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Introduction: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population., Methods: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment., Results: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77)., Conclusion: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data., (© 2023. Asian Pacific Association for the Study of the Liver.)

Objectives: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking., Materials and Methods: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort., Results: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients., Conclusion: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study delves into advanced methane purification techniques within anaerobic fermentation bioreactors, focusing on selective CO 2 absorption and comparing photosynthetic bacteria (PNSB) with chemical adsorbents. Our investigation demonstrates that MgO-Mg(OH) 2 composites exhibit remarkable CO 2 selectivity over CH 4 , substantiated through rigorous bulk and surface modelling analyses. To address the challenges posed by MgCO 3 shell formation on MgO particles, hindering CO 2 transport, we advocate for the utilisation of MgO-Mg(OH) 2 composites. In on-site experiments, these composites, particularly saturated MgO-Mg(OH) 2 solutions (S2), achieved an astonishing 100% CO 2 removal rate within a single day while preserving CH 4 content. In contrast, solid MgO powder (S3) retained a mere 5% of CH 4 over a 10 h period. Although PNSB (S1) exhibited slower CO 2 removal, it excelled in nutrient recovery from anaerobic effluent. We introduce a groundbreaking hybrid strategy that leverages S2's swift CO 2 removal and S1 PNSB's nutrient recovery capabilities, potentially resulting in a drastic reduction in bioreactor processing time, from 10 days when employing S1 to just 1 day with the use of S2. This represents a remarkable efficiency improvement of 1000%. This pioneering strategy has the potential to revolutionise methane purification, enhancing both efficiency and sustainability. Importantly, it can be seamlessly integrated into existing bioreactors through an additional CO 2 capture step, offering a promising solution for advancing biogas production and promoting sustainable waste treatment practices.

Liver fibrosis is generally preceded by various liver injuries and often leads to chronic liver diseases and even cirrhosis. Therefore, a liver fibrosis animal model is the cornerstone for the development of therapeutic strategies for hepatic diseases. Although administration of hepatotoxic substances and/or bile duct ligation have been widely performed to construct the in vivo model over the last decades, they are seriously hindered by time-consuming protocols, high mortality, and instability, indicating that an effective and safe approach for the induction of liver fibrosis is still urgently needed nowadays. In this study, we have developed asialoglycoprotein receptor (ASGPR)-targeted lipopolysaccharide (LPS)-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles named ALPNPs for establishing an animal model of liver fibrosis. The ALPNPs are characterized as having a spherical nanostructure with size of 182.9 ± 8.89 nm and surface charge of -8.3 ± 1.48 mV. An anti-ASGPR antibody bound to the surface of the nanoparticles with a crosslinking efficiency of 95.03% allows ALPNPs to have hepatocyte-binding specificity. In comparison to free LPSs, the ALPNPs can induce higher aspartate aminotransferase and total bilirubin concentrations in plasma, reduce the blood flow rate in the portal system and the kidneys, and increase vascular resistance in the liver, kidneys, and collateral shunting vasculature. Based on histological and RNA-seq analyses, the ALPNPs can provide similar capability on inducing hepatic inflammation and fibrosis compared to free LPS but possess higher liver targetability than the naked drug. In addition, the ALPNPs are less toxic in organs other than the liver in comparison to free LPS, demonstrating that the ALPNPs do not elicit off-target effects in vivo . Given the aforementioned efficacies with other merits such as biocompatibility and drug release controllability provided by PLGA, we anticipate that the developed ALPNPs are highly applicable in establishing animal models of liver fibrosis in pre-clinical studies.

Background: Although percutaneous transthoracic catheter drainage (PCD) has been proven effective in lung abscesses, the optimal timing of PCD is still unclear. The study aimed to evaluate the safety and efficacy of early versus delayed drainage in patients with lung abscesses., Methods: This retrospective study included 103 consecutive patients with liquefied lung abscesses more than 3 cm confirmed by a CT scan received CT-guided PCD over 16 years, from July 2005 to September 2021, in a single institution were reviewed. Early drainage was defined as PCD within one week after a lung abscess was diagnosed. The primary outcome was 90-day mortality. The secondary outcomes included perioperative complications and patients' length of hospital stay (LoS). Factors associated with 90-day mortality and LoS were also analyzed. The key statistical methods were Chi-square test, Fisher's exact test, Student t -test, and Pearson correlation., Results: Amount the 103 patients, there were 64 patients who received early PCD, and 39 patients received delayed PCD. Between the two groups, there were no significant differences in clinical characteristics, 90-day mortality, or perioperative complications. The LoS was significantly shortened in early PCD group (28.6 ± 25.5 vs. 39.3 ± 26.8 (days), p = 0.045). Higher Charlson comorbidity index, secondary lung abscess, and liver cirrhosis were associated with higher mortality (all p < 0.05). Positive sputum culture significantly increased the LoS (coefficient 19.35 (10.19, 28.50), p < 0.001)., Conclusion: The 90-day mortality and complications were similar for early PCD and delayed PCD patients, but LoS was significantly shortened in early PCD patient., 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 © 2023 Chiang, Lin, Hsu, Huang, Chung, Liu and Chang.)

Purpose: Dendritic cell infiltrates are increased in thyroid cancer but may have a defective ability to provoke effective immune responses. In this study, we aimed to identify potential thyroid cancer biomarkers linked to dendritic cell development and evaluate their prognostic relevance., Methods: Through a bioinformatics search, we identified the dendrocyte-expressed seven transmembrane protein (DCSTAMP) as a prognostic gene involved in dendritic cell differentiation for thyroid cancer. Immunohistochemical analyses of DCSTAMP expression were performed and correlated with clinical outcomes., Results: DCSTAMP was overexpressed in a variety of types of thyroid cancers, while normal thyroid tissue or benign thyroid lesions exhibited low or undetectable DCSTAMP immunoreactivity. The results of automated quantification were consistent with subjective semiquantitative scoring. Among 144 patients with differentiated thyroid cancer, high DCSTAMP expression was associated with papillary tumor type (p < 0.001), extrathyroidal extension (p = 0.007), lymph node metastasis (p < 0.001), and BRAF V600E mutation (p = 0.029). Patients with tumors showing high DCSTAMP expression had shorter overall (p = 0.027) and recurrence-free (p = 0.042) survival., Conclusion: This study provides the first evidence of DCSTAMP overexpression in thyroid cancer. Apart from the prognostic implications, studies are needed to explore its potential immunomodulatory role in thyroid cancer., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares., Methods: This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n = 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ≥12 months before cessation (n = 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment., Results: Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001)., Discussion: Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome., (Copyright © 2023 by The American College of Gastroenterology.)

Purpose: The incidence of thyroid cancer has increased substantially over the past few decades and is partially explained by overdiagnosis. Geographical variations in incidence rates were reported to be related to national development status. This study aimed to gain deeper insights into global thyroid cancer burden by incorporating additional social and economic factors to account for cross-national disparities., Methods: We performed a multivariate analysis of age-standardized incidence and mortality data from the GLOBOCAN 2020 database for 126 countries that had more than 100 incident cases of thyroid cancer. The human development index (HDI), current health expenditure, and additional Global Health Observatory indicators were extracted from multiple sources., Results: Age-standardized incidence was highly correlated with HDI (standardized coefficient beta = 0.523, 95% confidence interval [CI] = 0.275-0.771) among the countries studied. The prevalence of raised fasting blood glucose was associated with age-standardized mortality (beta = 0.277, 95% CI = 0.038-0.517). Generally, the mortality-to-incidence ratio was higher in males than in females. In multivariate analysis, HDI (beta = - 0.767, 95% CI = - 0.902 to - 0.633), current health expenditure (beta = 0.265, 95% CI = 0.137-0.394), and fine particulate matter (PM 2.5 ) concentrations (beta = 0.192, 95% CI = 0.086-0.298) were associated with mortality-to-incidence ratios., Conclusions: National developments gauged by HDI explain the majority of the variation in incidence rates of thyroid cancer but play a smaller role in disparities in mortality rates. The association between air pollution and thyroid cancer outcomes warrants further investigation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: In order to correct the varying vocal fold positions to meet the various clinical requirements in patients with bilateral vocal fold immobility, we present pertinent surgical methods to treat them., Materials and Methods: From 2005 to 2020, 115 patients diagnosed with bilateral vocal fold immobility were addressed for ventilation in 89 patients and for phonation in 26 patients. In the ventilation surgery group, all the neurogenic subjects received mere suture lateralization (SL) procedures and the mechanical ones underwent arytenoid release (AR) plus SL procedures if the cricoarytenoid joint fixation (CAJF) could be confirmed before operation. In the phonation group, neurogenic subjects received nonsurgical treatment and the mechanical ones underwent AR plus arytenoid adduction (AA) procedure. The decannulation rate and respiratory comfort rate for each subgroup will be calculated and the phonatory tests were conducted., Results: In the ventilation group, 55% (49/89) of subjects received related surgeries. Mere SL offered 40 successful decannulation or respiratory comfort in 42 neurogenic subjects (95.2%). The single episode rate was high as 95%. An AR plus SL procedure also obtained 100% of decannulation or respiratory comfort with a single episode of surgical procedure if the CAJF could be confirmed preoperatively. In the phonation group, 15% (4/26) of subjects received appropriate surgeries. Single AR plus AA procedures also led to 100% (4/4) of the appropriate candidates serviceable sound., Conclusion: SL procedure keeping intact laryngeal mucosa usually offered permanent glottis enlarging effect or decannulation with a single episode of procedure. The use of arytenoid release for CAJF has led to remarkable advances in the ultimate surgical outcomes of both the ventilation and phonation in terms of decreasing revision surgeries., Levels of Evidence: level 4., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Prenatal infection has been implicated in the development of neuropsychiatric disorders in children. We hypothesised that exposure to lipopolysaccharide during prenatal development could induce anxiety-like behaviour and sensorineural hearing loss in offspring, as well as disrupt neural differentiation during embryonic neural development., Methods: We simulated prenatal infection in FVB mice and mouse embryonic stem cell (ESC) lines, specifically 46C and E14Tg2a, through lipopolysaccharide treatment. Gene expression profiling analyses and behavioural tests were utilized to study the effects of lipopolysaccharide on the offspring and alterations in toll-like receptor (TLR) 2-positive and TLR4-positive cells during neural differentiation in the ESCs., Results: Exposure to lipopolysaccharide (25 µg/kg) on gestation day 9 resulted in anxiety-like behaviour specifically in male offspring, while no effects were detected in female offspring. We also found significant increases in the expression of GFAP and CNPase, as well as higher numbers of GFAP + astrocytes and O4+ oligodendrocytes in the prefrontal cortex of male offspring. Furthermore, increased scores for genes related to oligodendrocyte and lipid metabolism, particularly ApoE, were observed in the prefrontal cortex regions. Upon exposure to lipopolysaccharide during the ESC-to-neural stem cell (NSC) transition, Tuj1, Map2, Gfap, O4, and Oligo2 mRNA levels increased in the differentiated neural cells on day 14. In vitro experiments demonstrated that lipopolysaccharide exposure induced inflammatory responses, as evidenced by increased expression of IL1b and ApoB mRNA., Conclusions: Our findings suggest that prenatal infection at different stages of neural differentiation may result in distinct disturbances in neural differentiation during ESC-NSC transitions. Furthermore, early prenatal challenges with lipopolysaccharide selectively induce anxiety-like behaviour in male offspring. This behaviour may be attributed to the abnormal differentiation of astrocytes and oligodendrocytes in the brain, potentially mediated by ApoB/E signalling pathways in response to inflammatory stimuli., (© 2023. University of Wroclav.)

Background: Lower extremity venous disease (LEVD) is a complex disorder, and determining the etiology of LEVD is paramount for treatment selection. Two-dimensional phase-contrast magnetic resonance imaging (2D PC-MRI) can provide an objective measure of hemodynamic status and may help differentiate between different etiologies of LEVD. A total of 271 participants, including 256 symptomatic patients with venous lower extremity disease and 15 healthy volunteers, were collected in this cohort study., Methods: It is a single-center prospective observational study using 2D PC-MRI analysis to assess the hemodynamic characteristics of patients with LEVD among participants recruited between April 2017 and October 2021 at a tertiary hospital. The approval institutional review board number for this study were 201802137B0, 201901058B0, 202100938B0, and 202102344B0. Participants were classified as venous reflux (VR) and venous obstruction (VO) by standard ultrasonography. 2D PC-MRI by 1.5 T scanner revealed stroke volume (SV), forward flow volume (FFV), absolute stroke volume (ASV), mean flux (MF), velocity time integral (VTI), and mean velocity (MV) for each selected venous segments., Results: 2D PC-MRI assessed 167 diseased legs from the 116 VR patients [mean age ± standard deviation (SD): 57.9±12.8 years; 39 males] and 113 diseased legs from the 95 VO patients (mean age ± SD: 66.4±12.8 years; 42 males). 2D PC-MRI analysis demonstrated discrimination ability to differentiate from VR to VO [SV, FFV, ASV, MF, VTI, and MV in the various venous segments, respectively, P≤0.001; area under the curve (AUC) =62-68.8%, P≤0.001 by Mann-Whitney U test]. The ratio data (morbid limb to normal limb) in the same individual with single-leg disease revealed differences between VR and VO (SV, FFV, ASV, and MF in the various venous segments, respectively; P<0.05; AUC =60.2-68.7%, P≤0.05 by Mann-Whitney U test). The most favorable differentiating variables of ratios were FFV in the great saphenous veins [AUC =68.7%, 95% confidence interval (CI): 59.8-77.6%] and ASV in the external iliac veins (AUC =67.4%, 95% CI: 58.7-76.2%)., Conclusions: Quantitative 2D PC-MRI analysis is capable of differentiating VR from VO. It also provides an important diagnostic capability for preoperative evaluation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-1194/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Chronic hepatitis B virus (HBV) infection affects about 296 million people worldwide and is the leading aetiology of cirrhosis and liver cancer globally. Major medical complications also include acute flares and extrahepatic manifestations. In addition, people living with HBV infection also experience stigma. HBV-related cirrhosis resulted in an estimated 331,000 deaths in 2019, and it is estimated that the number of deaths from HBV-related liver cancer in 2019 was 192,000, an increase from 156,000 in 2010. Meanwhile, HBV remains severely underdiagnosed and effective measures that can prevent infection and disease progression are underutilized. Birth dose coverage for HBV vaccines remains low, particularly in low-income countries or regions where HBV burden is high. Patients with HBV infection are inadequately evaluated and linked to care and are undertreated worldwide, even in high-income countries or regions. Despite the goal of the World Health Organization to eliminate viral hepatitis as a public health problem by 2030, the annual global deaths from HBV are projected to increase by 39% from 2015 to 2030 if the status quo remains. In this Review, we discuss the current status and future projections of the global burden of HBV infection. We also discuss gaps in the current care cascade and propose future directions., (© 2023. Springer Nature Limited.)

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The lung dose of nebulized drugs for spontaneous breathing is influenced by breathing patterns and nebulizer performance. This study aimed to develop a system for measuring breath patterns and a formula for estimating inhaled drugs, and then to validate the hypothesized prediction formula. Methods: An in vitro model was first used to determine correlations among the delivered dose, breath patterns, and doses deposited on the accessories and reservoirs testing with a breathing simulator to generate 12 adult breathing patterns ( n  = 5). A pressure sensor was developed to measure breathing parameters and used along with a prediction formula that accounted for the initial charge dose, respiratory pattern, and dose on the accessory and reservoir of a nebulizer. Three brands of nebulizers were tested by placing salbutamol (5.0 mg/2.5 mL) in the drug holding chamber. Ten healthy individuals participated in the ex vivo study to validate the prediction formula. The agreement between the predicted and inhaled doses was analyzed using the Bland-Altman plot. Results: The in vitro model showed that the inspiratory time to total respiratory cycle time ( T i / T total ; %) was significantly directly correlated with the delivered dose among the respiratory factors, followed by inspiratory flow, respiratory rate, and tidal volume. The ex vivo model showed that T i / T total was significantly directly correlated with the delivered dose among the respiratory factors, in addition to the nebulization time and accessory dose. The Bland-Altman plots for the ex vivo model showed similar results between the two methods. Large differences in inhaled dose measured at the mouth were observed among the subjects, ranging from 12.68% to 21.68%; however, the difference between the predicted dose and inhaled dose was lower, at 3.98%-5.02%. Conclusions: The inhaled drug dose could be predicted with the hypothesized estimation formula, which was validated by the agreement between the inhaled and predicted doses of breathing patterns of healthy individuals.

The objective of this study is to develop hydroxyapatite (HAp) particles for targeted delivery of honokiol to tumor sites after glioma surgical management. Honokiol is released from the HAp-honokiol particles inside cancer cells through endocytosis and subsequent acid lysosomal dissolution. HAp is synthesized using a co-precipitation method, and egg white is added to create porous structures. The HAp is then surface-modified with stearic acid to enhance its hydrophobicity and loaded with honokiol to form HAp-honokiol particles. The synthesized particles are of appropriate size and characteristics for cancer cell uptake. Honokiol remains attached on to the HAp particles in neutral environments due to its hydrophobic nature, but undergoes rapid burst release in acidic environments such as lysosomes. The HAp-honokiol treatment shows a delayed effect on cell viability and cytotoxicity, indicating sustained drug release without compromising drug efficacy. Flow cytometry analysis demonstrates the apoptosis pathway induced by HAp-honokiol in ALTS1C1 glioma cells. In the in vivo study using a mouse glioma model, MRI results showed a 40% reduction in tumor size after HAp-honokiol treatment. These findings suggest that HAp-honokiol particles have potential as an effective drug delivery system for the treatment of glioma., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: To propose a novel Numerical fitting method of the Extrapolated semisolid Magnetization transfer Reference (NEMR) signal for quantifying the CEST effect., Theory and Methods: Modified two-pool Bloch-McConnell equations were used to numerically fit the magnetization transfer (MT) and direct water saturation (DS) signals at far off-resonance frequencies, which was subsequently extrapolated into the frequency range of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) pools. Then the subtraction of the fitted two-pool z-spectrum and the experimentally acquired z-spectrum yielded APT # and NOE # signals mostly free of MT and DS contamination. Several strategies were used to accelerate the NEMR fitting. Furthermore, the proposed NEMR method was compared with the conventional extrapolated semisolid magnetization transfer reference (EMR) and magnetization transfer ratio asymmetry (MTR asym ) methods in simulations and stroke patients., Results: The combination of RF downsampling, MT lineshape look-up table, and conversion of MATLAB code to C code accelerated the NEMR fitting by over 2700-fold. Monte-Carlo simulations showed that NEMR had higher accuracy than EMR and eliminated the requirement of the steady-state condition. In ischemic stroke patients, the NEMR maps at 1 μT removed hypointense artifacts seen on EMR and MTR asym images, and better depicted stroke lesions than EMR. For NEMR, NOE # yielded significantly (p < 0.05) stronger signal contrast between stroke and normal tissues than APT # at 1 μT., Conclusion: The proposed NEMR method is suitable for arbitrary saturation settings and can remove MT and DS contamination from the CEST signal for improved detection of ischemic stroke., (© 2023 International Society for Magnetic Resonance in Medicine.)

Aims: To use machine learning algorithms to develop a model to accurately predict treatment responses to mirabegron or antimuscarinic agents in patients with overactive bladder (OAB), using real-world data from the FAITH registry (NCT03572231)., Methods: The FAITH registry data included patients who had been diagnosed with OAB symptoms for at least 3 months and were due to initiate monotherapy with mirabegron or any antimuscarinic. For the development of the machine learning model, data from patients were included if they had completed the 183-day study period, had data for all timepoints and had completed the overactive bladder symptom scores (OABSS) at baseline and end of study. The primary outcome of the study was a composite outcome combining efficacy, persistence, and safety outcomes. Treatment was deemed "more effective" if the composite outcome criteria for "successful," "no treatment change," and "safe" were met, otherwise treatment was deemed "less effective." To explore the composite algorithm, a total of 14 clinical risk factors were included in the initial data set and a 10-fold cross-validation procedure was performed. A range of machine learning models were evaluated to determine the most effective algorithm., Results: In total, data from 396 patients were included (266 [67.2%] treated with mirabegron and 130 [32.8%] treated with an antimuscarinic). Of these, 138 (34.8%) were in the "more effective" group and 258 (65.2%) were in the "less effective" group. The groups were comparable in terms of their characteristic distributions across patient age, sex, body mass index, and Charlson Comorbidity Index. Of the six models initially selected and tested, the decision tree (C5.0) model was chosen for further optimization, and the receiver operating characteristic of the final optimized model had an area under the curve result of 0.70 (95% confidence interval: 0.54-0.85) when 15 was used for the min n parameter., Conclusions: This study successfully created a simple, rapid, and easy-to-use interface that could be further refined to produce a valuable educational or clinical decision-making aid., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: Finite nucleos(t)ide analogue (NUC) therapy has been proposed as an alternative treatment strategy for chronic hepatitis B (CHB)., Aim: To quantify the incidence of severe hepatitis flares following NUC cessation in everyday clinical practice., Methods: This population-based cohort study enrolled 10,192 patients (male 71.7%, median age 50.9 years, cirrhosis 10.7%) who had received first-line NUCs for at least 1 year before discontinuing treatment. The primary outcome was severe flare with hepatic decompensation. We used competing risk analyses to assess event incidences and associated risk factors., Results: During a median follow-up of 2.2 years, 132 patients developed severe flares with hepatic decompensation, yielding a 4-year cumulative incidence of 1.8% (95% confidence interval [CI], 1.5%-2.2%). Significant risk factors were cirrhosis (adjusted sub-distributional hazard ratio [aSHR], 2.74; 95% CI, 1.82-4.12), manifestations of portal hypertension (aSHR, 2.46; 95% CI, 1.45-4.18), age (aSHR, 1.21 per 10 years; 95% CI, 1.03-1.42) and male sex (aSHR, 1.58; 95% CI, 1.04-2.38). In patients without cirrhosis or portal hypertension (n = 8863), the 4-year cumulative incidence of severe withdrawal flares stood at 1.3% (95% CI, 1.0%-1.7%). For those patients with available data confirming adherence to the standard stopping rules (n = 1274), the incidence was 1.1% (95% CI, 0.6%-2.0%)., Conclusions: Severe flares with hepatic decompensation were observed in 1%-2% of patients with CHB after stopping NUC therapy in daily practice. Risk factors included older age, cirrhosis, portal hypertension and male sex. Our findings argue against NUC cessation as part of routine clinical care., (© 2023 John Wiley & Sons Ltd.)

Background: Monitoring blood pressure and peripheral capillary oxygen saturation plays a crucial role in healthcare management for patients with chronic diseases, especially hypertension and vascular disease. However, current blood pressure measurement methods have intrinsic limitations; for instance, arterial blood pressure is measured by inserting a catheter in the artery causing discomfort and infection., Method: Photoplethysmogram (PPG) signals can be collected via non-invasive devices, and therefore have stimulated researchers' interest in exploring blood pressure estimation using machine learning and PPG signals as a non-invasive alternative. In this paper, we propose a Transformer-based deep learning architecture that utilizes PPG signals to conduct a personalized estimation of arterial systolic blood pressure, arterial diastolic blood pressure, and oxygen saturation., Results: The proposed method was evaluated with a subset of 1,732 subjects from the publicly available ICU dataset MIMIC III. The mean absolute error is 2.52 ± 2.43 mmHg for systolic blood pressure, 1.37 ± 1.89 mmHg for diastolic blood pressure, and 0.58 ± 0.79% for oxygen saturation, which satisfies the requirements of the Association of Advancement of Medical Instrumentation standard and achieve grades A for the British Hypertension Society standard., Conclusions: The results indicate that our model meets clinical standards and could potentially boost the accuracy of blood pressure and oxygen saturation measurement to deliver high-quality healthcare., (© 2023. The Author(s).)

Cerebral Small Vessel Disease (CSVD) frequently affects the elderly, with inflammation playing a crucial role in related health complications, including dementia, stroke, and SVD. Studies, including animal experiments, indicate a strong link between inflammation and SVD progression. The Neutrophil-Lymphocyte Ratio (NLR) serves as a possible biomarker for ongoing inflammatory risks. A total of 720 adults aged 50 years or older from the community-based I-Lan Longitudinal Aging Study were included in this study. General linear regression and ordinally logistic regression analyses were performed to evaluate the association between NLR and CSVD. We further examined the presence of lacune, microbleed, and white matter hyperintensity (WMH) on brain MRI, which were used to construct a combined CSVD score. The NLR was positively associated with WMH (adjusted r = 0.109, p = 0.003), microbleed (adjusted r = 0.102, p = 0.006), and lacune (adjusted r = 0.100, p = 0.008). After adjustments for smoking, drinking, and physical activity in the ordinal logistic regression analysis, age, gender, brachial Systolic Blood Pressure (SBP), fasting glucose, LDL-cholesterol, and Hs-CRP were compared among subjects with low tertile (T1), medium tertile (T2) and high tertile (T3) NLR. The results showed that T2 vs. T1 had an odds ratio of 1.23 (0.86-1.77); and T3 vs. T1 had an odds ratio of 1.87 (1.29-2.71) of CSVD scores in four groups (zero (reference group), one, two, and three or more). NLR could be used to assess the state of inflammation in cerebral vessels. A significant and positive correlation between NLR and CSVD was verified in this study. However, the practical clinical application of NLR in CSVD patients and prognosis prediction should be validated through more scientific attempts.

Background: Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients., Methods: We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment., Results: Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8 + T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8 + T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model., Conclusions: Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Helicobacter pylori infection is an important causal factor of gastric cancer and peptic ulcer disease and is associated with immune thrombocytopenic purpura and functional dyspepsia. In H pylori strains, point mutations in the 23S rRNA and gyrA genes are associated with clarithromycin resistance and levofloxacin resistance, respectively. Whether the efficacy of molecular testing-guided therapy is non-inferior to that of susceptibility testing-guided therapy for H pylori eradication is unclear. Therefore, we aimed to compare the efficacy and safety of molecular testing-guided therapy and traditional culture-based susceptibility testing-guided therapy in first-line and third-line treatment of H pylori infection., Methods: We did two multicentre, open-label randomised trials in Taiwan. In trial 1 (done at seven hospitals), treatment-naive individuals infected with H pylori who were aged 20 years or older were eligible for study inclusion. In trial 2 (done at six hospitals), individuals aged 20 years or older who failed treatment after two or more eradication therapies for H pylori infection were eligible for enrolment. Eligible patients were randomly assigned (1:1) to receive either molecular testing-guided therapy or susceptibility testing-guided therapy. The randomisation sequence was generated by computer using permuted block randomisation with a block size of 4. All investigators were masked to the randomisation sequence. Clarithromycin and levofloxacin resistance were determined by agar dilution test for measuring minimum inhibitory concentrations in the susceptibility testing-guided therapy group, and by PCR and direct sequencing for detection of 23S rRNA and gyrA mutations in the molecular testing-guided therapy group. Study participants received clarithromycin sequential therapy, levofloxacin sequential therapy, or bismuth quadruple therapy according to the resistance status to clarithromycin and levofloxacin. The 13 C-urease breath test was used to determine the status of H pylori infection at least 6 weeks after eradication therapy. The primary outcome was the eradication rate by intention-to-treat analysis. The frequency of adverse effects was analysed in patients with available data. The prespecified margins for non-inferiority were 5% for trial 1 and 10% for trial 2. The trials are ongoing for post-eradication follow-up and registered with ClinicalTrials.gov, NCT03556254 for trial 1, and NCT03555526 for trial 2., Findings: Between March 28, 2018, and April 23, 2021, 560 eligible treatment-naive patients with H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 1. Between Dec 28, 2017, and Oct 27, 2020, 320 eligible patients with refractory H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 2. 272 men and 288 women were recruited for trial 1, and 98 men and 222 women were recruited for trial 2. In first-line H pylori treatment, infection was eradicated in 241 (86%, 95% CI 82-90) of 280 patients in the molecular testing-guided therapy group and 243 (87%, 83-91) of 280 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·81). In third-line H pylori treatment, infection was eradicated in 141 (88%, 83-93) of 160 patients in the molecular testing-guided therapy group and 139 (87%, 82-92) of 160 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·74). The difference in the eradication rate between the molecular testing-guided therapy group and the susceptibility testing-guided therapy group was -0·7% (95% CI -6·4 to 5·0; non-inferiority p=0·071) in trial 1 and 1·3% (-6·0 to 8·5; non-inferiority p=0·0018 in trial 2 by intention-to-treat analysis. We found no difference in adverse effects across both treatment groups in trial 1 and trial 2., Interpretation: Molecular testing-guided therapy was similar to susceptibility testing-guided therapy in first-line therapy and non-inferior to susceptibility testing guided therapy in third-line treatment of H pylori infection, supporting the use of molecular testing-guided therapy for H pylori eradication., Funding: Ministry of Science and Technology of Taiwan, and Centre of Precision Medicine of the Higher Education Sprout Project by the Ministry of Education of Taiwan., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Inpatient glycemic management has become a common issue because of the increasing number of hospitalized patients with hyperglycemia. Point-of-care devices can enable timely inpatient glucose monitoring, which may lead to better outcomes. The accuracy of point-of-care testing in various clinical scenarios has been questioned, particularly in neonates and critically ill patients. This study aimed to evaluate the accuracy of the CONTOUR PLUS and CONTOUR PLUS ONE glucometers (new wireless systems that link to a smart mobile device) when used as point-of-care devices for blood glucose monitoring in neonates and critically ill adults in inpatient settings., Methods: This cross-sectional study was conducted at a medical center in central Taiwan and enrolled patients admitted to the neonatal intensive care unit, sick child room, or respiratory intensive care unit between November 2020 and April 2021. Neonates with suspected infection or abnormal blood coagulation and adults who had abnormal blood coagulation, were pregnant, had received organ transplants, or had undergone massive blood transfusions were excluded. The accuracy of the glucometers was determined based on the following criteria of the International Organization for Standardization (ISO) standard: 15197:2013., Findings: Overall, 114 neonates (mean age, 4.2 days [range, 0-28 days]; 65 boys [57.0%]) and 106 hospitalized critically ill adults (mean age, 68.2 years [range, 27-94 years]; 72 men [67.9%]) were enrolled in this study. The glucose values obtained with each glucometer had good precision, and all findings met the reference criteria of the within-lot results. All measurements of the neonates' venous blood by each glucometer met the accuracy criteria specified by ISO standard 15197:2013. Furthermore, 98.1% and 97.2% of the arterial blood glucose measurements for critically ill adults obtained with CONTOUR PLUS and CONTOUR PLUS ONE met the accuracy criteria, respectively., Implications: Both glucose management systems met the accuracy criteria for venous blood from neonates and arterial blood from critically ill adults. Thus, the use of these 2 point-of-care devices in inpatient settings, including for neonates and critically ill adults, can be recommended to minimize limitations associated with the clinical application of point-of-care testing in glucose management. The wireless connection may play a role in the subsequent development of institution-wide virtual glycemic management under the supervision of a team of endocrinologists., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non-EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk-expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3-positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3-positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: No published studies to date have evaluated the detailed pathologic and genetic features of lung adenocarcinoma after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and salvage surgery. We aimed to evaluate the pathologic and genetic changes of tumors in patients with advanced lung adenocarcinoma treated with EGFR TKI therapy and salvage surgery., Methods: This study retrospectively collected data from 29 advanced lung adenocarcinoma patients who underwent EGFR TKI therapy, followed by salvage operation, between January 2010 and December 2018. All patients had partial response or stable disease without evidence of progressive disease. Next-generation sequencing was used to determine whether acquired resistant mutations in morphologically treatment-sensitive and morphologically treatment-resistant regions of tumor existed., Results: There were 3, 22, and 4 patients with clinical stage IIIB, IVA, and IVB, respectively. After a mean TKI treatment duration of 134 days, 27 patients had partial response, 2 had stable disease, and 27.6% of patients were downstaged before salvage surgery. All patients had residual viable tumor cells in their tumor bed; 5 patients (17.2%) had a major pathologic response. Acquired T790M mutations (n = 4), histologic transformations (n = 2), and acquired T790M mutation with histologic transformation (n = 1) were identified in the morphologically treatment-resistant regions of tumors. The 3-year overall survival was 75.9%., Conclusions: The presence of morphologically treatment-resistant tumor regions with acquired T790M mutations and histologic transformations demonstrate the existence of resistant subclones in TKI-treated tumors before disease progression. Salvage surgery performed in selected patients before disease progression may improve survival by removing TKI-resistant subclones., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

A sulfated galactoglucan (3-SS) was discovered in Antrodia cinnamomea with antiproliferative and anti-inflammatory activities. Chemical identification of 3-SS resulted in the determination of a partial repeat unit as a 2-O sulfated 1,3-/1,4-linked galactoglucan with a two-residual 1,6-O-β-Glc branch on the 3-O position of a Glc. by monosaccharide analysis and 1D and 2D NMR spectroscopy. The anti-inflammation effects of 3-SS on RAW264.7 macrophage cells, such as IL-6 inhibition, restoration of LPS-induced IκB protein degradation, and inhibited LPS-induced TGFRII protein degradation, were confirmed to occur via AKT, ERK1/2, and p-38. In addition, 3-SS impaired the proliferation of H1975 lung cancer cells through EGFR/ERK/slug signaling. This is the first finding of 2-O sulfated 1,3-/1,4-galactoglucan with 1,6-β-Glc branches with dual functions of anti-inflammatory and antiproliferative activities., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Emerging laboratory and animal studies suggest that aspirin may prevent non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), however clinical evidence remains lacking., Methods: Using Taiwan's National Health Insurance Research Database, we screened 145,212 NAFLD patients from 1997 through 2011. After excluding any confounding conditions, 33,484 patients who continuously received a daily dose of aspirin for 90 days or more (treated group), along with 55,543 patients who had not received antiplatelet therapy (untreated group), were respectively recruited. Inverse probability of treatment weighting using the propensity score was applied to balance the baseline characteristics. Cumulative incidence of, and hazard ratio (HR) for HCC occurrence were analyzed after adjusting competing events. The high-risk patients, who were defined as age ≥ 55 years & elevated serum alanine aminotransferase, were further analyzed., Findings: The 10-year cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group (0.25% [95% CI, 0.19-0.32%] vs. 0.67% [95% CI, 0.54-0.81%]; P < 0.001). Aspirin therapy was significantly associated with a reduced HCC risk (adjusted HR [aHR] 0.48 [95% CI, 0.37-0.63]; P < 0.001). In the high-risk patients, the 10-year cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group (3.59% [95% CI, 2.99-4.19%] vs. 6.54% [95% CI, 5.65-7.42%]; P < 0.001). Aspirin therapy remained associated with a reduced HCC risk (aHR 0.63 [95% CI, 0.53-0.76]; P < 0.001). Subgroup sensitivity analyses verified this significant association in nearly all subgroups. In the time-varying model amongst aspirin users, HCC risk was significantly lower through the use of aspirin for ≥ 3 years (aHR 0.64 [95% CI, 0.44-0.91]; P = 0.013), when compared with short-term use (< 1 year)., Interpretation: Daily aspirin therapy is significantly associated with a reduced HCC risk in NAFLD patients., Funding: Ministry of Science and Technology, Ministry of Health and Welfare, and Taichung Veterans General Hospital, Taiwan., Competing Interests: YCH has received research grants from Taiwan’s National Science and Technology Council, Gilead Sciences, E-Da Hospital, Stanford University, and Tomorrow Medical Foundation; speaker fees from Gilead Sciences, Abbvie Bristol-Myers Squibb, and Roche; advisory board fees from Gilead Sciences and Sysmex; and support for attending meetings from Gilead Sciences and Abbvie. The other authors have reported no disclosures of interest., (© 2023 The Author(s).)

Introduction: Subjective cognitive decline (SCD) and migraine are often comorbid. Hippocampal structural abnormalities have been observed in individuals with both SCD and migraine. Given the known structural and functional heterogeneity along the long axis (anterior to posterior) of the hippocampus, we aimed to identify altered patterns of structural covariance within hippocampal subdivisions associated with SCD and migraine comorbidities., Methods: A seed-based structural covariance network analysis was applied to examine large-scale anatomical network changes of the anterior and posterior hippocampus in individuals with SCD, migraine and healthy controls. Conjunction analyses were used to identify shared network-level alterations in the hippocampal subdivisions in individuals with both SCD and migraine., Results: Altered structural covariance integrity of the anterior and posterior hippocampus was observed in the temporal, frontal, occipital, cingulate, precentral, and postcentral areas in individuals with SCD and migraine compared with healthy controls. Conjunction analysis revealed that, in both SCD and migraine, altered structural covariance integrity was shared between the anterior hippocampus and inferior temporal gyri and between the posterior hippocampus and precentral gyrus. Additionally, the structural covariance integrity of the posterior hippocampus-cerebellum axis was associated with the duration of SCD., Conclusion: This study highlighted the specific role of hippocampal subdivisions and specific structural covariance alterations within these subdivisions in the pathophysiology of SCD and migraine. These network-level changes in structural covariance may serve as potential imaging signatures for individuals who have both SCD and migraine., 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 © 2023 Tsai, Chou, Lee, Liang, Kuo, Lin, Lin, Hsu, Ko, Yang and Lin.)

One-third of patients with end-stage chronic kidney disease (CKD) experience diabetic nephropathy (DN), which worsens the progression of renal dysfunction. However, preventive measures for DN are lacking. Lactobacillus acidophilus TYCA06, Bifidobacterium longum subsp. infantis BLI-02, and Bifidobacterium bifidum VDD088 probiotic strains have been demonstrated to delay CKD progression. This study evaluated their biological functions to stabilize blood-glucose fluctuations and delay the deterioration of renal function. The db/db mice were used to establish a DN animal model. This was supplemented with 5.125 × 10 9 CFU/kg/day (high dose) or 1.025 × 10 9 CFU/kg/day (low dose) mixed with probiotics containing TYCA06, BLI-02, and VDD088 for 8 weeks. Blood urea nitrogen (BUN), serum creatinine, blood glucose, and urine protein were analyzed. Possible mechanisms underlying the alleviation of DN symptoms by probiotic strains were evaluated through in vitro tests. Animal experiments revealed that BUN, serum creatinine, and blood glucose upon probiotic administration were significantly lower than in the control group. The rate of change of urine protein decreased significantly, and blood pressure, glucose tolerance, and renal fibrosis were improved. In vitro testing indicated that TYCA06 and BLI-02 significantly increased acetic acid concentration. TYCA06, BLI-02, and VDD088 were associated with better antioxidation, anti-inflammation, and glucose consumption activities relative to the control. A combination of the probiotics TYCA06, BLI-02, and VDD088 attenuated renal function deterioration and improved blood-glucose fluctuation in a diabetes-induced CKD mouse model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus behind the coronavirus disease 2019 (COVID-19) pandemic, is a type of RNA virus that is nonsegmented. Cardiovascular diseases (CVDs) increase the mortality risk of patients. In this review article, we overview the existing evidence regarding the potential mechanisms of myocardial damage in coronavirus disease 2019 (COVID-19) patients. Having a comprehensive knowledge of the cardiovascular damage caused by SARS-CoV-2 and its underlying mechanisms is essential for providing prompt and efficient treatment, ultimately leading to a reduction in mortality rates. Severe COVID-19 causes acute respiratory distress syndrome and shock in patients. In addition, awareness regarding COVID-19 cardiovascular manifestations has increased, including the adverse impact on prognosis with cardiovascular involvement. Angiotensin-converting enzyme 2 receptor may play a role in acute myocardial injury caused by SARS-CoV-2 infection. COVID-19 patients experiencing heart failure may have their condition exacerbated by various contributing factors and mechanisms. Increased oxygen demand, myocarditis, stress cardiomyopathy, elevated pulmonary pressures, and venous thrombosis are potential health issues. The combination of these factors may lead to COVID-19-related cardiogenic shock, resulting in acute systolic heart failure. Extracorporeal membrane oxygenation (ECMO) and left ventricular assist devices (LVADs) are treatment options when inotropic support fails for effective circulatory support. To ensure effective COVID-19-related cardiovascular disease (CVD) surveillance, it is crucial to closely monitor the future host adaptation, viral evolution, and transmissibility of SARS-CoV-2, given the virus's pandemic potential., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Tzu Chi Medical Journal.)

Chemical exchange saturation transfer (CEST) imaging benefits from a longer saturation duration and a higher saturation duty cycle. Dielectric shading effects occur when the radiofrequency (RF) wavelength approaches the object size. Here, we proposed a simultaneous parallel transmission-based CEST (pTx-CEST) sequence to prolongate the saturation duration at a 100% duty cycle and improve the RF saturation homogeneity in CEST imaging. The simultaneous pTx-CEST sequence was implemented by switching the CEST saturation module from the non-pTx to pTx mode, using the pTx functionality with both transmit channels being driven simultaneously (instead of time-interleaved). The optimization of amplitude ratio and phase difference settings between RF channels for best B1 homogeneity was performed in phantoms of two different sizes mimicking the human brain and abdomen. The optimal amplitude and phase settings generating the best B1 homogeneity in the phantoms were used in pTx-CEST scans of the human study. The comparison of the maximum achievable saturation duration between the non-pTx-CEST and pTx-CEST sequences was performed in a protein phantom, healthy volunteers, and a metastatic brain tumor patient. The optimal amplitude ratio and phase difference setting between transmit channels manifested circular and elliptical polarization in the head-sized and abdomen-sized phantoms. In the brain, the maximum saturation durations achieved at a 100% duty cycle using the simultaneous pTx-CEST sequence were prolonged to 2240, 3220, and 4200 ms compared with 980 ms using the non-pTx-CEST sequence at repetition times of 3, 4, and 5 s, respectively. The longer saturation duration helped improve the image contrast between the tumor and the normal tissue in the patient. The optimized elliptical polarization mode saturation pulses yielded improved uniformity of CEST signals acquired from the human abdomen. The proposed simultaneous pTx-CEST sequence enabled essentially arbitrarily long saturation duration at a 100% duty cycle and helped reduce the dielectric shading effects with the optimized RF setting., (© 2022 John Wiley & Sons, Ltd.)

Background and Aims: Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy., Methods: This study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen-negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods., Results: During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups., Conclusions: TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Thyroid cancer incidence has increased over recent decades with considerable geographic variations in incidence patterns. Here, we analyzed temporal trends in the incidence and mortality rates of thyroid cancer in Taiwan., Methods: We obtained age-standardized rates at a national level using data from the Taiwan Cancer Registry annual reports from 1995 to 2019. Trends in age-standardized rates were characterized by joinpoint regression analysis., Results: The age-standardized incidence rate of thyroid cancer increased from 3.00 per 100,000 person-years in 1995 to 15.46 per 100,000 person-years in 2019 (p < 0.001). Significant upward trends were observed in virtually all age groups, including adolescents and the geriatric population. The average annual percent changes were 7.97%, 2.60%, 2.77%, and 1.43% for papillary, follicular, medullary, and anaplastic thyroid cancers, respectively. The mortality rate from thyroid cancer decreased over time in women but remained stable in men., Conclusion: The incidence rates of thyroid cancer have steadily increased across gender, age groups, and tumor types over the past two decades. Future studies are needed to investigate potential etiological factors other than overdiagnosis that may drive these trends., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive responses to anti-PD-1 therapy. Neoantigens are sequence-altered proteins resulting from somatic mutations in cancer. This study identified the neoantigens of Hep-55.1C and Dt81 Hepa1-6 HCCs by comparing their whole exome sequences with those of a normal C57BL/6 mouse liver. Immunogenic long peptides were pooled as peptide vaccines. The vaccination elicited tumor-reactive immune responses in C57BL/6 mice, as demonstrated by IFN-γ ELISPOT and an in vitro killing assay of splenocytes. In the treatment of three mouse HCC models, combined neoantigen vaccination and anti-PD-1 resulted in more significant tumor regression than monotherapies. Flow cytometry of the tumor-infiltrating lymphocytes showed decreased Treg cells and monocytic myeloid-derived suppressor cells, increased CD8 + T cells, enhanced granzyme B expression, and reduced exhaustion-related markers PD-1 and Lag-3 on CD8 + T cells in the combination group. These findings provide a strong rationale for conducting clinical studies of using neoantigen vaccination in combination with anti-PD-1 to treat patients with HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To compare the efficacy and safety of the sandwich method with GreenLight photoselective vaporization (GLPVP) and bipolar transurethral resection (B-TURP) with those of the enucleation method in patients with BPH and a prostate volume ≥ 80 g., Methods: Patients with BPH who underwent either the sandwich method with GLPVP and B-TURP or the enucleation method between 2014 and 2021 were included in the analysis. The primary outcome was the comparison of uroflowmetry results between the 2 groups. Safety analysis of the complication rates was also compared., Results: The cohort included 55 patients in the sandwich group and 41 patients in the enucleation group. In the efficacy analysis, both groups showed comparable uroflowmetry results, except for a higher postoperative average flow rate in the enucleation group. Regarding perioperative parameters, the sandwich method required a longer operating time, and the enucleation group had a higher incidence of manual Foley irrigation. Both groups demonstrated similar postoperative complications., Conclusion: The sandwich method exhibited comparable efficacy and safety to the enucleation method in patients with BPH with a prostate volume ≥ 80 g. Thus, for surgeons who are familiar with GLPVP and B-TURP, the sandwich method may be an alternative surgical approach for BPH patients with large prostates., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patients, health professionals, and communities use social media to communicate information about health determinants and associated risk factors. Studies have highlighted the potential for social media to reach underserved populations, suggesting these platforms can be used to disseminate health information tailored for diverse and hard-to-reach populations. Little is known, however, about the use of social media among American Indian and Alaska Native populations. The objective of this cross-sectional study is to better understand the use of social media platforms to disseminate information across these populations. Our team surveyed 429 American Indian and Alaska Native adults attending cultural events in Washington State on their use of various types of social media. We used logistic regressions to assess participant use of Twitter, Snapchat, Facebook, and Instagram as related to participant demographics, including age, gender, education, and their place of residence (on-reservation, rural off-reservation areas, or large metropolitan areas). Findings showed that Facebook was used by more participants than other platforms (79%), followed by Instagram (31%). Nearly half of participants used only one social media platform (48%). Age was negatively associated with using Instagram (0.8 OR, 95% CI: 0.7, 0.9) and Snapchat (0.6 OR, 95% CI: 0.5, 0.7). College education was associated with higher odds of using an additional social media platform compared to those without any college education (2.0 OR, 95% CI: 1.1, 3.6). Most participants used social media platforms, which suggests these platforms may be a useful tool in disseminating information to American Indian and Alaska Native peoples. Further research should document how social media can be used to effectively disseminate risk and health information and assess whether it can influence health knowledge and behaviors among these populations.

Importance: The incidence of inflammatory bowel disease (IBD) is increasing in newly industrialized countries but disease etiologies remain unclear., Objective: To investigate the association between physical fitness and subsequent IBD risk among children and adolescents in Taiwan., Design, Setting, and Participants: This nationwide cohort study was conducted between January 1, 2010, and December 31, 2018. Data sources included the Taiwan National Health Insurance Research Database, the National Student Fitness Tests Database, and the Air Quality Monitoring System Database. This study included students who were aged 10 years, completed physical fitness tests between grades 4 and 13, and had at least 1 year of follow-up. Data analysis was last performed on January 15, 2023., Exposures: Physical fitness tests included cardiorespiratory endurance (CE; number of minutes to complete an 800-m run), musculoskeletal endurance (ME; number of bent-leg curl-ups in 1 minute), musculoskeletal power (MP; standing broad jump distance), and flexibility fitness (FF; 2-leg sit-and-reach distance)., Main Outcomes and Measures: Subsequent risk of IBD was compared among students based on physical fitness test results. Six-year cumulative incidences and hazard ratios (HRs) were calculated after adjusting for competing mortality. Performance was reported in quantiles, ranging from 1 (best) to 4 (poorest)., Results: There were 4 552 866 students who completed physical fitness tests between grades 4 and 13; among these students, 1 393 641 were aged 10 years and were included in the analysis. Six-year cumulative incidence of IBD risk was lowest among students in the best-performing quantile of CE (quantile 1, 0.74% [95% CI, 0.63%-0.86%]; P < .001), ME (0.77% [0.65%-0.90%]; P < .001), and MP (0.81% [0.68%-0.93%]; P = .005) compared with students in quantiles 2 through 4, respectively; however, no association was observed for quantiles of FF. After adjusting for competing HRs for mortality and other confounders, better CE was inversely associated with IBD risk (adjusted HR, 0.36 [95% CI, 0.17-0.75]; P = .007). Other measures of physical fitness were not independently associated with IBD risk., Conclusions and Relevance: The results of this study suggest that CE was inversely associated with IBD risk among children and adolescents, but ME, MP, and FF were not independently associated with IBD risk. Future studies that explore the mechanisms are needed.

Ultrasound has emerged as a highly valuable tool in imaging peripheral nerve lesions in the wrist region, particularly for common pathologies such as carpal tunnel and Guyon's canal syndromes. Extensive research has demonstrated nerve swelling proximal to the entrapment site, an unclear border, and flattening as features of nerve entrapments. However, there is a dearth of information regarding small or terminal nerves in the wrist and hand. This article aims to bridge this knowledge gap by providing a comprehensive overview concerning scanning techniques, pathology, and guided-injection methods for those nerve entrapments. The median nerve (main trunk, palmar cutaneous branch, and recurrent motor branch), ulnar nerve (main trunk, superficial branch, deep branch, palmar ulnar cutaneous branch, and dorsal ulnar cutaneous branch), superficial radial nerve, posterior interosseous nerve, palmar common/proper digital nerves, and dorsal common/proper digital nerves are elaborated in this review. A series of ultrasound images are used to illustrate these techniques in detail. Finally, sonographic findings complement electrodiagnostic studies, providing better insight into understanding the whole clinical scenario, while ultrasound-guided interventions are safe and effective for treating relevant nerve pathologies.

To evaluate the kinetics of serum and urinary hepcidin levels along with anemia-related parameters during the infection course of infants with febrile urinary tract infection (UTI), we enrolled febrile infants aged one to four months in this prospective study. Febrile patients with UTI were allocated into Escherichia coli ( E. coli ) or non- E. coli groups according to urine culture results. Septic workup, blood hepcidin, iron profile, urinalysis, and urinary hepcidin-creatinine ratio were collected upon admission and 3 days after antibiotic treatment. In total, 118 infants were included. On admission, the febrile UTI group showed a significant reduction in serum iron level and a significant elevation of urinary hepcidin-creatinine ratio compared to the febrile control counterpart. Moreover, urinary hepcidin-creatinine ratio had the highest odds ratio, 2.01, in logistics regression analysis. After 3 days of antibiotic treatment, hemoglobin and the urinary hepcidin-creatinine ratio were significantly decreased. Patients with an E. coli UTI had a significantly decreased urinary hepcidin-creatinine ratio after 3 days of antibiotics treatment, whereas the non- E. coli group showed insignificant changes. Our study suggested that the urinary hepcidin-creatinine ratio elevated during acute febrile urinary tract infection and significantly decreased after 3 days of antibiotics treatment, especially in E. coli UTI.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular complications of DM are the leading cause of morbidity and mortality in diabetic patients. There are three major types of pathophysiologic cardiac remodeling including coronary artery atherosclerosis, cardiac autonomic neuropathy, and DM cardiomyopathy in patients with DM. DM cardiomyopathy is a distinct cardiomyopathy characterized by myocardial dysfunction in the absence of coronary artery disease, hypertension, and valvular heart disease. Cardiac fibrosis, defined as the excessive deposition of extracellular matrix (ECM) proteins, is a hallmark of DM cardiomyopathy. The pathophysiology of cardiac fibrosis in DM cardiomyopathy is complex and involves multiple cellular and molecular mechanisms. Cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction (HFpEF), which increases mortality and the incidence of hospitalizations. As medical technology advances, the severity of cardiac fibrosis in DM cardiomyopathy can be evaluated by non-invasive imaging modalities such as echocardiography, heart computed tomography (CT), cardiac magnetic resonance imaging (MRI), and nuclear imaging. In this review article, we will discuss the pathophysiology of cardiac fibrosis in DM cardiomyopathy, non-invasive imaging modalities to evaluate the severity of cardiac fibrosis, and therapeutic strategies for DM cardiomyopathy.

Enzymatic catalysis has fueled considerable interest from chemists due to its high efficiency and selectivity. However, the structural complexity and vulnerability hamper the application potentials of enzymes. Driven by the practical demand for chemical conversion, there is a long-sought quest for bioinspired catalysts reproducing and even surpassing the functions of natural enzymes. As nanoporous materials with high surface areas and crystallinity, metal-organic frameworks (MOFs) represent an exquisite case of how natural enzymes and their active sites are integrated into porous solids, affording bioinspired heterogeneous catalysts with superior stability and customizable structures. In this review, we comprehensively summarize the advances of bioinspired MOFs for catalysis, discuss the design principle of various MOF-based catalysts, such as MOF-enzyme composites and MOFs embedded with active sites, and explore the utility of these catalysts in different reactions. The advantages of MOFs as enzyme mimetics are also highlighted, including confinement, templating effects, and functionality, in comparison with homogeneous supramolecular catalysts. A perspective is provided to discuss potential solutions addressing current challenges in MOF catalysis.

Background and Goal: Noninvasive prediction of isocitrate dehydrogenase (IDH) mutation status in glioma guides surgical strategies and individualized management. We explored the capability on preoperatively identifying IDH status of combining a convolutional neural network (CNN) and a novel imaging modality, ultra-high field 7.0 Tesla (T) chemical exchange saturation transfer (CEST) imaging., Method: We enrolled 84 glioma patients of different tumor grades in this retrospective study. Amide proton transfer CEST and structural Magnetic Resonance (MR) imaging at 7T were performed preoperatively, and the tumor regions are manually segmented, leading to the "annotation" maps that offers the location and shape information of the tumors. The tumor region slices in CEST and T1 images were further cropped out as samples and combined with the annotation maps, which were inputted to a 2D CNN model for generating IDH predictions. Further comparison analysis to radiomics-based prediction methods was performed to demonstrate the crucial role of CNN for predicting IDH based on CEST and T1 images., Results: A fivefold cross-validation was performed on the 84 patients and 4090 slices. We observed a model based on only CEST achieved accuracy of 74.01% ± 1.15%, and the area under the curve (AUC) of 0.8022 ± 0.0147. When using T1 image only, the prediction performances dropped to accuracy of 72.52% ± 1.12% and AUC of 0.7904 ± 0.0214, which indicates no superiority of CEST over T1. However, when we combined CEST and T1 together with the annotation maps, the performances of the CNN model were further boosted to accuracy of 82.94% ± 1.23% and AUC of 0.8868 ± 0.0055, suggesting the importance of a joint analysis of CEST and T1. Finally, using the same inputs, the CNN-based predictions achieved significantly improved performances above those from radiomics-based predictions (logistic regression and support vector machine) by 10% to 20% in all metrics., Conclusion: 7T CEST and structural MRI jointly offer improved sensitivity and specificity of preoperative non-invasive imaging for the diagnosis of IDH mutation status. As the first study of CNN model on imaging acquired at ultra-high field MR, our results could demonstrate the potential of combining ultra-high-field CEST and CNN for facilitating decision-making in clinical practice. However, due to the limited cases and B1 inhomogeneities, the accuracy of this model will be improved in our further study., Competing Interests: Authors Y-HC and Y-CH were employed by the company Siemens Healthineers Ltd, China. Author PL was employed by Siemens Healthcare GmbH, Germany. The remaining 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 © 2023 Yuan, Yu, Chang, Chu, Yu, Hsu, Patrick, Liu and Yue.)

Lay Abstract: White matter is the neural pathway that connects neurons in different brain regions. Although research has shown white matter differences between autistic and non-autistic people, little is known about the properties of white matter in non-autistic siblings. In addition, past studies often focused on the whole neural tracts; it is unclear where differences exist in specific segments of the tracts. This study identified neural segments that differed between autistic people, their non-autistic siblings, and the age- and non-autistic people. We found altered segments within the tracts connected to anterior brain regions corresponding to several higher cognitive functions (e.g. executive functions) in autistic people and non-autistic siblings. Segments connecting to regions for social cognition and Theory of Mind were altered only in autistic people, explaining a large portion of autistic traits and may serve as neuroimaging markers. Segments within the tracts associated with fewer autistic traits or connecting brain regions for diverse highly integrated functions showed compensatory increases in the microstructural properties in non-autistic siblings. Our findings suggest that differential white matter segments that are shared between autistic people and non-autistic siblings may serve as potential "intermediate phenotypes"-biological or neuropsychological characteristics in the causal link between genetics and symptoms-of autism. These findings shed light on a promising neuroimaging model to refine the intermediate phenotype of autism which may facilitate further identification of the genetic and biological bases of autism. Future research exploring links between compensatory segments and neurocognitive strengths in non-autistic siblings may help understand brain adaptation to autism.

The ubiquity of Internet gaming as part of the younger generation's (11-35 year-olds) lifestyle to-day warrants a deeper understanding of its impact on their mental health. In particular, there has been scant research investigating the link between Internet Gaming Disorder (IGD) and suicidal behaviors in this demographic group, even though several mental health symptoms of the former are known risk factors for the latter. This paper aims to establish the presence or absence of association between IGD and each of suicidal ideation, self-harm, and suicide attempt among the younger generation. A large-scale online survey on Internet gamers in Hong Kong was conducted in February 2019. 3430 respondents were recruited through purposive sampling. Study samples were stratified into distinct age groups and multiple logistic regression was conducted for each measured suicidal behavior in each age group. After controlling for sociodemographics, Internet usage, self-reported bullying perpetration and bullying victimization, social withdrawal, and self-reported psychiatric diagnoses such as depression and psychosis, analyses revealed that adolescent (11-17 year-old) gamers with IGD were more likely than their peers who had no IGD to have had suicidal ideation, self-harm, and suicide attempt in their lifetime. These associations did not hold for 18-35 year-old gamers. Findings suggest that it may be prudent to recognize IGD as a growing public mental health priority for the young populace, particularly adolescents. Existing suicide prevention efforts can be complemented through screening adolescents for IGD, and could be expanded to online gaming platforms to reach more hidden at-risk individuals., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Organisms often acquire physiological and morphological modifications to conquer ecological challenges when colonizing new environments which lead to their adaptive evolution. However, deciphering the genomic mechanism of ecological adaptation is difficult because ecological environments are often too complex for straightforward interpretation. Thus, we examined the adaptation of a widespread songbird-the rufous-capped babbler (Cyanoderma ruficeps)-to a relatively simple system: distinct environments across elevational gradients on the mountainous island of Taiwan. We focused on the genomic sequences of 43 birds from five populations to show that the Taiwan group split from its sister group in mainland China around 1-2 million years ago (Ma) and colonized the montane habitats of Taiwan at least twice around 0.03-0.22 Ma. The montane and lowland Taiwan populations diverged with gene flow between them, suggesting strong selection associated with different elevations. We found that the montane babblers had smaller beaks than the lowland ones, consistent with Allen's rule, and identified candidate genes-COL9A1 and SOX11-underlying the beak size changes. We also found that altitudinally divergent mutations were mostly located in noncoding regions and tended to accumulate in chromosomal inversions and autosomes. The altitudinally divergent mutations might regulate genes related to haematopoietic, metabolic, immune, auditory and vision functions, as well as cerebrum morphology and plumage development. The results reveal the genomic bases of morphological and physiological adaptation in this species to the low temperature, hypoxia and high UV light environment at high elevation. These findings improve our understanding of how ecological adaptation drives population divergence from the perspective of genomic architecture., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

(1) Background: A premature termination codon (PTC) can be induced by a type of point mutation known as a nonsense mutation, which occurs within the coding region. Approximately 3.8% of human cancer patients have nonsense mutations of p53. However, the non-aminoglycoside drug PTC124 has shown potential to promote PTC readthrough and rescue full-length proteins. The COSMIC database contains 201 types of p53 nonsense mutations in cancers. We built a simple and affordable method to create different nonsense mutation clones of p53 for the study of the PTC readthrough activity of PTC124. (2) Methods: A modified inverse PCR-based site-directed mutagenesis method was used to clone the four nonsense mutations of p53, including W91X, S94X, R306X, and R342X. Each clone was transfected into p53 null H1299 cells and then treated with 50 μM of PTC124. (3) Results: PTC124 induced p53 re-expression in H1299-R306X and H1299-R342X clones but not in H1299-W91X and H1299-S94X clones. (4) Conclusions: Our data showed that PTC124 more effectively rescued the C-terminal of p53 nonsense mutations than the N-terminal of p53 nonsense mutations. We introduced a fast and low-cost site-directed mutagenesis method to clone the different nonsense mutations of p53 for drug screening.