (BCNFs). A bilayered coacervate is generated at the W/S interface by employing the controlled electrostatic interaction between the positively charged AHNPs and the negatively charged BCNFs. The W/S interface with the bilayered coacervate shows a significant increase in the interfacial modulus by 2 orders of magnitude than that with the AHNPs only. In addition, we observe that water droplets are interconnected by the BCNF bridging across the continuous phase of silicon, which is attributed to the diffusive transport phenomenon. This droplet interconnection results in the effective prevention of drop coalescence, which is confirmed via emulsion sedimentation kinetics. These results indicate that our bilayered coacervation technology has the potential of developing a promising Pickering emulsion platform that can be used in the pharmaceutical and cosmetic industries.

Glycaemic control with add-on thiazolidinedione or a sodium-glucose co-transporter-2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24-week, randomized controlled trial.

AIM: To evaluate the effectiveness and safety of adding either a sodium-glucose co-transporter-2 inhibitor (SGLT2i) or thiazolidinedione (TZD) in patients with type 2 diabetes (T2D) inadequately controlled with triple therapy. MATERIALS AND METHODS: In this prospective, open-label, multicentre, 24-week clinical trial, we randomly assigned 119 patients with T2D who failed to achieve glycaemic control (7% < HbA1c ≤ 10%) with conventional triple oral antidiabetic agents (OADs; metformin, sulphonylurea and dipeptidyl peptide-4 [DPP-4] inhibitor) into two groups who received either an SGLT2i or TZD. The primary endpoint was mean change in HbA1c level between the two groups at 24 weeks. RESULTS: In total, 119 patients were enrolled in the SGLT2i (n = 60) and TZD (n = 59) groups. Mean age of the study subjects was 61.86 years, and the mean duration of T2D was 13.89 years. After 24 weeks, both groups showed significant reductions in HbA1c (from 7.94% ± 0.74% to 6.97% ± 0.84% in the SGLT2i group and from 8.00% ± 0.78% to 7.18% ± 0.98% in the TZD group), without a significant between-group difference (P = .235). A significant body mass index (BMI) reduction was noted in the SGLT2i group, whereas an increase in BMI was noted in the TZD group (-0.79 ± 1.37 vs. 0.92 ± 0.86 kg/m2 , P < .001). Other safety profiles were favourable in both groups. CONCLUSIONS: The current study shows that an SGLT2i or TZD could be a valid option as a fourth OAD for treatment of patients with T2D inadequately controlled with a triple combination of OADs.

Nonalcoholic fatty liver disease, diastolic dysfunction, and impaired myocardial glucose uptake in patients with type 2 diabetes.

AIMS: To investigate whether degree of nonalcoholic fatty liver disease (NAFLD) is associated with myocardial dysfunction related to impaired myocardial glucose uptake in patients with type 2 diabetes. MATERIALS AND METHODS: In total, 131 patients with type 2 diabetes from a tertiary care hospital were included in this study. Myocardial glucose uptake was assessed using [18 F]-fluorodeoxyglucose-positron emission tomography. Hepatic steatosis and fibrosis were determined using transient liver elastography. Echocardiography was performed to evaluate cardiac structure and function. RESULTS: Patients with NAFLD had cardiac diastolic dysfunction with higher left ventricular filling pressure (E/e' ratio) and left atrial (LA) volume index than patients without NAFLD (all P < 0.05). Hepatic steatosis correlated with E/e' ratio and LA volume index, and hepatic fibrosis also correlated with E/e' ratio (all P < 0.05). Even after adjusting for confounding factors, a higher degree of hepatic steatosis (r2 = 0.409, P = 0.041) and a higher degree of fibrosis (r2 = 0.423, P = 0.009) were independent contributing factors to a higher E/e' ratio. Decreased myocardial glucose uptake was associated with a higher degree of steatosis (P for trend = 0.084) and fibrosis (P for trend = 0.012). At the same time, decreased myocardial glucose uptake was an independent contributing factor for a higher E/e' ratio (r2 = 0.409; P = 0.040). CONCLUSIONS: Hepatic steatosis and fibrosis were significantly associated with diastolic heart dysfunction in patients with type 2 diabetes coupled with impaired myocardial glucose uptake.

Using knowledge translation to establish a model of hospital-based early supported community reintegration for stroke patients in South Korea.

BACKGROUND: In 2019, the South Korean government started designating rehabilitation medical institutions to facilitate the early return of patients with stroke (PWS) to their communities after discharge. However, a detailed operating model has not yet been suggested. We aimed to develop a hospital-based early supported community reintegration model for PWS that is suitable for South Korea based on knowledge translation in cooperation with clinical experts and PWS. METHODS: Clinical experts (n = 13) and PWS (n = 20) collaboratively participated in the process of developing the early supported community reintegration model at a national hospital in South Korea, using the following phases of the knowledge-to-action cycle: (1) identifying knowledge, (2) adapting the knowledge to the local situation, (3) assessing barriers and facilitators to local use of knowledge, and (4) tailoring and developing the program. Barriers and facilitators to local use of knowledge were assessed multidimensionally at the individual, interpersonal, organizational, and community level based on the social-ecological model. Literature reviews, workshops, individual and group interviews, and group meetings using nominal group technique were conducted in each phase of the knowledge-to-action cycle. RESULTS: Each phase of the knowledge-to-action cycle for developing the early supported community reintegration model and a newly developed model including the following components were reported: (1) revision of strategies of organizations related to community reintegration support, (2) establishment of a multidepartmental and multidisciplinary community reintegration support system, (3) standardization of patient-centered multidisciplinary goal setting, (4) multidimensional classification of community reintegration support areas, and (5) development of guidelines for a tailored community reintegration support program. CONCLUSIONS: We designed a hospital-based multidimensional and multidisciplinary early supported community reintegration model that comprehensively included several elements of community rehabilitation in connection with hospitals and communities, taking into account the South Korean situation of lacking community rehabilitation infrastructure. In developing a guideline for a tailored community reintegration support program, we attempted to take into consideration various situations faced by PWS in South Korea, which is in a transitional stage for community rehabilitation. It is expected that this early supported community reintegration model can be referenced in other countries that are in a transitional stage of community rehabilitation.