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Wei-Chen Tai,1 Chih-Ming Liang,1 Kuo-Wei Bi,2 Chung-Mou Kuo,1 Lung-Sheng Lu,1 Cheng-Kun Wu,1 Shih-Cheng Yang,1 Yuan-Hung Kuo,1 Chen-Hsiang Lee,3 Chih-Fang Huang,4 Chien-Ning Hsu,5 Pin-I Hsu,6 Deng-Chyang Wu,7 Tsung-Hui Hu,1,8 Keng-Liang Wu,1,8 Seng-Kee Chuah1,8 1Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Division of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Division of Family Physician, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 5Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 6Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, National Yang-Ming University, Kaohsiung, Taiwan; 7Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan; 8Chang Gung University College of Medicine, Taoyuan City, TaiwanCorrespondence: Seng-Kee Chuah; Chung-Mou KuoDivision of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung 833, TaiwanTel +886 7 731 7123 ext. 8301Fax +886 7 732 2402Email chuahsk@seed.net.tw; kuo51116@gmail.comPurpose: Steadily maintaining high intra-gastric PH is the major factor for successful Helicobacter pylori (H.pylori) eradication. It is important to search for a stronger PPI. Dexlansoprazole MR is a dual delayed release formulation PPI taken once daily which is capable of maintaining longer duration of high intra-gastric PH. It is very effective in treating gastroesophageal disease but reports on H, pylori eradication is very rare. This study sought to compare dexlansoprazole MR-based concomitant treatment and lansoprazole-based concomitant treatment in H. pylori infection and to investigate the factors that affect the eradication rates.Methods: Two hundred two participants with H. pylori infection were included and randomly assigned to seven days of dexlansoprazole MR-based concomitant therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily and metronidazole 500 mg twice daily; DACM group) or a seven days of lansoprazole-based concomitant therapy (lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily, and metronidazole 500 mg twice daily; LACM group). The participants were asked to perform urea breath tests eight weeks later.Results: The eradication rates in the DACM group were 86.1% [95% confidence interval (CI): 77.8%–92.2%] in the ITT analysis and 90.6% (95% CI: 82.9%–95.6%) in the PP analysis, respectively, as compared with 90.1% (95% CI: 82.6%–95.2%) and 92.6% (95% CI: 85.5%–96.9%) (p=0.384 and p=0.572, respectively) in the LACM group for the same analyses. The adverse event rates were 11.5% in the DACM group and 10.2% in the LACM group (p=0.779).Conclusion: As a first-line H. pylori treatment regimen, dexlansoprazole MR-based concomitant therapy attained a successful eradication rate of 90%, which was non inferior to that of lansoprazole-based concomitant treatment.ClinicalTrials.gov identifier: NCT03829150.Keywords: Helicobacter pylori eradication, strong proton-pump inhibitor, dexlansoprazole MR-based concomitant therapy, lansoprazole-based concomitant therapy, antibiotic resistance

The Barcelona Clinic Liver Cancer (BCLC) staging offers prognostic stratification and treatment allocation for hepatocellular carcinoma (HCC). We conducted this retrospective study to assess the efficacy of different treatment options for patients with initial HCC diagnosis. Survival rate and median survival times associated with different treatment options in each stage of BCLC classification were compared using the Kaplan-Meier method and log-rank test. A total of 3892 patients were enrolled. Overall survival rates were 46.2% at 1 year and 16.6% at 5 years. The median survival times decreased from 57.7 months in very early stage to 1.6 months in terminal stage. Surgical resection offered the best survival benefit for patients in very early, early and even intermediate stages. Transarterial embolisation and conformal radiotherapy offered survival benefits for selected patients in advanced and terminal stages. In conclusion, following the treatment schedules allocated by BCLC staging had survival benefits for HCC patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE/AIM: Hepatocellular carcinoma (HCC) surveillance is a common practice for patients with liver cirrhosis. The aims of the study were to assess impacts of surveillance and therapeutic options on survival of patients with HCC. METHODS: A total of 1436 cirrhotic patients with newly diagnosed HCC were enrolled between January 2002 and December 2004. Patients with HCC detected within periodic surveillance were the surveillance group (n=318, 22.1%). The other patients with HCC incidentally detected were the non-surveillance group (n=1118, 77.95%). Initial treatment options were recorded and overall survival was analysed. RESULTS: Compared with patients in the non-surveillance group, larger proportions of patients in the surveillance group possessed small tumours, at an early stage without vascular invasion or metastases, and afforded more curative treatment options including surgical resection, radiofrequency ablation and percutaneous ethanol injection. The overall survival was better for patients in surveillance (3-year survival rate: 59.1% versus 29.3%, p<0.001), early stages by Barcelona Clinic Liver Cancer (BCLC) staging or curative treatment options. Multivariate analysis demonstrated surveillance, hepatitis aetiology, alpha-fetoprotein, tumour gross type, tumour stage and treatment options were associated factors for patients' survival. Moreover, surveillance patients in curative BCLC stage following the treatment guideline for HCC proposed by the American association for the study of liver disease (AASLD) had a significantly better 3-year survival rate (77.1% versus 55.2%, p<0.001). CONCLUSIONS: HCC surveillance for cirrhotic patients could detect HCC at early and curative stages. However, appropriate treatment options following AASLD guideline further improve the survival for patients in early stage. [ABSTRACT FROM AUTHOR]

Background: With the widespread outbreak of monkeypox, it is crucial to enhance awareness and understanding of the disease, especially among high-risk individuals. This study aimed to investigate the knowledge levels of individuals seeking preexposure vaccination in Taiwan., Methods: This descriptive cross-sectional questionnaire survey was conducted online, and included a nationwide sample of high-risk adults receiving preexposure vaccination. The questionnaire comprised 30 items with six aspects and explanatory variables. A multivariate logistic regression model was used to identify the factors that influenced participants' knowledge of human monkeypox., Results: Among 2,604 participants, 97.3 % were male, 76.4 % identified as homosexual, and 24.4 % had a history of HIV infection. Approximately half of the participants displayed inadequate knowledge of human monkeypox, with weaker performance in diagnosis and treatment aspects. Using a multivariate logistic model, we found that those with a medical background or higher education level had a better understanding after adjustment for potential confounding factors. Among those with an educational level of college or below, men who had sex with men (MSM) without HIV displayed significantly lower knowledge levels (OR: 0.68; 95 % CI 0.51-0.91)., Conclusions: The existence of a knowledge gap within subgroups of MSM highlights the necessity for targeted educational interventions., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Effects of screening for Helicobacter pylori on gastric cancer incidence and mortality are unknown., Objective: To evaluate the effects of an invitation to screen for H pylori on gastric cancer incidence and mortality., Design, Setting, and Participants: A pragmatic randomized clinical trial of residents aged 50 to 69 years in Changhua County, Taiwan, eligible for biennial fecal immunochemical tests (FIT) for colon cancer screening. Participants were randomized to either an invitation for H pylori stool antigen (HPSA) + FIT assessment or FIT alone. The study was conducted between January 1, 2014, and September 27, 2018. Final follow-up occurred December 31, 2020., Intervention: Invitation for testing for H pylori stool antigen., Main Outcomes and Measures: The primary outcomes were gastric cancer incidence and gastric cancer mortality. All invited individuals were analyzed according to the groups to which they were randomized., Results: Of 240 000 randomized adults (mean age, 58.1 years [SD, 5.6]; 46.8% female), 63 508 were invited for HPSA + FIT, and 88 995 were invited for FIT alone. Of the 240 000 randomized, 38 792 who were unreachable and 48 705 who did not receive an invitation were excluded. Of those invited, screening participation rates were 49.6% (31 497/63 508) for HPSA + FIT and 35.7% (31 777/88 995) for FIT alone. Among 12 142 participants (38.5%) with positive HPSA results, 8664 (71.4%) received antibiotic treatment, and eradication occurred in 91.9%. Gastric cancer incidence rates were 0.032% in the HPSA + FIT group and 0.037% in the FIT-alone group (mean difference, -0.005% [95% CI, -0.013% to 0.003%]; P = .23). Gastric cancer mortality rates were 0.015% in the HPSA + FIT group and 0.013% in the FIT-alone group (mean difference, 0.002% [95% CI, -0.004% to 0.007%]; P = .57). After adjusting for differences in screening participation, length of follow-up, and patient characteristics in post hoc analyses, an invitation for HPSA + FIT was associated with lower rates of gastric cancer (0.79 [95% CI, 0.63-0.98]) but not with gastric cancer mortality (1.02 [95% CI, 0.73-1.40]), compared with FIT alone. Among participants who received antibiotics, the most common adverse effects were abdominal pain or diarrhea (2.1%) and dyspepsia or poor appetite (0.8%)., Conclusions and Relevance: Among residents of Taiwan, an invitation to test for HPSA combined with FIT did not reduce rates of gastric cancer or gastric cancer mortality, compared with an invitation for FIT alone. However, when differences in screening participation and length of follow-up were accounted for, gastric cancer incidence, but not gastric cancer mortality, was lower in the HSPA + FIT group, compared with FIT alone., Trial Registration: ClinicalTrials.gov Identifier: NCT01741363.

In 2023, a new nomenclature, metabolic dysfunction-associated steatotic liver disease (MASLD), replaced the term non-alcoholic fatty liver disease (NAFLD). With the global rise in MASLD prevalence, concurrent MASLD and chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) are becoming increasingly common. This study aimed to evaluate the clinical impact of concurrent MASLD on long-term survival outcomes in patients with CHB-related early-stage HCC following curative resection. This retrospective study included patients diagnosed with CHB-related early-stage HCC who underwent curative hepatectomy between January 2010 and December 2019. We examined the association between histologically confirmed MASLD and clinical outcomes, with overall survival (OS) and recurrence-free survival (RFS) calculated using the Kaplan-Meier method and compared using the log-rank test. Of 587 eligible patients, 275 (46.8%) were diagnosed with concurrent MASLD. Patients with concurrent MASLD had a higher prevalence of diabetes, hypertension, body mass index (BMI) > 23 kg/m 2 , a lower proportion of AFP > 200 ng/ml, and microvascular invasion compared to those without MASLD. After a median follow-up of 66 months, patients with concurrent MASLD exhibited a lower risk of death (HR: 0.57, 95% CI: 0.34-0.95, P = 0.030) but no significant difference in HCC recurrence rates. Subgroup analysis revealed significantly higher OS in females, individuals with BMI ≥ 23 kg/m 2 , and non-cirrhotic patients (all P < 0.05). In conclusion, concurrent MASLD is associated with improved survival in patients with CHB-related HCC following curative resection, particularly in females, those with BMI ≥ 23 kg/m 2 , and non-cirrhotic patients., Competing Interests: None., (AJCR Copyright © 2024.)

Objectives: To explore the establishment of a risk prediction model for concurrent bronchiolitis obliterans (BO) in children with refractory Mycoplasma pneumoniae pneumonia (RMPP)., Methods: A retrospective study included 116 RMPP children treated in the Department of Pediatrics of Xiangya Changde Hospital from June 2021 to December 2023. Eighty-one cases were allocated to the training set and thirty-five cases to the validation set based on a 7:3 ratio. Among them, 26 cases in the training set developed BO, while 55 did not. The multivariate logistic regression was used to select variable factors for constructing the BO risk prediction model. Nomograms were drawn, and the receiver operating characteristic (ROC) curve was used to assess the discriminative ability of the model, while calibration curves and Hosmer-Lemeshow tests evaluated the model's calibration., Results: Multivariate logistic regression analysis indicated that several factors were significantly associated with concurrent BO in RMPP children, including length of hospital stay, duration of fever, atelectasis, neutrophil percentage (NEUT%), peak lactate dehydrogenase (LDH), ferritin, peak C reactive protein (CRP), oxygenation index (PaO 2 /FiO 2 ), ≥2/3 lung lobe consolidation, pleural effusion, bronchial mucous plugs, bronchial mucosal necrosis, and arterial oxygen partial pressure (PaO 2 ) ( P <0.05). ROC curve analysis for the training set indicated an area under the curve of 0.904 with 88% sensitivity and 83% specificity; the validation set showed an area under the curve of 0.823 with 76% sensitivity and 93% specificity. The Hosmer-Lemeshow test's Chi-square values for the training and validation sets were 2.17 and 1.92, respectively, with P values of 0.221 and 0.196, respectively., Conclusions: The risk prediction model for BO in RMPP children based on logistic regression has good performance. Variables such as length of hospital stay, duration of fever, atelectasis, peak LDH, peak CRP, NEUT%, ferritin, ≥2/3 lung lobe consolidation, pleural effusion, bronchial mucous plugs, bronchial mucosal necrosis, PaO 2 /FiO 2 , andPaO 2 can be used as predictors.

Acetaminophen (APAP), or paracetamol, is one of the most widespread and commonly used non-prescription pain medication in the world, and is effective at managing wide range of pain, including headache, muscle ache, and minor arthritic pain. While the pharmacokinetics of APAP is generally understood, there is a lack of data for its transfer ratio especially into the knee. A novel multi-microdialysis model was developed to simultaneously sample from blood, forelimb extensor muscle, brain striatum, and the knee joint cavity in the same experimental subject to investigate the potential interaction between APAP and Achyranthes bidentata Blume (A. bidentata), another widely used traditional Chinese medicininal herb especially for pain in the lower extremity. Rats were pre-treated with A. bidentata extract (ABex), APAP was then administered (60 mg/kg, i.v.), dialysates then subsequently analyzed using HPLC-PDA. Our analysis demonstrated that APAP concentrations, achieved after its administration either alone or in combination with ABex (1 and 3 g/kg, q.d. gavage), could be modelled effectively with a one-compartment model. The distribution ratio (AUC organ /AUC blood ) of blood-to-muscle, blood-to-brain and blood-to-knee was 0.372 ± 0.053, 0.277 ± 0.095 and 0.191 ± 0.042, respectively after administration of APAP (60 mg/kg, i.v.). No significant difference was observed between the pharmacokinetics of APAP administered alone and in combination with ABex; and APAP concentration exceed the half maximal effective concentration (EC 50 ) in all sampled organs for close to 3 hours with one single dose of drug administration, providing evidence for its broad-range analgesic effect., 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 © 2024 Elsevier B.V. All rights reserved.)

Objectives: Scarce research explores factors of concurrent psychologic distress (prolonged grief disorder [PGD], post-traumatic stress disorder [PTSD], and depression). This study models surrogates' longitudinal, heterogenous grief-related reactions and multidimensional risk factors drawing from the integrative framework of predictors for bereavement outcomes (intrapersonal, interpersonal, bereavement-related, and death-circumstance factors), emphasizing clinical modifiability., Design: Prospective cohort study., Setting: Medical ICUs of two Taiwanese medical centers., Subjects: Two hundred eighty-eight family surrogates., Interventions: None., Measurements and Main Results: Factors associated with four previously identified PGD-PTSD-depressive-symptom states (resilient, subthreshold depression-dominant, PGD-dominant, and PGD-PTSD-depression concurrent) were examined by multinomial logistic regression modeling (resilient state as reference). Intrapersonal: Prior use of mood medications correlated with the subthreshold depression-dominant state. Financial hardship and emergency department visits correlated with the PGD-PTSD-depression concurrent state. Higher anxiety symptoms correlated with the three more profound psychologic-distress states (adjusted odds ratio [95% CI] = 1.781 [1.562-2.031] to 2.768 [2.288-3.347]). Interpersonal: Better perceived social support was associated with the subthreshold depression-dominant state. Bereavement-related: Spousal loss correlated with the PGD-dominant state. Death circumstances: Provision of palliative care (8.750 [1.603-47.768]) was associated with the PGD-PTSD-depression concurrent state. Surrogate-perceived quality of patient dying and death as poor-to-uncertain (4.063 [1.531-10.784]) correlated with the subthreshold depression-dominant state, poor-to-uncertain (12.833 [1.231-133.775]), and worst (12.820 [1.806-91.013]) correlated with the PGD-PTSD-depression concurrent state. Modifiable social-worker involvement (0.004 [0.001-0.097]) and a do-not-resuscitate order issued before death (0.177 [0.032-0.978]) were negatively associated with the PGD-PTSD-depression concurrent and the subthreshold depression-dominant state, respectively. Apparent unmodifiable buffering factors included surrogates' higher educational attainment, married status, and longer time since loss., Conclusions: Surrogates' concurrent bereavement distress was positively associated with clinically modifiable factors: poor quality dying and death, higher surrogate anxiety, and palliative care-commonly provided late in the terminal-illness trajectory worldwide. Social-worker involvement and a do-not-resuscitate order appeared to mitigate risk., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Acyl-CoA-Binding Proteins (ACBPs) bind acyl-CoA esters and function in lipid metabolism. Although acbp3-1, the ACBP3 mutant in Arabidopsis thaliana ecotype Col-0, displays normal floral development, the acbp3-2 mutant from ecotype Ler-0 characterized herein exhibits defective adaxial anther lobes and improper sporocyte formation. To understand these differences and identify the role of ERECTA in ACBP3 function, the acbp3 mutants and acbp3-erecta (er) lines were analyzed by microscopy for anther morphology and high-performance liquid chromatography for lipid composition. Defects in Landsberg anther development were related to the ERECTA-mediated pathway because the progenies of acbp3-2 × La-0 and acbp3-1 × er-1 in Col-0 showed normal anthers, contrasting to that of acbp3-2 in Ler-0. Polymorphism in the regulatory region of ACBP3 enabled its function in anther development in Ler-0 but not Col-0 which harbored an AT-repeat insertion. ACBP3 expression and anther development in acbp3-2 were restored using ACBP3pro (Ler)::ACBP3 not ACBP3pro (Col)::ACBP3. SPOROCYTELESS (SPL), a sporocyte formation regulator activated ACBP3 transcription in Ler-0 but not Col-0. For anther development, the ERECTA-related role of ACBP3 is required in Ler-0, but not Col-0. The disrupted promoter regulatory region for SPL binding in Col-0 eliminates the role of ACBP3 in anther development., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

Ritonavir, an excellent inhibitor of CYP3A4, has recently been combined with nirmatrelvir to form Paxlovid for the treatment of severe acute respiratory syndrome coronavirus 2 infections. The root of Scutellaria baicalensis Georgi (S. baicalensis), a traditional Chinese medicinal (TCM) herb commonly used to treat heat/inflammation in the lung and digestive tracts, which are major organs targeted by viral infections, contains flavones that can influence the CYP3A metabolism pathway. To investigate the ability of ritonavir to cross the bloodbrain barrier (BBB) and its potential herb-drug interactions with an equivalent TCM clinical dose of S. baicalensis, multisite microdialysis coupled with an LCMS/MS system was developed using rat model. Pretreatment with S. baicalensis extract for 5 days, which contains less flavones than those used in previous studies, had a significant influence on ritonavir, resulting in a 2-fold increase in the total concentration of flavones in the blood and brain. Treatment also boosted the maximum blood concentration of flavones by 1.5-fold and the maximum brain concentration of flavones by 2-fold, all the while exerting no noticeable influence on the transfer ratio across the bloodbrain barrier. These experimental results demonstrated that the use of a typical traditional Chinese medicinal dose of S. baicalensis is sufficient to influence the metabolic pathway and synergistically increase the concentration of ritonavir in rats., 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 © 2024 Elsevier B.V. All rights reserved.)

Aim of the Study: Our hypothesis is that nirmatrelvir can penetrate the blood‒brain barrier and reach effective concentrations in the brain. Furthermore, herbal formulations can help maintain nirmatrelvir levels in the body, suggesting potential interactions between these medications., Materials and Methods: To investigate this hypothesis, an animal model combining multisite microdialysis, ultrahigh-performance liquid chromatography and tandem mass spectrometry (UHPLC-MS/MS) methods was developed to monitor nirmatrelvir levels in the blood and brain of rats., Results: The pharmacokinetic results showed that the area under the curve (AUC) of nirmatrelvir in the blood and brain was 798.3 ± 58.56 and 187.2 ± 23.46 min μg/mL, respectively, after the administration of nirmatrelvir alone (15 mg/kg, iv). When the Scutellaria baicalensis formulations were administered for five consecutive days prior to drug administration, the AUC of nirmatrelvir in the blood increased., Conclusions: These results provide constructive preclinical information that the concentrations of nirmatrelvir in the blood and brain were greater than the effective concentration (EC 90 ) for more than 6 h, and the Scutellaria baicalensis formulations had synergistic pharmacokinetic effects by increasing the concentration of nirmatrelvir in the blood., Competing Interests: 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., (© 2024 The Authors.)

Background: The association between lifestyle risk factors and the risk of mortality and chronic diseases has been established, while limited research has explored the impact of healthy lifestyle factors on lifetime health care expenditure using longitudinal individual data., Objective: We aimed to determine the individual and combined effects of 5 healthy lifestyle factors on life expectancy and lifetime health care expenditure in Taiwan., Methods: Using data from the National Health Interview Survey cohort, 5 healthy lifestyle behaviors were defined and analyzed: nonsmoking, avoiding excessive alcohol consumption, engaging in sufficient physical activity, ensuring sufficient fruit and vegetable intake, and maintaining a normal weight. We used a rolling extrapolation algorithm that incorporated inverse probability of treatment weighting to estimate the life expectancy and lifetime health care expenditure of the study populations with and without healthy lifestyle factors., Results: A total of 19,893 participants aged ≥30 (mean age 48.8, SD 13.4) years were included, with 3815 deaths recorded during a median follow-up period of 15.6 years. The life expectancy and per capita estimated lifetime health care expenditures for the overall study population were 35.32 years and US $58,560, respectively. Multivariable-adjusted hazard ratios for all-cause mortality in participants adhering to all 5 healthy lifestyle factors, compared with those adhering to none, were 0.37 (95% CI 0.27-0.49). We found significant increases in life expectancy for nonsmokers (2.31 years; 95% CI 0.04-5.13; P=.03), those with sufficient physical activity (1.85 years; 95% CI 0.25-4.34; P=.02), and those with adequate fruit and vegetable intake (3.25 years; 95% CI 1.29-6.81; P=.01). In addition, nonsmokers experienced a significant reduction in annual health care expenditure (-9.78%; 95% CI -46.53% to -1.45%; P=.03), as did individuals maintaining optimal body weight (-18.36%; 95% CI -29.66% to -8.57%; P=.01). Overall, participants adhering to all 5 healthy lifestyle behaviors exhibited a life gain of 7.13 years (95% CI 1.33-11.11; P=.02) compared with those adhering to one or none, with a life expectancy of 29.19 years (95% CI 25.45-33.62). Furthermore, individuals adopting all 5 healthy lifestyle factors experienced an average annual health care expenditure reduction of 28.12% (95% CI 4.43%-57.61%; P=.02) compared with those adopting one or none., Conclusions: Adopting a healthy lifestyle is associated with a longer life expectancy and a reduction of health care expenditure in Taiwanese adults. This contributes to a more comprehensive understanding of the impact of healthy lifestyle factors on the overall health and economic burden., (©Wei-Cheng Lo, Tsuey-Hwa Hu, Cheng-Yu Shih, Hsien-Ho Lin, Jing-Shiang Hwang. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 17.07.2024.)

Colon cancer has a poor clinical response to anti-PD1 therapy. This study aimed to evaluate the effect of cordycepin on the efficacy of anti-PD1 treatment in colon cancer. The viability of CT26 mouse colon carcinoma cells, cell-cycle progression, morphology, and the expression of mRNA and protein were assessed. A syngeneic animal model was established by implanting CT26 cells into BALB/c mice for in vivo experiments. Multi-parameter flow cytometry was used to analyze the splenic cell lineages and tumor microenvironment (TME). The in vitro data revealed that cordycepin, but not adenosine, inhibited CT26 cell viability. The protein, but not mRNA, expression levels of A2AR and A2BR were suppressed by cordycepin but not by adenosine in CT26 cells. The combination of cordycepin, but not adenosine, with anti-PD1 exhibited a greater tumor-inhibitory effect than anti-PD1 alone as well as inhibited the expression of A2AR and A2BR in splenic macrophages. In the TME, the combination of cordycepin and anti-PD1 increased the number of CD3+ T cells and neutrophils and decreased the number of natural killer (NK) cells. Overall, cordycepin augmented the antitumor effects of anti-PD1 against mouse colon carcinoma cells and inhibited the expression of the adenosine receptors A2AR and A2BR in splenic macrophages and intratumoral NK cells.

Background: The aim of this study was to assess the efficacy and safety of NRICM101 in hospitalized patients with COVID-19., Research Design and Methods: We conducted a retrospective study from 20 April 2021 to 8 July 2021, and evaluated the safety and outcomes (mortality, hospital stay, mechanical ventilation, oxygen support, diarrhea, serum potassium) in COVID-19 patients. Propensity score matching at a 1:2 ratio was performed to reduce confounding factors., Results: A total of 201 patients were analyzed. The experimental group ( n  = 67) received NRICM101 and standard care, while the control group ( n  = 134) received standard care alone. No significant differences were observed in mortality (10.4% vs. 14.2%), intubation (13.8% vs. 11%), time to intubation (10 vs. 11 days), mechanical ventilation days (0 vs. 9 days), or oxygen support duration (6 vs. 5 days). However, the experimental group had a shorter length of hospitalization (odds ratio = 0.12, p  = 0.043) and fewer mechanical ventilation days (odds ratio = 0.068, p  = 0.008) in initially severe cases, along with an increased diarrhea risk ( p  = 0.035)., Conclusion: NRICM101 did not reduce in-hospital mortality. However, it shortened the length of hospitalization and reduced mechanical ventilation days in initially severe cases. Further investigation is needed.

Importance: Improving end-of-life care in the intensive care unit (ICU) is a priority, but clinically modifiable factors of quality of dying and death (QODD) are seldom identified., Objectives: To comprehensively identify factors associated with QODD classes of dying ICU patients, emphasizing clinically modifiable factors based on the integrative framework of factors associated with for bereavement outcomes., Design, Setting, and Participants: This observational cohort study was conducted at medical ICUs of 2 Taiwanese medical centers from January 2018 to March 2020 with follow-up through December 2022. Eligible participants included primary family surrogates responsible for decision making for critically ill ICU patients at high risk of death (Acute Physiology and Chronic Health Evaluation II score >20) but who survived more than 3 days after ICU admission. Data analysis was conducted from July to September 2023., Main Outcomes and Measures: QODD was measured by the 23-item ICU-QODD questionnaire. Factors associated with patient membership in 4 previously determined QODD classes (high, moderate, poor to uncertain, and worst) were examined using a 3-step approach for latent class modeling with the high QODD class as the reference category., Results: A total of 309 family surrogates (mean [SD] age, 49.83 [12.55] years; 184 women [59.5%] and 125 men [40.5%]) were included in the study. Of all surrogates, 91 (29.4%) were the patients' spouse and 66 (53.7%) were the patients' adult child. Patient demographics were not associated with QODD class. Two family demographics (age and gender), relationship with the patient (spousal or adult-child), and length of ICU stay were associated with QODD classes. Patients of surrogates perceiving greater social support were less likely to be in the poor to uncertain (adjusted odds ratio [aOR], 0.89; 95% CI, 0.83-0.94) and worst (aOR, 0.92; 95% CI, 0.87-0.96) QODD classes. Family meetings were associated with the poor to uncertain QODD class (aOR, 8.61; 95% CI, 2.49-29.74) and worst QODD class (aOR, 7.28; 95% CI, 1.37-38.71). Death with cardiopulmonary resuscitation was associated with the worst QODD class (aOR, 7.51; 95% CI, 1.12-50.25). Family presence at patient death was uniformly negatively associated with the moderate QODD class (aOR, 0.16; 95% CI, 0.05-0.54), poor to uncertain QODD class (aOR, 0.21; 95% CI, 0.05-0.82), and worst QODD class (aOR, 0.08; 95% CI, 0.02-0.38). Higher family satisfaction with ICU care was negatively associated with the poor to uncertain QODD class (aOR, 0.93; 95% CI, 0.87-0.98) and worst QODD class (aOR, 0.86; 95% CI, 0.81-0.92)., Conclusions and Relevance: In this cohort study of critically ill patients and their family surrogates, modifiable end-of-life ICU-care characteristics played a more significant role in associations with patient QODD class than did immutable family demographics, preexisting family health conditions, patient demographics, and patient clinical characteristics, thereby illuminating actionable opportunities to improve end-of-life ICU care.

Bisphenol A (BpA) is an endocrine-disrupting substance commonly found in plastics and resins. It is reported that BpA exposure induces lipid accumulation in humans, similar to obesogenic compounds. The main objective of this study is to investigate the removal of BpA using Lactiplantibacillus sp. D10-2, and to examine its potential for reducing BpA-induced lipid accumulation in 3T3-L1 cell line model. The heat-dried cells of Lactiplantibacillus sp. D10-2 showed 69.7% removal efficiency for initial BpA concentration of 10 μg/mL, which was 30.5% higher than the live cells. The absence of metabolites or intermediates in BpA removal studies indicates that the Lactiplantibacillus sp. D10-2 strain removed BpA by adsorption process. The hydrophobic interactions of heat-dried Lactiplantibacillus sp. D10-2 cells were observed to be higher with 33.7% compared to live cells (15.0%), suggesting a stronger ability to bind with BpA. Although the BpA binding onto Lactiplantibacillus sp. D10-2 was not affected by pH, it was confirmed that as the temperature increases, the binding ability got decreased due to mass transfer and diffusion of BpA molecules. Treatment with Lactiplantibacillus sp. D10-2 (0.1, 0.25, 0.5, 1%) reduced lipid accumulation by 61.7, 58.0, 52.7 and 60.4% in 3T3-L1 cells exposed with BpA. In addition, it was confirmed that Lactiplantibacillus sp. D10-2 treatment suppressed the protein expression levels of lipogenesis-related PPARγ and C/EBPα in 3T3-L1 cells. The results of the study suggest that the Lactiplantibacillus sp. D10-2 strain can remove BpA and reduce BpA-accelerated lipid accumulation in 3T3-L1 cells., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To examine associations between family surrogates' bereavement outcomes and four previously determined quality of dying and death (QODD) latent classes (high, moderate, poor-to-uncertain, and worst)., Design: Prospective, longitudinal, observational study., Setting: Medical ICUs at two academically affiliated medical centers in Taiwan., Patients/participants: Three hundred nine family surrogates responsible for decision-making for critically ill patients at high risk of death (Acute Physiology and Chronic Health Evaluation II scores > 20) from a disease., Interventions: None., Measurements and Main Results: Participants were assessed by the depression and anxiety subscales of the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised, 11 items of the Prolonged Grief Disorder (PGD) scale, and the Medical Outcomes Study 36-Item Short-Form Health Survey at 1, 3, 6, 13, 18, and 24 months post-loss. We simultaneously examined associations of four QODD latent classes with physical and mental health-related quality of life (HRQOL) and symptoms of anxiety, depression, post-traumatic stress disorder (PTSD), and PGD assessed over 24 bereavement months using multivariate hierarchical linear modeling. Surrogates' distinct QODD latent classes assessed at 1-month post-loss were significantly associated with bereavement outcomes, except for physical HRQOL and PGD symptoms. Significantly more depressive symptoms and worse mental HRQOL (β [95% CI]) were reported by bereaved surrogates in the moderate (1.958 [1.144-2.772], -2.245 [-3.961 to -0.529]), poor-to-uncertain (2.224 [1.438-3.010], -7.026 [-8.683 to -5.369]), and worst (2.081 [1.215-2.964], -4.268 [-6.096 to -2.440]) QODD classes than those in the high QODD class. Bereaved surrogates in the moderate (2.095 [1.392-2.798]) and poor-to-uncertain (0.801 [0.123-1.480]) QODD classes reported more anxiety symptoms, whereas those in the poor-to-uncertain QODD class suffered more PTSD symptoms (2.889 [1.005-4.774]) than those in the high QODD class., Conclusions: The four distinct QODD latent classes were significantly associated with ICU family surrogates' bereavement outcomes, suggesting targets to improve end-of-life care quality in ICUs., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes., (© 2024. The Author(s).)

Whether serum Mac-2 binding protein glycosylation isomer (M2BPGi) level at year 5 of treatment could predict hepatocellular carcinoma (HCC) development and mortality beyond year 5 of entecavir or tenofovir disoproxil fumarate (TDF) treatment in chronic hepatitis B (CHB) patients with cirrhosis remain unclear. This retrospective study investigated the role of M2BPGi level at year 5 of treatment in predicting HCC and mortality beyond year 5 in CHB patients with cirrhosis. This study analyzed 1385 cirrhotic patients receiving entecavir or TDF treatment. Of them, 899 patients who did not develop HCC within the first 5 years of treatment were enrolled. In the entire cohort, there was no significant difference in the annual incidence of HCC before and after year 5 of entecavir or TDF treatment ( P = 0.455). Multivariable Cox analysis identified old age, higher AFP and M2BPGi levels at 5 years of treatment as independent predictors of HCC occurrence beyond year 5. We developed the HCC risk prediction model, AMA, based on age, M2BPGi and AFP levels at 5 years of treatment, with the total score ranging from 0 to 8. The AMA model accurately categorized patients into low (≤2), medium (2-5), and high (≥5) risk groups in the development and validation groups ( P <0.001) and exhibited good discriminant function in predicting HCC beyond year 5 in cirrhotic patients (AUROC: 0.743 at 5 years). The M2BPGi of 1.0 COI at 5 years of treatment stratified the risk of all-cause and liver-related mortality beyond year 5 ( P <0.001). In conclusions, M2BPGi level at 5 years of treatment is a useful marker for predicting HCC development and mortality beyond year 5 of entecavir or TDF therapy in CHB patients with cirrhosis., Competing Interests: Cheng-Yuan Peng has served as an advisory committee member for AbbVie, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme, and Roche., (AJCR Copyright © 2024.)

Introduction: Despite the serious risks of diabetes with hepatitis C virus (HCV) infection, this preventable comorbidity is rarely a priority for HCV elimination. We aim to examine how a shared care model could eliminate HCV in patients with diabetes (PwD) in primary care., Methods: There were 27 community-based Diabetes Health Promotion Institutes in each township/city of Changhua, Taiwan. PwD from these institutes from January 2018 to December 2020 were enrolled. HCV screening and treatment were integrated into diabetes structured care through collaboration between diabetes care and HCV care teams. Outcome measures included HCV care continuum indicators. Township/city variation in HCV infection prevalence and care cascades were also examined., Results: Of the 10,684 eligible PwD, 9,984 (93.4%) underwent HCV screening, revealing a 6.18% (n = 617) anti-HCV seroprevalence. Among the 597 eligible seropositive individuals, 507 (84.9%) completed the RNA test, obtaining 71.8% positives. Treatment was initiated by 327 (89.8%) of 364 viremic patients, and 315 (86.5%) completed it, resulting in a final cure rate of 79.4% (n = 289). Overall, with the introduction of antivirals in this cohort, the prevalence of viremic HCV infection dropped from 4.44% to 1.34%, yielding a 69.70% (95% credible interval 63.64%-77.03%) absolute reduction., Discussion: Although HCV prevalence varied, the care cascades achieved consistent results across townships/cities. We have further successfully implemented the model in county-wide hospital-based diabetes clinics, eventually treating 89.6% of the total PwD. A collaborative effort between diabetes care and HCV elimination enhanced the testing and treatment in PwD through an innovative shared care model., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF)., Methods: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled., Results: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment., Conclusions: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment., (© 2024. The Author(s).)

Background: Estimating the demand for HCV care cascade plays an important role in planning, monitoring, and assessing the performance of introducing a new community-based hepatitis C virus (HCV) elimination program but such an analytic and systematic approach has been barley addressed., Methods: A new collaborative care program for HCV elimination in the Changhua Community of Taiwan has been offered to a total of 895,353 residents since 2018. To grasp the variation of demand for HCV care cascade across demographic and geographic features in the planning stage, we applied the age-period-cohort spatial model to the antecedent anti-HCV survey enrolling 123,617 participants aged 30 years or older between 2005 and 2018. Based on this precise denominator, we then employed a "before-and-after" study design to routinely evaluate whether the WHO criteria of 90% RNA positive diagnosis and 80% successful treatments could be reached., Results: The overall demand for HCV care cascade was 4.28% (HCV infection) of the underlying population but a declining trend was noted. The early cohort had a higher demand, whereas the demand of the young cohort decreased with each passing year. The demand also differed by township. The demand, allowing for these variations, for antiviral treatment was 22,362, yielding the WHO target of 12,880 for achieving HCV elimination. With 11,844 successful treatments, the effectiveness of elimination has already reached 92% (11,844/12,880) by the end of 2022., Conclusions: The demand for HCV care cascade allows health care decision-makers to timely and properly assess the performance of a novel community-based collaborative care program in achieving HCV elimination., (© 2023. The Author(s).)

Background/aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients., Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks., Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported., Conclusion: 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Background: Whether the etiology of chronic liver disease (CLD) impacts the overall survival (OS) of patients with hepatocellular carcinoma (HCC) remains unclear. We aim to clarify this issue., Materials and Methods: Between 2011 and 2020, 3941 patients who were newly diagnosed with HCC at our institution were enrolled in this study. In patients with multiple CLD etiologies, etiology was classified using the following hierarchy: hepatitis C virus (HCV) > hepatitis B virus (HBV) > alcohol-related > all negative. All negative was defined as negative for HCV, HBV, and alcohol use disorder., Results: Among 3941 patients, 1407 patients were classified with HCV-related HCC, 1677 patients had HBV-related HCC, 145 patients had alcohol-related HCC, and 712 patients had all-negative HCC. Using the all-negative group as the reference group, multivariate analysis showed that HBV is an independent predictor of mortality (hazard ratio: 0.856; 95% confidence interval: 0.745-0.983; p = 0.027). Patients with HBV-related HCC had superior OS compared with patients with other CLD etiologies (p<0.001). Subgroup analyses were performed, for Barcelona Clinic Liver Cancer (BCLC) stages 0-A (p<0.001); serum alpha-fetoprotein (AFP) levels≧20 ng/ml (p<0.001); AFP levels < 20 ng/ml (p<0.001); age > 65 years (p<0.001); and the use of curative treatments (p = 0.002). No significant difference in OS between HBV and other etiologies was observed among patients aged ≤ 65 years (p = 0.304); with BCLC stages B-D (p = 0.973); or who underwent non-curative treatments (p = 0.1)., Conclusion: Patients with HBV-related HCC had superior OS than patients with other HCC etiologies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The genus Svistella Gorochov, 1987 includes 10 species from Asia, with nine documented in China. In this study, a new species, Svistellayayun He, sp. nov. , is described from Xizang, China. Morphologically, it resembles S.rufonotata (Chopard, 1932) but can be distinguished by a smaller inner tympanum, dark-brown setae on the 5 th segment of the maxillary palp, and a rounded apex on the ectoparamere. To validate our morphological inferences and support the description of S.yayun sp. nov. as a new species, we performed a PCA based on bioacoustics parameters and molecular analysis. All Svistella species documented in China are distinguished by integrating their songs and DNA barcoding., Competing Interests: The authors have declared that no competing interests exist., (Jing-Wen Hou, Yue Xu, Tian-Hao Hu, Zi-Heng Zhang, Shi-Yang Wu, Pu Gong, Zhu-Qing He.)

Background: Computed tomography (CT) plays a great role in characterizing and quantifying changes in lung structure and function of chronic obstructive pulmonary disease (COPD). This study aimed to explore the performance of CT-based whole lung radiomic in discriminating COPD patients and non-COPD patients., Methods: This retrospective study was performed on 2785 patients who underwent pulmonary function examination in 5 hospitals and were divided into non-COPD group and COPD group. The radiomic features of the whole lung volume were extracted. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied for feature selection and radiomic signature construction. A radiomic nomogram was established by combining the radiomic score and clinical factors. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were used to evaluate the predictive performance of the radiomic nomogram in the training, internal validation, and independent external validation cohorts., Results: Eighteen radiomic features were collected from the whole lung volume to construct a radiomic model. The area under the curve (AUC) of the radiomic model in the training, internal, and independent external validation cohorts were 0.888 [95% confidence interval (CI) 0.869-0.906], 0.874 (95%CI 0.844-0.904) and 0.846 (95%CI 0.822-0.870), respectively. All were higher than the clinical model (AUC were 0.732, 0.714, and 0.777, respectively, P < 0.001). DCA demonstrated that the nomogram constructed by combining radiomic score, age, sex, height, and smoking status was superior to the clinical factor model., Conclusions: The intuitive nomogram constructed by CT-based whole-lung radiomic has shown good performance and high accuracy in identifying COPD in this multicenter study., (© 2024. The Author(s).)

Background: Ritonavir is one of the most potent CYP3A4 inhibitor currently on the market, and is often used together with other antiviral drugs to increase their bioavailability and efficacy. Paxlovid, consisting of nirmatrelvir and ritonavir, was approved for the treatment of COVID-19. As previous studies regarding the use of ritonavir during pregnancy were limited to ex-vivo experiments and systemic safety data, to fully explore the detailed pharmacokinetics of ritonavir in pregnant rats' blood and conceptus, an analytical method consisted of multi-microdialysis coupled with UHPLC-MS/MS were developed to analyze the pharmacokinetics of ritonavir, both as a component of Paxlovid and by itself. 17 days pregnant female Sprague-Dawley rats were randomly split into three experimental group: normal dosage of ritonavir alone (7 mg kg -1 ), normal dosage of Paxlovid (ritonavir 7 mg kg -1  + nirmatrelvir 15 mg kg -1 ), and 3× dosage of ritonavir (21 mg kg -1 )., Results: 3× dosage of ritonavir produced a more than 3× increase in rats' blood and placenta. Transfer rate of ritonavir to the placenta, amniotic fluid, and fetus were determined to be 20.7%, 13.8%, and 4.7% respectively. Concentration of ritonavir in the placenta, amniotic fluid, and fetus did not significantly go down after 8 h., Significance: Overall, ritonavir's metabolism was not influenced by the presence of nirmatrelvir in pregnant rats. A 3× increase in dosage produced a concentration of roughly 4×, most likely a result of ritonavir's auto-inhibition effect on cytochrome P450 proteins. Accumulation of ritonavir is possible in placenta, amniotic fluid, and fetus., Competing Interests: The authors declare that they have no known competing financial interests nor personal relationships that could have influence the work reported in this paper., (© 2024 The Authors.)

Objective: This cohort study identified patterns/classes of surrogates' assessment of their relative's quality of dying and death (QODD) and to evaluate their associations with family satisfaction with intensive care unit (ICU) care., Methods: We identified QODD classes through latent class analysis of the frequency component of the QODD questionnaire and examined their differences in summary questions on the QODD and scores of the Family Satisfaction in the ICU questionnaire among 309 bereaved surrogates of ICU decedents., Results: Four distinct classes (prevalence) were identified: high (41.3%), moderate (20.1%), poor-to-uncertain (21.7%) and worst (16.9%) QODD classes. Characteristics differentiate these QODD classes including physical symptom control, emotional preparedness for death, and amount of life-sustaining treatments (LSTs) received. Patients in the high QODD class had optimal physical symptom control, moderate-to-sufficient emotional preparedness for death and few LSTs received. Patients in the moderate QODD class had adequate physical symptom control, moderate-to-sufficient emotional preparedness for death and the least LSTs received. Patients in the poor-to-uncertain QODD class had inadequate physical symptom control, insufficient-uncertain emotional preparedness for death and some LSTs received. Patients in the worst QODD class had poorest physical symptom control, insufficient-to-moderate emotional preparedness for death and substantial LSTs received. Bereaved surrogates in the worst QODD class scored significantly lower in evaluations of the patient's overall QODD, and satisfaction with ICU care and decision-making process than those in the other classes., Conclusions: The identified distinct QODD classes offer potential actionable direction for improving quality of end-of-life ICU care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inflammatory bowel disease (IBD) is a global health concern with varying levels and trends across countries and regions. Understanding these differences is crucial for effective prevention and treatment strategies., Methods: Using data from the 2019 Global Burden of Disease study, we examine IBD incidence, mortality, and disability-adjusted life years (DALYs) rates in 198 countries from 1990 to 2019. To assess changes in the burden of IBD, estimated annual percentage changes (EAPC) were calculated, and a Bayesian age-period-cohort model was used to predict the future 30-year trends of IBD., Results: In 2019, there were 405,000 new IBD cases globally (95% uncertainty interval (UI) 361,000 to 457,000), with 41,000 deaths (95% UI 35,000 to 45,000) and 1.62million DALYs (95% UI 1.36-1.92million). The global age-standardized incidence rate in 2019 was 4.97 per 100,000 person-years (95% UI 4.43 to 5.59), with a mortality rate of 0.54 (95% UI 0.46 to 0.59) and DALYs rate of 20.15 (95% UI 16.86 to 23.71). From 1990 to 2019, EAPC values for incidence, mortality, and DALYs rates were - 0.60 (95% UI - 0.73 to - 0.48), - 0.69 (95% UI - 0.81 to - 0.57), and - 1.04 (95% UI - 1.06 to - 1.01), respectively. Overall, the burden of IBD has shown a slow decline in recent years. In SDI stratification, regions with higher initial SDI (high-income North America and Central Europe) witnessed decreasing incidence and mortality rates with increasing SDI, while regions with lower initial SDI (South Asia, Oceania, and Latin America) experienced a rapid rise in incidence but a decrease in mortality with increasing SDI. Predictions using a Bayesian model showed lower new cases and deaths from 2020 to 2050 than reference values, while the slope of the predicted incidence-time curve closely paralleled that of the 2019 data., Conclusion: Increasing cases, deaths, and DALYs highlight the sustained burden of IBD on public health. Developed countries have stabilized or declining incidence rates but face high prevalence and societal burden. Emerging and developing countries experience rising incidence. Understanding these changes aids policymakers in effectively addressing IBD challenges in different regions and economic contexts., (© 2023. The Author(s).)

Objective: To investigate the expression and significance of GDF3 in testicular cancer through bioinformatics analysis., Methods: Using the TCGA and GTEx databases, differential expression analysis and pan-cancer analysis were performed to identify the target gene GDF3, and the clinical relevance of GDF3 in testicular cancer was analyzed using the UALCAN database. Based on the R packages "org.Hs.eg.db" and "clusterProfiler," gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to explore the potential functions of GDF3 in testicular cancer. The correlation of GDF3 with immune chemokines and immune inhibitors in testicular cancer was investigated using the TISIDB database., Results: The GDF3 was significantly upregulated in testicular cancer (P<0.001) and closely associated with clinical staging (P<0.05) and tumor subtypes (P<0.001). The immune-related analysis revealed that GDF3 was strongly correlated with immune chemokines CCL26 (rho=0.599, P<0.001), CCL7 (rho=0.525, P<0.001), immune inhibitor ADORA2A (rho=0.723, P<0.001), and PVRL2 (rho=0.585, P<0.001)., Conclusion: The GDF3 is closely related to the occurrence, development, and immune microenvironment of testicular cancer.

Lenvatinib has been approved as one of the first-line treatments for advanced hepatocellular carcinoma (HCC) due to its high treatment efficacy being non-inferior to sorafenib. Previous studies have shown well-controlled viremia contributes to the prognosis of HCC patients receiving first-line sorafenib; hence, we postulated this association might also exist in HCC patients with lenvatinib treatment. From April 2018 to December 2021, 201 unresectable HCC patients with first-line lenvatinib treatment in our institute were assessed. High-effect nucleoside analogues were administered for hepatitis B virus (HBV) control, while direct-acting antivirals were used for hepatitis C virus (HCV) elimination. Based on our previous study, well-controlled viremia was defined as patients who had undetectable viremia, or who had been receiving antivirals at least 6 months before lenvatinib. This study enrolled 129 patients, including 85 patients with HBV-related HCC (HBV-HCC) and 44 patients with HCV-related HCC (HCV-HCC), respectively. Progression-free survival (PFS) and overall survival (OS) rates between the two groups were not different. Before administration of lenvatinib, 57.1% of the HBV-HCC patients and 88.4% of the HCV-HCC patients had well-controlled viremia, and their PFS (8.8 vs. 3.1 months, p < 0.001) and OS (30.2 vs. 12.8 months, p = 0.041) were better than those who had uncontrolled viremia; moreover, well-controlled viremia reduced tumor progression in multivariate analysis (Hazard ratio: 0.41, 95% confidence interval: 0.25-0.68, p = 0.001) after adjusting for albumin-bilirubin grade and concurrent treatment. HBV or HCV infection was not associated with tumor progression of HCC patients receiving lenvatinib, but viremia, controlled or not, was., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Despite recent advances in cancer therapy, anthracycline-based combination therapy remains the standardized first-line strategy and has been found to have effective antitumor actions. Anthracyclines are extremely cardiotoxic, which limits the use of these powerful chemotherapeutic agents. Although numerous studies have been conducted on the cardiotoxicity of anthracyclines, the precise mechanisms by which doxorubicin causes cardiomyocyte death and myocardial dysfunction remain incompletely understood. This review highlights recent updates in mechanisms and therapies involved in doxorubicin-induced cardiomyocyte death, including autophagy, ferroptosis, necroptosis, pyroptosis, and apoptosis, as well as mechanisms of cardiovascular dysfunction resulting in myocardial atrophy, defects in calcium handling, thrombosis, and cell senescence. We sought to uncover potential therapeutic approaches to manage anthracycline cardiotoxicity via manipulation of crucial targets involved in doxorubicin-induced cardiomyocyte death and dysfunction., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Background: Prophylaxis antiviral therapy is recommended for patients with hepatitis B receiving chemotherapy but the ideal treatment duration after chemotherapy cessation needs more evidence for clarification., Aims: This study aimed to compare the relapse rate of short finite intervals of 6 months and 12 months of -nucleos(t)ide analogue (NA) therapy in patients stratified by low hepatitis B virus (HBV)-DNA of < 2000 IU/ml or high HBV DNA of ≥ 2000 IU/ml., Methods: Patients started tenofovir or entecavir treatment 1 week before chemotherapy and were assigned to different treatment duration groups randomly after stratified by HBV DNA pretreatment: (1) HBV DNA of < 2000 IU/ml at 6-month or 12-month duration; (2)HBV DNA of ≥ 2000 IU/ml at 6-month or 12-month duration. Virological relapse (VR) was defined as HBV DNA of > 2000 IU/ml, and clinical relapse (CR) was defined as HBV DNA of > 2000 IU/ml and alanine aminotransferase of > 80 IU/L during the follow-up period. The primary endpoint was to compare the durability between groups 1 year after antiviral therapy cessation. The secondary endpoint was VR and CR rate at long-term follow-up after antiviral therapy cessation., Results: This study enrolled 61 patients, and 5 patients were lost to follow-up or tumor recurrence. VR and CR rates were 46.4% and 14.3% at 1-year and 55.3% and 16.1%, at long-term follow-up, respectively. VR and CR rates demonstrated no difference between the groups. Pretreatment HBV DNA at ≥ 2000 IU/ml and end-of-treatment hepatitis B surface antigen (HBsAg) at ≥ 500 IU/ml were the predictor of VR (hazard ratio [HR]: 2.98; p = 0.010 and HR: 2.38; p = 0.037)., Conclusions: Prolongation from 6 months to 12 months of NA consolidation after chemotherapy cessation did not affect the VR or CR of HBV. High pretreatment HBV DNA and end-of-treatment HBsAg levels could predict VR after antiviral therapy cessation for chemotherapy., Competing Interests: Declaration of Competing Interest The authors who have taken part in this study declare they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

When attempting to maximize the crop yield from field-grown soybean (Glycine max (L.) Merr.) by means of improving the light conditions for photosynthesis in the canopy, it is crucial to find the optimal planting density and nitrogen application rate. The soybean plants that were the subject of our experiment were cultivated in N-dense mutual pairs, and included two cultivars with different leaf shapes; one cultivar sported ovate leaves (O-type) and the other lanceolate leaves (L-type). We analyzed the results quantitatively to determine the amount of spatial variation in light distribution and photosynthetic efficiency across the canopy, and to gauge the effect of the experimental parameters on the yield as well as the photosynthetic light and nitrogen use efficiency of the crop. Results indicate that the different leaf shapes were responsible for significant disparities between the photosynthetic utilization of direct and diffuse light. As the nitrogen fertilizer rate and the planting density increased, the soybean plants responded by adjusting leaf morphology in order to maximize the canopy apparent photosynthetic light use efficiency, which in turn affected the leaf nitrogen distribution in the canopy. Despite the fact that the light interception rate of the canopy of the L-type cultivar was lower than that of the canopy of the O-type cultivar, we found its canopy apparent photosynthetic nitrogen and light use efficiency were higher. It was interesting to note, however, that the nitrogen and light use efficiency contributions associated with exposure to diffuse light were greater for the latter than for the former., 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 Masson SAS. All rights reserved.)

In this study, in situ silver (Ag) - porous ZnO photocatalysts were synthesized via solvothermal and post-annealing treatment. The formation of the porous ZnO structure due to the removal of organic moieties from the inorganic-organic hybrids Ag-ZnS(en) 0.5 during the annealing process. The optimal Ag-ZnO photocatalyst showed excellent photocatalytic degradation activity, with 95.5% orange II dye and 97.2% bisphenol A (BPA) degradation under visible light conditions. Additionally, the photocatalytic inactivation of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) led to a 97% inactivation rate after 2 h under dark conditions. Trapping experiments suggest that the superoxide anion (O 2 - ) radicals are the main active species to degrade the organic dye. The improved photocatalytic dye degradation activity and inactivation of bacteria were attributed to the synergistic effect of Ag and porous ZnO structure, increased surface area, and efficiently separated the photoexcited charge carriers. This work could provide an effective strategy for the synthesis of porous structures toward organic pollutant degradation and bacterial inactivation in wastewater., 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 Ltd. All rights reserved.)

In nature, plants are exposed to a dynamic light environment. Fluctuations in light decreased the photosynthetic light utilization efficiency (PLUE) of leaves, and much more severely in C 4 species than in C 3 species. However, little is known about the plasticity of PLUE under dynamic light in C 4 species. Present study focused on the influence of planting density to the photosynthesis under dynamic light in maize (Zea mays L.), a most important C 4 crop. In addition, the molecular mechanism behind photosynthetic adaptation to planting density were also explored by quantitative proteomics analysis. Results revealed that as planting density increases, maize leaves receive less light that fluctuates more. The maize planted at high density (HD) improved the PLUE under dynamic light, especially in the middle and later growth stages. Quantitative proteomics analysis showed that the transfer of nitrogen from Rubisco to RuBP regeneration and C 4 pathway related enzymes contributes to the photosynthetic adaptation to lower and more fluctuating light environment in HD maize. This study provides potential ways to further improve the light energy utilization efficiency of maize in HD., (© 2023 John Wiley & Sons Ltd.)

Importance: Family surrogates of patients who die in an intensive care unit (ICU) are at risk of cooccurring prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and depressive disorder during bereavement, but symptom trajectories are often explored individually., Objectives: To simultaneously examine and determine co-occurrence of PGD, PTSD, and depressive symptom trajectories., Design, Setting, and Participants: This cohort study was conducted in ICUs of 2 Taiwanese medical centers from January 2018 to March 2020, with follow-up through July 2022. Participants included surrogates responsible for decision-making who provided data 6 to 24 months after the death of their loved one. Data were analyzed from August to December 2022., Main Outcomes and Measures: PGD was assessed with the 11 grief symptom items of the PG-13; PTSD, the Impact of Event Scale-Revised; and depressive symptoms, the depression subscale of the Hospital Anxiety and Depression Scale at 6, 13, 18, and 24 months after the death. Latent growth mixture modeling was conducted to identify distinct trajectories, and joint latent class analysis was used to assess joint patterns of trajectories., Results: A total of 303 participants were included, with most younger than 56 years (207 participants [68.3%]), female (177 participants [58.4%]), and married (228 participants [75.2%]), and their relationship with the patient was mostly spouse (88 participants [29.0%]) or adult child (166 participants [54.8%]). Three trajectories were identified each for PGD, PTSD, and depressive symptoms. A resilience trajectory was predominant across PGD (253 participants [83.5%]), PTSD (250 participants [82.5%]), and depressive (200 participants [66.0%]) symptoms. Second most common was a recovery trajectory identified for PGD (36 participants [11.9%]) and PTSD (41 participants [13.5%]) symptoms, while for depressive symptoms, a moderate trajectory (72 participants [23.8%]) signified persistent moderate distress. A chronic trajectory characterized by persistently high distress was identified for PGD (14 participants [4.6%]) and depressive (31 participants [10.2%]) symptoms, whereas a unique delayed-onset trajectory (12 participants [4.0%]) was identified for PTSD symptoms. Most family surrogates (228 participants [75.2%]) experienced cooccurring PGD, PTSD, and depressive symptom trajectories, but multiple patterns were discordant. Symptom trajectories cooccurred in joint patterns: resilient (247 participants [81.5%]), recovered (43 participants [14.1%]), and distressed (14 participants [4.5%]). These patterns were characterized by high conditional probabilities for the resilience (PGD, 0.999; PTSD, 0.999; depressive, 0.804), recovery (PGD, 0.854; PTSD, 0.890; depressive, 0.588), and chronic (PGD, 0.921; PTSD, 0.789; depressive, 0.980) symptom trajectories., Conclusions and Relevance: In this cohort study, grief-related psychological symptoms evolved in complex ways during ICU bereavement, as characterized by heterogeneous trajectories. Some ICU bereaved surrogates experienced persistent elevated PGD, PTSD, and depressive symptoms individually or conjointly, underscoring the importance of early screening to identify this population at high risk of comorbid psychological distress trajectories.

Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The antiviral drug molnupiravir is an orally bioavailable prodrug of the nucleoside analog β-D-N4-hydroxycytidine (NHC), which is used to treat coronavirus disease 2019 (COVID-19). However, there is very little information on the barrier distribution of molnupiravir. Our hypothesis is that molnupiravir and NHC can penetrate the blood‒brain barrier (BBB) into brain tissue and that nucleoside transporters (equilibrative nucleoside transporters; ENT and concentrative nucleoside transporters; CNT) can modulate this process., Methods: To investigate the mechanism of molnupiravir transport through the BBB, multiple microdialyses coupled to a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC‒MS/MS) was developed to monitor dialysates, and nitrobenzylthioinosine (NBMPR; an inhibitor of ENT) was administered concomitantly with molnupiravir (100 mg/kg, i.v.) in the male rat., Results: Here, we show that molnupiravir is rapidly metabolized to NHC in the blood and crossed the BBB in 20 min. Furthermore, when NBMPR is concomitantly administered to inhibit efflux, the concentrations of molnupiravir and NHC in the brain increased significantly., Conclusions: In summary, molnupiravir rapidly transforms into NHC and crosses the BBB and reaches the brain at approximately 0.3-0.8% of the blood‒brain ratio. The maximum concentration of NHC in the blood and brain is above the average half maximal inhibitory concentration (IC50) of the drug required to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, suggesting a therapeutic effect. The penetration of NHC is modulated by NBMPR. These findings provide constructive information on brain disorders in clinical patients with COVID-19., (© 2023. Springer Nature Limited.)

The aim of this study was to explore the effects of herbal drug pharmacokinetic interactions on the biotransformation of molnupiravir and its metabolite β-D-N4-hydroxycytidine (NHC) in the blood and brain. To investigate the biotransformation mechanism, a carboxylesterase inhibitor, bis(4-nitrophenyl)phosphate (BNPP), was administered. Not only molnupiravir but also the herbal medicine Scutellaria formula-NRICM101 is potentially affected by coadministration with molnupiravir. However, the herb-drug interaction between molnupiravir and the Scutellaria formula-NRICM101 has not yet been investigated. We hypothesized that the complex bioactive herbal ingredients in the extract of the Scutellaria formula-NRICM101, the biotransformation and penetration of the bloodbrain barrier of molnupiravir are altered by inhibition of carboxylesterase. To monitor the analytes, ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLCMS/MS) coupled with the microdialysis method was developed. Based on the dose transfer from humans to rats, a dose of molnupiravir (100 mg/kg, i.v.), molnupiravir (100 mg/kg, i.v.) + BNPP (50 mg/kg, i.v.), and molnupiravir (100 mg/kg, i.v.) + the Scutellaria formula-NRICM101 extract (1.27 g/kg, per day, for 5 consecutive days) were administered. The results showed that molnupiravir was rapidly metabolized to NHC and penetrated into the brain striatum. However, when concomitant with BNPP, NHC was suppressed, and molnupiravir was enhanced. The blood-to-brain penetration ratios were 2% and 6%, respectively. In summary, the extract of the Scutellaria formula-NRICM101 provides a pharmacological effect similar to that of the carboxylesterase inhibitor to suppress NHC in the blood, and the brain penetration ratio was increased, but the concentration is also higher than the effective concentration in the blood and brain., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Grief-related psychological distress often co-occurs to conjointly impair function during bereavement. Knowledge of comorbid grief-related psychological distress is limited: no longitudinal study has examined dynamic patterns of co-occurring prolonged grief disorder (PGD), posttraumatic stress disorder (PTSD), and depression, and previous assessment time frames have been variable and potentially inadequate given the duration criterion for PGD. Therefore, the purpose of this study was to investigate the transition of distinct symptom states based on the co-occurrence of PGD, PTSD, and depression symptoms for ICU bereaved surrogates over their first two bereavement years., Design: Prospective, longitudinal, observational study., Setting: Medical ICUs at two academically affiliated medical centers in Taiwan., Patients/participants: Three hundred three family surrogates responsible for decision-making for critically ill patients at high risk of death (Acute Physiology and Chronic Evaluation II scores > 20) from a disease., Intervention: None., Measurements and Main Results: Participants were assessed by 11 items of the Prolonged Grief Disorder (PG-13) scale, the Impact of Event Scale-Revised, and the depression subscale of the Hospital Anxiety and Depression Scale at 6, 13, 18, and 24 months postloss. PGD-PTSD-depression-symptom states and their evolution were examined by latent transition analysis. The following four distinct PGD-PTSD-depression-symptom states (prevalence) were initially identified: resilient (62.3%), subthreshold depression-dominant (19.9%), PGD-dominant (12.9%), and PGD-PTSD-depression comorbid (4.9%) states. These PGD-PTSD-depression-symptom states remained highly stable during the first two bereavement years, with transitions predominantly toward resilience. Prevalence for each state at 24 months postloss was 82.1%, 11.4%, 4.0%, and 2.5%, respectively., Conclusions: Four highly stable PGD-PTSD-depression-symptom states were identified, highlighting the importance of screening for subgroups of ICU bereaved surrogates with increased PGD or comorbid PGD, PTSD, and depression symptoms during early bereavement., Competing Interests: Drs. Wen and Chuang disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Molnupiravir is an orally bioavailable prodrug of the nucleoside analogue β-D-N4-hydroxycytidine (NHC) and is used to treat coronavirus disease 2019 (COVID-19). However, the pharmacokinetics and transplacental transfer of molnupiravir in pregnant women are still not well understood. In the present study, we investigated the hypothesis that molnupiravir and NHC cross the blood-placenta barrier into the fetus., Methods: A multisite microdialysis coupled with a validated ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC‒MS/MS) system was developed to monitor the dialysate levels of molnupiravir and NHC in maternal rat blood and conceptus (the collective term for the fetus, placenta, and amniotic fluid). Molnupiravir was administered intravenously (100 mg/kg, i.v.) on gestational day 16. To investigate the mechanism of transport of molnupiravir across the blood-placenta barrier, we coadministered nitrobenzylthioinosine (NBMPR, 10 mg/kg, i.v.) to inhibit equilibrative nucleoside transporter (ENT)., Findings: We report that molnupiravir is rapidly metabolized to NHC and then rapidly transformed in the fetus, placenta, amniotic fluid, and maternal blood. Our pharmacokinetics analysis revealed that the area under the concentration curve (AUC) for the mother-to-fetus ratio (AUC fetus /AUC blood ) of NHC was 0.29 ± 0.11. Further, we demonstrated that the transport of NHC in the placenta may not be subject to modulation by the ENT., Interpretation: Our results show that NHC is the predominant bioactive metabolite of molnupiravir and rapidly crosses the blood-placenta barrier in pregnant rats. The NHC concentration in maternal blood and conceptus was above the average median inhibitory concentration (IC 50 ) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), suggesting a therapeutic effect. These findings support the use of molnupiravir in pregnant patients infected with COVID., Funding: This study was supported in part by research grants from the National Science and Technology Council of Taiwan (NSTC 111-2113-M-A49-018 and NSTC 112-2321-B-A49-005)., Competing Interests: Declaration of interests The authors declare no conflicts of interest related to this study., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background/aims: Little is known about the role of post-treatment HBsAg decline in HBsAg loss following nucleos(t)ide analogues cessation., Methods: HBeAg-negative patients without cirrhosis who previously received entecavir or tenofovir disoproxil fumarate (TDF) were enrolled (n=530). All patients were followed-up post-treatment for >24 months., Results: Of the 530 patients, 126 achieved sustained response (Group I), 85 experienced virological relapse without clinical relapse and retreatment (Group II), 67 suffered clinical relapse without retreatment (Group III) and 252 received retreatment (Group IV). The cumulative incidence of HBsAg loss at 8 years was 57.3% in Group I, 24.1% in Group II, 35.9% in Group III and 7.3% in Group IV. Cox regression analysis showed that nucleos(t)ide analogue experience, lower HBsAg levels at end-of-treatment (EOT) and higher HBsAg decline at 6 months after EOT were independently associated with HBsAg loss in Group I and Groups II+III. The rates of HBsAg loss at 6 years in patients with HBsAg decline >0.2 log IU/mL in Group I and HBsAg decline >0.15 log IU/mL in Group II+III at 6 months after EOT were 87.7% and 47.1%, respectively., Conclusion: The HBsAg loss rate was high and post-treatment HBsAg decline could predict high HBsAg loss rate among HBeAg-negative patients who discontinued entecavir or TDF and did not need retreatment., Competing Interests: Conflict of interest None declared., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)