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Ming-Hsueh Tsai,1 Tom C Chan,2 Meng-Sui Lee,3,4 Mei-Shu Lai5 1Department of Internal Medicine, Taipei City Hospital, Taipei, Taiwan; 2Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan; 3Department of Dermatology, Taipei City Hospital, Taipei, Taiwan; 4Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 5Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, TaiwanCorrespondence: Meng-Sui LeeDepartment of Dermatology, Taipei City Hospital, No. 33, Sec. 2, Zhonghua Road, Taipei, 100, TaiwanTel/Fax +886 2 23889595 Ext 2225Email leemengsui@hotmail.comMei-Shu LaiInstitute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, 5Fl. No. 17, Hsu Chow Road, Taipei, 100, TaiwanTel +886 2 33668018Email mslai@ntu.edu.twPurpose: Psoriasis is an inflammatory disease associated with cardiovascular disease. Methotrexate (MTX) is a first-line systemic anti-psoriatic agent that may also protect against cardiovascular disease. We examined the cardiovascular risks among patients with psoriasis who were receiving MTX or the comparator, retinoids.Patients and Methods: We analysed data from the Taiwanese National Health Insurance database. The primary outcome was a composite of hospitalisation for ischaemic heart disease, ischaemic stroke and all-cause mortality (composite cardiovascular outcome). Propensity score-weighted analyses were used to evaluate patients who were followed from therapy initiation to the earliest instance of outcome occurrence, insurance disenrollment, death or study termination.Results: We identified 13,777 patients who received MTX and 6020 patients who received retinoids from 2000 to 2012. Compared to retinoids, MTX was associated with lower crude incidences of cardiovascular outcomes, hospitalisation for ischaemic heart disease, ischaemic stroke and all-cause mortality. In intention-to-treat analyses, MTX was associated with lower risks of composite cardiovascular outcomes (adjusted hazard ratio [HR]: 0.84, 95% confidence interval [CI]: 0.76– 0.94), ischaemic heart disease (HR: 0.87, 95% CI: 0.71– 1.06), ischaemic stroke (HR: 1.06, 95% CI: 0.89– 1.27) and all-cause mortality (HR: 0.75, 95% CI: 0.66– 0.85). Similar results were found in as-treated analyses.Conclusion: In this nationwide cohort of patients with psoriasis, compared to retinoids, MTX was associated with a modestly lower risk of cardiovascular events.Keywords: cardiovascular events, inflammation, psoriasis, pharmacoepidemiology

Yaa-Hui Dong,1,2,* Chia-Lin Hsu,3,4,* Ying-Ying Li,5 Chia-Hsuin Chang,6,7 Mei-Shu Lai2,7 1Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2Center of Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan; 3Division of Pulmonary Medicine, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan; 4Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 5Department of Pharmacy, Sijhih Cathay General Hospital, New Taipei City, Taiwan; 6Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 7Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan *These authors contributed equally to this work Background: Bronchodilators are commonly used as maintenance and rescue therapy in patients with COPD. We aimed to examine the prescribing patterns of bronchodilators in clinical practice.Methods: We identified patients with COPD who initiated oral or inhaled bronchodilators between 2001 and 2010 from the Taiwan National Health Insurance Research Database. We followed the patients for 1 year. For bronchodilator prescriptions, we classified the treatments based on medication classes and regimens (oral bronchodilators alone, oral and inhaled bronchodilators in combination, or inhaled bronchodilators alone). For inhaled bronchodilator prescriptions, we further classified the treatments as short-acting bronchodilators alone, short-acting and long-acting bronchodilators in combination, and long-acting bronchodilators alone. We evaluated the prescribing patterns and the change with time, in different physician specialists, and in different hospital accreditation levels.Results: Among a cohort of 4,387 study-eligible patients, we identified 21,235 bronchodilator prescriptions for the analysis. The majority of prescriptions were oral xanthines or beta-2 agonists (62.63% and 47.54%, respectively) rather than prescriptions for inhaled bronchodilators (less than 10%). Nearly 80% of prescriptions were oral bronchodilator alone regimens. Use of oral bronchodilators declined with time and varied with health care providers, which were most commonly prescribed by non-chest specialists and in primary care clinics. Despite limited use of inhaled bronchodilators, it was noted that short-acting bronchodilators alone regimens accounted for 60% of the inhaled bronchodilator prescriptions.Conclusion: Excessive use of oral and short-acting bronchodilators is noted in general practice. Further research and education programs are warranted to decrease inadequate oral bronchodilators and optimize inhaled treatments in the management of patients with COPD. Keywords: bronchodilators, chronic obstructive pulmonary disease, prescribing patterns Taiwan

Background: Press Ganey (PG) inpatient survey is widely used to track patient satisfaction with the hospital experience. Our aim was to use the PG survey to determine if there are racial differences in overall hospital experience and perception of nurses and surgeons following hip and knee arthroplasty. Methods: We retrospectively analyzed Black and White patients from hip and knee arthroplasty registries from a single institution between July 2010 and February 2012. The overall assessment score for the hospital experience and perception of the nurse and surgeon questions from the PG inpatient survey were dichotomized as “not completely satisfied” or “completely satisfied”. Multivariable logistic regression models were developed to determine the impact of race on the likelihood of being ‘completely satisfied’ in the hip and knee cohorts. Results: There were 2517 hip and 2114 knee patients who underwent surgery and completed the PG survey, of whom 3.9% were Black and 96.0% were White. Black patients were less likely to be completely satisfied with their hospital experience compared to White patients in the hip (odds ratio 0.62, confidence interval 0.39-1.00, P = .049) and knee (odds ratio 0.52, confidence interval 0.33-0.82, P = .005) cohorts. Black patients were also less likely to be completely satisfied with multiple aspects of care they received from the nurse and surgeon in both cohorts. Conclusions: We found that the PG Survey shows Black patients were less likely to be completely satisfied than White patients with the hospital experience, including their interactions with nurses and surgeons. More work is needed to understand this difference.

Background Pim-1 is overexpressed in cancer tissues and plays a vital role in carcinogenesis. However, its clinical significance in cancers is not fully verified by meta-analysis, especially in relation to prognosis and clinicopathological features. Methods Four databases, PubMed, Embase, Cochrane Library, and Web of Science, were searched. Literature screening and data extraction according to the inclusion and exclusion criteria. The quality of the included literatures was evaluated using the Newcastle-Ottawa scale and the data analysis was performed using STATA and Review Manager software. Results 15 articles were finally included for meta-analysis, involving 1651 patients. Effect-size pooling analysis showed that high Pim-1 was related to poor overall survival (OS) (HR 1.68 [95% CI 1.17-2.40], P = .004) and disease-free survival (DFS) (HR 2.15 [95 %CI 1.15-4.01], P = .000). Subgroup analysis indicated that the detection techniques of Pim-1 were the main sources of heterogeneity, and 2 literatures using quantitative polymerase chain reaction (qPCR) for Pim-1mRNA had high homogeneity (I 2 = .0%, P = .321) in OS. Another 13 studies that applied immunohistochemistry (IHC) for Pim-1 protein had significant heterogeneity (I 2 =82.2%, P = .000; I 2 =92%, P = .000) in OS and DFS, respectively, and further analysis demonstrated that ethnicity, sample size, and histopathological origin were considered to be the main factors affecting their heterogeneity. In addition, high Pim-1 was associated with lymph node metastasis (OR 1.40 [95% CI 1.02-1.92], P = .04), distant metastasis (OR 2.69 [95%CI 1.67-4.35], P < .0001), and clinical stage III-IV (OR .7 [95% CI .50-.96, P = .03). Sensitivity analysis suggested that the pooled results of each effect-size were stable and reliable, and there was no significant publication bias ( P = .138) in all included articles. Conclusion High Pim-1 can not only predict poor OS and DFS of cancer, but also help to infer the malignant clinical characteristics of tumor metastasis. Pim-1 may be a potential and promising biomarker for early diagnosis, prognostic analysis and targeted therapy of tumors.

Objective: This study aimed to investigate whether adding low-molecular-weight dextran to oral steroids in patients with idiopathic sudden sensorineural hearing loss resulted in better hearing outcomes than those in patients receiving oral corticosteroids alone.Study Design: Historical cohort study.Setting: Tertiary teaching hospital.Subjects and Methods: The authors reviewed the clinical records of 166 patients with idiopathic sudden sensorineural hearing loss. Therapeutic effectiveness was measured by the gain of pure-tone averages and 4 categories of hearing outcome (complete recovery, marked recovery, mild improvement, or no improvement). To manage potential confounding factors associated with treatment allocation, the authors matched the subjects from each group according to the propensity score (ie, the predicted probability that they would receive a specific treatment).Results: The authors identified 50 pairs of propensity score-matched subjects (n = 100) without significant difference of all clinical factors (P > .05). Subsequent analyses demonstrated that the average hearing gain in subjects receiving additional dextran to oral steroid was 31.7 ± 21.5 dB, which did not differ from 33.0 ± 21.8 dB in subjects receiving steroids alone (P = .76). Difference of hearing outcomes between the 2 groups was also nonsignificant (P = .92).Conclusion: Matching propensity scores successfully balanced the heterogeneity between the dextran and steroid groups. Analytical results demonstrated that adding low-molecular-weight dextran to oral corticosteroids was not associated with greater hearing gain or better hearing outcome in idiopathic sudden sensorineural hearing loss. [ABSTRACT FROM AUTHOR]

PURPOSE: The aim of this study was to assess the performance of 3 different influenza-like illness (ILI) case definitions, adopted by the European (European-CDC), USA (USA-CDC), and Taiwan Centers for Disease Prevention and Control (Taiwan-CDC), as screening tools for influenza during the 2009 H1N1 pandemic. METHODS: From August 15 to 30, 2009, all emergency department patients with clinical symptoms or at epidemiologic risk for influenza were enrolled in an observational cohort study. Influenza diagnosis was established by positive rapid influenza diagnostic test or virus isolation. Sensitivity, specificity, positive predictive value, and negative predictive value of the European-, USA, and Taiwan-CDC ILI case definitions for screening were determined. RESULTS: A total of 870 patients were screened during the study period. Rapid influenza diagnostic test was positive in 315 patients, 273 (85.6%) of whom had fever duration less than 72 hours. Virus isolation identified 4 more patients with influenza A initially negative by rapid influenza diagnostic test. The mean (SD) age of these 319 patients was 24.3 (18.1) years. Of the 870 screened patients, 670 (77.0%), 476 (54.7%), and 325 (37.4%) met the European-, USA-, and Taiwan-CDC ILI case definition, respectively. Screening sensitivity was 95%, 77.7%, and 57.7% and specificity was 33.4%, 58.6%, and 74.4%, respectively. Differences in sensitivity and specificity between any 2 of the 3 groups were statistically significant (P < .05). CONCLUSION: First-line physicians should recognize the advantage and limitation of different ILI case definitions in influenza screening, especially confronted by pandemic or highly pathogenic avian influenza in the future. [ABSTRACT FROM AUTHOR]

Purpose: The progression rates of colorectal cancer by Dukes' stage in a high-risk group were estimated and applied to evaluate the efficacy of different screening regimens.Patients and Methods: Of 6303 high-risk subjects invited to a colorectal cancer screening project with colonoscopy, 39 screen-detected cases and 16 postscreening cases were diagnosed with information available on Dukes' stage. A five-state Markov process was applied to estimate parameters pertaining to the disease natural history of colorectal cancer by Dukes' stage.Results: The estimates of the mean sojourn time in years were 3.10 for preclinical Dukes' A and B and 1.92 for preclinical Dukes' stages C and D. The predicted reductions of Dukes' stages C and D achieved by annual, biennial, 3-yearly, and 6-yearly screening regimens against the control group were 60%, 49%, 40%, and 25%, respectively. These, in turn, yield the corresponding predicted mortality reductions of 39%, 33%, 28%, and 18%.Conclusions: These findings suggest that to achieve a 30% mortality reduction, as observed in annual fecal occult blood testing, a prudent interscreening interval with colonoscopy for this high-risk group should not be longer than 3 years. [ABSTRACT FROM AUTHOR]

Background: Medication claims are commonly used to calculate the risk adjustment for measuring healthcare cost. The Rx-defined Morbidity Groups (Rx-MG) which combine the use of medication to indicate morbidity have been incorporated into the Adjusted Clinical Groups (ACG) Case Mix System, developed by the Johns Hopkins University. This study aims to verify that the Rx-MG can be used for adjusting risk and for explaining the variations in the healthcare cost in Taiwan.Methods: The Longitudinal Health Insurance Database 2005 (LHID2005) was used in this study. The year 2006 was chosen as the baseline to predict healthcare cost (medication and total cost) in 2007. The final sample size amounted to 793,239 (81%) enrolees, and excluded any cases with discontinued enrolment. Two different kinds of models were built to predict cost: the concurrent model and the prospective model. The predictors used in the predictive models included age, gender, Aggregated Diagnosis Groups (ADG, diagnosis- defined morbidity groups), and Rx-defined Morbidity Groups. Multivariate OLS regression was used in the cost prediction modelling.Results: The concurrent model adjusted for Rx-defined Morbidity Groups for total cost, and controlled for age and gender had a better predictive R-square = 0.618, compared to the model adjusted for ADGs (R2 = 0.411). The model combined with Rx-MGs and ADGs performed the best for concurrently predicting total cost (R2 = 0.650). For prospectively predicting total cost, the model combined Rx-MGs and ADGs (R2 = 0.382) performed better than the models adjusted by Rx-MGs (R2 = 0.360) or ADGs (R2 = 0.252) only. Similarly, the concurrent model adjusted for Rx-MGs predicting pharmacy cost had a better performance (R-square = 0.615), than the model adjusted for ADGs (R2 = 0.431). The model combined with Rx-MGs and ADGs performed the best in concurrently as well as prospectively predicting pharmacy cost (R2 = 0.638 and 0.505, respectively). The prospective models showed a remarkable improvement when adjusted by prior cost.Conclusions: The medication-based Rx-Defined Morbidity Groups was useful in predicting pharmacy cost as well as total cost in Taiwan. Combining the information on medication and diagnosis as adjusters could arguably be the best method for explaining variations in healthcare cost. [ABSTRACT FROM AUTHOR]

Background: The purpose of the present study was to investigate people's willingness to pay to sustain the current National Health Insurance (NHI) program in Taiwan and to extend that program to cover long-term care services.Methods: A survey was administered to 1800 inpatients and 1800 outpatients, selected from health care facilities across all accreditation levels that were operating under the supervision of six different regional branches of Taiwan's Bureau of National Health Insurance (BNHI). We used a contingent valuation method with closed-ended questions to elicit participants' willingness to pay for continued national heath insurance and additional institutional long-term care services. We divided participants into six subgroups and asked individuals in these groups referendum-like yes-no questions about whether they were willing to pay one of six price bids: New Taiwan Dollar (NT$) 50, NT$100, NT$200, NT$300, NT$400, or NT$500. Logistic regression was used to analyze willingness to pay.Results: We found maximum willingness to pay for continued coverage by the NHI program and additional institutional long-term care services to be NT$66 and NT$137 dollars per month, respectively.Conclusion: We found that people were willing to pay more for their insurance coverage. With regard to methodology, we also found that using a contingent valuation method to elicit peoples' willingness to pay for health policy issues is valid. The results of the present referendum-like study can serve as a reference for future policy decision making. [ABSTRACT FROM AUTHOR]

Background: This study aims to reveal early breast cancer (BC) specific competing endogenous RNA (ceRNA) network through the expression profiles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and mRNAs. Methods: Based on The Cancer Genome Atlas (TCGA), we obtained the differentially expressed mRNAs, miRNAs, and lncRNAs (DEmRNAs, DEmiRNAs and DElncRNAs) between early BC and normal samples. The lncRNA–miRNA–mRNA interaction network was constructed using Cytoscape. Functional enrichment were performed using GeneCoDis3. The expression of selected genes were validated by qRT-PCR. Based on the published dataset, we validated the result of TCGA integration analysis. The diagnostic and prognostic value of candidate genes was evaluated by ROC curve analysis and survival analysis, respectively. Results: Totally, 1207 DEmRNAs, 194 DElncRNAs and 37 DEmiRNAs were obtained. Functional enrichment analysis results showed that all of DEmRNAs were enriched in pathway of cytokine-cytokine receptor interaction, PPAR signaling pathway and pathways in cancer. The DEmRNA-DEmiRNA-DElncRNA interaction network in early BC was consisted of 23 DEmiRNAs, 95 DElncRNAs and 309 DEmRNAs. Among ceRNA network, IL-6-hsa-miR-182-5p-ADAMTS9-AS1 interactions, LIFR-hsa-miR-21-5p-ADAMTS9-AS1 interactions and MMP1/MMP11-hsa-miR-145-5p-CDKN2B-AS1 interactions were speculated to involve in the development of early BC. The qRT-PCR results were consistent with our integrated analysis. Except for ADAMTS9-AS1 and CDKN2B-AS1, expression of the others results in the Gene Expression Omnibus (GEO) dataset were generally consistent with TCGA integrated analysis. The area under curve (AUC) of the ADAMTS9-AS1, CDKN2B-AS1, IL-6, MMP11, hsa-miR-145-5p and hsa-miR-182-5p were 0.947, 0.862, 0.842, 0.993, 0.960 and 0.944, and the specificity and sensitivity of the 6 biomarkers were 83.4% and 95.6%, 72.2% and 90.3%, 80.1% and 74.3%, 96.2% and 96.5%, 90.1% and 92.3%, and 88.7% and 90.4%, respectively. In addition, IL-6 had potential prognostic value for early BC. Conclusion: These findings may provide novel insights into the lncRNA-miRNA-mRNA network and uncover potential therapeutic targets in early BC.

Objective: We describe our experience with routinely capturing and analyzing Mediterranean diet data via structured clinical documentation support tools built into the electronic medical record and describe adherence to the Mediterranean diet in patients at risk for either stroke or dementia in a US neurology clinical practice. Patients and Methods: The Mediterranean diet is associated with a reduced risk of stroke and dementia. The Department of Neurology at NorthShore University HealthSystem routinely evaluates patients at initial and annual outpatient visits using structured clinical documentation support (SCDS) tools built into the electronic medical record (EMR). For patient evaluations in our Vascular Neurology and Brain Health subspecialty clinics, SCDS tools in the EMR include the validated 14-item questionnaire for Mediterranean diet adherence (PREvención con DIeta MEDiterránea [PREDIMED]) that autoscores, auto-interprets, writes to the progress note, and electronically captures data. Our study population includes patients seen at these clinics from July 1, 2015, through November 29, 2017. Results: At their initial office visit, 25.5% (95/373) of Brain Health patients scored 10 or more points (“strongly adherent”) on the PREDIMED (median, 8; range, 0-14) whereas 6.7% (55/829) of Vascular Neurology patients achieved a score of 10 or more points (median, 6; range, 0-12). By contrast, 34.7% (2586/7447) of individuals in the original PREDIMED cohort were strongly adherent to the Mediterranean diet. Conclusion: PREDIMED scores can be electronically captured to tailor nutrition interventions by assessing baseline adherence at the time of their initial neurology clinic visit. Patients in our Midwestern US clinics were weakly adherent to the Mediterranean diet. This suggests a major opportunity for nutrition intervention and education in US neurology clinical practices, toward preserving and improving brain health.

Parkinson's disease dementia (PDD) is commonly developed in patients at the late stage of Parkinson's disease (PD) with unknown progression mechanisms. From the post-mortem tissues and animal models, the ventral tegmental area (VTA) and the CA2 regions are closely associated with dementia development in PDD. However, the structural connection between the two regions has not been fully traced. In this study, we applied tissue clearing and adeno-associated virus (AAV) tracing to map the neural circuits in a 3D manner. Hence, we have confirmed the direct connection between the regions with two dual AAV tracing systems and traced the VTA-CA2 circuit in 3D reconstruction. With the immunostaining, we have shown that the GABAergic neurons are the potential subtype of the postsynaptic CA2 neurons in the VTA-CA2 circuit. Under the 6-hydroxydopamine (6-OHDA), we have demonstrated the degeneration of the VTA-CA2 circuit from the observation of fragmented axonal projections. Collectively, we have first traced the direct connection of the whole VTA-CA2 circuit in an intact 3D manner and monitored the fragmentation of this target circuit in the 6-OHDA model. This VTA-CA2 circuit can be a target for future studies of the pathological spreading and degeneration mechanism from PD to PDD., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: Alcohol-associated liver disease (ALD) burden has been rising globally, fueled by increases in high-risk alcohol use following the coronavirus disease 2019 (COVID-19) pandemic. We evaluated trends in annual incidence of alcohol-associated hepatitis (AH) before and following the onset of the COVID-19 pandemic across two geographically distinct populations in the USA and Hong Kong., Methods: Using US national Veterans Affairs (VA) data and Hong Kong territory-wide data, trends in annual incidence of AH were evaluated from 2000 to 2023. AH was identified using a combination of International Classification of Diseases (ICD)-9/10 diagnostic codes, laboratory data, and available alcohol use data., Results: Among the VA data, annual incidence of AH rose steadily from 39.4 to 53.7 per 100,000 persons (2010-2020), then declined to 36.2 per 100,000 persons in 2023. Annual AH incidence was substantially lower in Hong Kong, but demonstrated similar trends, peaking at 0.28 per 100,000 persons during the first year of the pandemic. Among both cohorts, incidence of AH was significantly higher in men vs . women, but particularly for the VA cohort, the increase in AH incidence was more rapid in women. Among both cohorts, the highest incidence of AH in 2023 was among the 40-49-year age group (VA: 72.7 per 100,000 persons; Hong Kong: 1.89 per 100,000 persons)., Conclusions: We provide a comprehensive analysis of epidemiological trends in AH incidence across two distinct populations, highlighting the need for continued awareness of targeted interventions to curb unhealthy alcohol use and its complications., Impact and Implications: Alcohol-associated hepatitis (AH) is a severe complication of high-risk alcohol use associated with significant morbidity and mortality. Increasing alcohol use fueled by the COVID-19 pandemic has led to parallel increases in alcohol-related comorbidities. The current study provides a comprehensive analysis of trends in the incidence of AH across two distinct world regions before and following the onset of the COVID-19 pandemic. Better identification of epidemiological trends in AH incidence as well as highlighting populations most affected can help target public health resources and health system interventions to address the dangers of high-risk alcohol use more effectively., Competing Interests: T.C-F.Y. has served as an advisory committee member and a speaker for Gilead Sciences. J.C-T.L. has served as an advisory committee member for Boehringer Ingelheim and Gilead Sciences, and a speaker Gilead Sciences and Abbott. V.W-S.W. has served as a consultant or advisory committee member for AbbVie, Boehringer Ingelheim, Echosens, Intercept, Inventiva, Novo Nordisk, Pfizer, and TARGET PharmaSolutions; and a speaker for Abbott, AbbVie, Gilead Sciences, and Novo Nordisk. He has received a research grant from Gilead Sciences, and is a cofounder of Illuminatio Medical Technology Limited. G.L-H.W. has served as an advisory committee member for AstraZeneca, Gilead Sciences, GlaxoSmithKline, Janssen and Virion Biotherapeutics, as a speaker for Abbott, AbbVie, Ascletis, Bristol-Myers Squibb, Echosens, Ferring, Gilead Sciences, GlaxoSmithKline, Janssen, and Roche. She has also received a research grant from Gilead Sciences. R.J.W. has received research grants (to his institution) from Gilead Sciences, Exact Sciences, Theratechnologies, and Durect Corporation. He also serves as a consultant (without compensation) for Gilead Sciences, Salix, and Mallinckrodt Pharmaceuticals. The remaining authors have no competing interests to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Author(s).)

Postoperative cognitive dysfunction (POCD) is a common complication that affects memory, executive function, and processing speed postoperatively. The pathogenesis of POCD is linked to excessive neuroinflammation and pre-existing Alzheimer's disease (AD) pathology. Previous studies have shown that acupuncture improves cognition in the early phase of POCD. However, POCD can last for longer periods (up to weeks and years). The long-term effects of acupuncture are unknown. In this study, we hypothesized that electroacupuncture (EA) could reduce inflammation and cognitive dysfunction induced by laparotomy over a longer period. We characterized the effects of postoperative EA on cognitive changes and investigated the underlying molecular mechanisms in mice. Laparotomy was performed in 3-month-old mice followed by daily EA treatment for 2 weeks. Our data indicated that laparotomy induced prolonged impairment in memory and executive functions, which were mitigated by postoperative EA. EA also reduced tau phosphorylation and suppressed the activation of tau-related kinases and glia, with effects comparable to ibuprofen. These findings demonstrate the beneficial effects of EA in a mouse model of POCD, suggesting that EA's ability to suppress neuroinflammation may contribute to its protective effects. In conclusion, EA may be a viable non-pharmacological intervention for managing POCD in different phases of the medical condition.

Background & Aims: The use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB)., Methods: Patients with CHB aged ≥60 years receiving entecavir or TDF between January 2008 and December 2022 were identified using a territory-wide database in Hong Kong. The risk of incident fracture in entecavir- and TDF-treated patients before and after month 24 were compared after propensity score matching., Results: A total of 41,531 patients with CHB (mean age 69.8±7.8 years, 61.6% male) receiving entecavir (n = 39,897 [96.1%]) and TDF (n = 1,634 [3.9%]) were analysed. At a median follow-up of 25.3 (9.1-58.5) months, 1,733 (4.2%) patients developed incident fracture. Patients with incident fracture were more likely to have diabetes, hypertension, congestive heart failure, rheumatoid arthritis, osteoporosis, and a history of fracture. Compared with propensity score-matched entecavir-treated patients, the risk of incident fracture in TDF-treated patients was comparable in the first 24 months (weighted subdistribution hazard ratio [sHR] 0.99, 95% CI 0.56-1.73, p = 0.960) but increased after month 24 (weighted sHR 1.80, 95% CI 1.11-2.93, p = 0.019). The 24-, 60-, and 96-month cumulative incidences (95% CI) of fracture in TDF-treated and entecavir-treated patients were 2.3% (1.6%-3.4%) vs. 2.6% (1.9%-3.5%), 6.4% (5.0%-8.2%) vs. 4.7% (3.8%-6.0%), and 10.2% (8.3%-12.6%) vs. 6.8% (5.4%-8.5%), respectively., Conclusions: The risk of fracture increased with TDF treatment for ≥24 months in elderly patients with CHB. Selection of nucleos(t)ide analogues should be individualised based on age and comorbidities., Impact and Implications: Previous literature suggested that the use of tenofovir disoproxil fumarate (TDF) is associated with a decrease in bone mineral density. However, data on the impact of TDF on long-term incident clinical fracture remains scarce. In this real-world territory-wide study of 41,531 treated patients with chronic hepatitis B in Hong Kong, patients who received TDF were at a higher risk of fracture after 2 years of treatment than those who received entecavir. Given the ageing population of patients with chronic hepatitis B and the rising prevalence of comorbidities, our findings support the current treatment guidelines that recommend selecting antiviral treatment based on age and comorbidities., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Bacterial infections are not prevalent among patients hospitalized with COVID-19, while unnecessary prescription of antibiotics was commonly observed. This study aimed to determine the impact of procalcitonin testing on antibiotics prescription in the real-world setting., Methods: We performed a territory-wide retrospective cohort study involving all laboratory-confirmed patients hospitalized in public hospitals in Hong Kong in 2020 with COVID-19. We determined the prevalence of bacterial co-infections (documented infections within 72 h of admission) and secondary bacterial infections (infections after 72 h of admission) and antibiotics consumption, and the correlation between procalcitonin testing and antibiotics prescription., Results: The cohort included 8666 patients, with mean age 45.3 ± 19.9 years, 48.5% male, and comorbidities in 26.9%. Among 2688 patients with bacterial cultures performed, 147 (5.5%) had bacterial co-infections, and 222 (8.3%) had secondary bacterial infections. Antibiotics were prescribed for 2773 (32.0%) patients during the hospital admission. Procalcitonin tests were performed for 2543 (29.3%) patients. More patients with procalcitonin testing received antibiotics (65.9% vs. 17.9%, p < 0.001). Procalcitonin testing was associated with 5-fold increased risk of antibiotics prescription after adjusting for confounding variables. At hospital level, procalcitonin testing correlated with antibiotics prescription. Patients with procalcitonin level < 0.5 ng/mL had a lower probability of antibiotics initiation and shorter duration of antibiotics therapy., Conclusions: Procalcitonin testing was not associated with lower prescription of antibiotics. Patients with low procalcitonin level had lower antibiotics exposure, supporting the use of procalcitonin to exclude bacterial infections aiding early stopping of antibiotics among patients hospitalized with COVID-19., (© 2024. The Author(s).)

Background & Aims: We examined whether changing clinical characteristics and presence of diabetes mellitus (DM) impact the performance of hepatocellular carcinoma (HCC) risk scores., Methods: Adult patients with chronic hepatitis B (CHB) on ≥6 months of entecavir/tenofovir treatment between January 2005 and March 2020 were identified using a territory-wide electronic database in Hong Kong. DM was defined by antidiabetic agents, hemoglobin A1c ≥6.5%, fasting glucose ≥7 mmol/L, and/or diagnosis codes. PAGE-B, modified PAGE-B (mPAGE-B), and aMAP scores were assessed by area under the time-dependent receiver operating characteristic curves (AUROCs) and compared with CAMD and REAL-B scores with DM as a component., Results: Of 48,706 patients, 2792, 11,563, 15,471, and 18,880 started entecavir/tenofovir treatment between 2005-2008, 2009-2012, 2013-2016, and 2017-2020, respectively; DM prevalence rose from 15.5% in 2005-2008 to 24.3% in 2017-2020. AUROCs were comparable across the 4 periods in the 5 HCC risk scores (AUROCs ranged between 0.75 and 0.81). At a median follow-up of 4.4 years, 1512 non-diabetic (4.0%) and 645 (6.2%) diabetic patients developed HCC. AUROCs of all 5 scores were lower in diabetic patients than in non-diabetic patients (AUROCs ranged between 0.67-0.71 vs 0.78-0.82; all P < .001). REAL-B score achieved an AUROC of 0.71 in diabetic and 0.82 in non-diabetic patients. Both diabetic and non-diabetic patients in the low-risk group by REAL-B score had a low HCC incidence below the threshold of cost-effective HCC surveillance, ie, 0.2% annually., Conclusions: REAL-B score is accurate and preferred in entecavir/tenofovir-treated CHB patients because of the increasing prevalence of DM., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The latest Baveno VII consensus has provided guidance for identifying patients who have truly recompensated from those with hepatic decompensation. This study aimed to evaluate patients' transplant-free survival in three different stages of cirrhosis., Methods: All patients with chronic HBV infection and liver cirrhosis treated with oral nucleos(t)ide analogues from March 2006 to December 2022 were identified from a territory-wide database in Hong Kong. Patients with follow-up duration of <1 year were excluded. Participants were classified into three mutually exclusive groups: (1) no decompensated events ( i.e. compensated group); (2) decompensated events occurred ( i.e. decompensated group); or (3) decompensated events occurred followed by recompensation according to Baveno VII criteria ( i.e. recompensated group). A time-dependent Cox proportional hazard model was adopted for evaluation. The follow-up period was 5 years., Results: A total of 4,701 patients with cirrhosis and HBV who were treated with entecavir, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) were identified. During a median follow-up of 5 years (interquartile range 3.7, 5 years), 3,327 (70.8%), 1,347 (29.2%), and 265 (5.6%) patients had compensated, decompensated, and recompensated cirrhosis, respectively, at least once before the end of the study. In the time-dependent multivariable model, the recompensated group had similar transplant-free survival compared with the compensated group (adjusted hazard ratio 1.16; 95% CI 0.72-1.86; p  = 0.536). The 5-year transplant-free survival rate was 89.3% for the compensated group, whereas it was 76.0% for the recompensated group, reflecting a minimal difference between the two groups., Conclusions: The clinical significance of recompensation of cirrhosis in improving patient outcomes for individuals with CHB infection was highlighted in this study. Early identification and treatment with nucleos(t)ide analogues might promote hepatic recompensation and thus reduce mortality in patients with CHB., Impact and Implications: The latest Baveno VII consensus introduces the new concept of hepatic recompensation, which refers to the reversal of the structural and functional changes of cirrhosis after removal, cure, or suppression of the aetiology of cirrhosis. It is essential to investigate the transplant-free survival rates of patients who are able to achieve hepatic recompensation, as this has significant implications for the medical resources required to manage liver failure and transplantation. This study features the clinical significance of hepatic recompensation by comparing patient outcomes of those who achieve it to those who do not. The early identification and use of antiviral treatment with nucleos(t)ide analogues is a pivotal strategy to promote hepatic recompensation, which has the potential to significantly reduce mortality rates in patients with chronic HBV infection and ultimately aid in the elimination of hepatitis., Competing Interests: GLHW has served as an advisory committee member for Gilead Sciences and Janssen. She has also served as a speaker for Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead, and Janssen. VWSW has served as an advisory committee member for 3V-BIO, AbbVie, Allergan, Echosens, Gilead Sciences, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, and Terns; and a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences, and Merck. He has also received a research grant from Gilead Sciences. HLYC is an advisor for Aligos, Aptorum, Arbutus, Janssen, Gilead, GSK, Roche, Vaccitech, Vir Biotechnology, and Viron Therapeutics; and a speaker for Gilead, Roche, and Viatris. TCFY has served as an advisory committee member and a speaker for Gilead Sciences. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background & Aims: We aimed to determine the trends in risk factor control and treatment among patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) in 2000-2020., Methods: We conducted a territory-wide cohort study of adult patients with NAFLD and T2D diagnosed between 1 January 2000 and 31 July 2021 in Hong Kong. T2D was defined by use of any anti-diabetic agents, laboratory tests and/or diagnosis codes., Results: This study included 16,084 patients with NAFLD and T2D (mean age, 54.8 ± 12.0 years; 7124 male [44.3%]). The percentage of patients achieving individualised haemoglobin A 1c (HbA 1c ) targets increased from 44.5% (95% confidence interval [CI], 42.9-46.1) to 64.8% (95% CI, 64.1-65.5), and percentage of patients achieving individualised low-density lipoprotein-cholesterol (LDL-C) targets increased from 23.3% (95% CI, 21.9-24.7) to 54.3% (95% CI, 53.5-55.1) from 2000-2005 to 2016-2020, whereas percentage of patients achieving blood pressure control (<140/90 mm Hg) remained static at 53.1-57.2%. Combination therapy for diabetes increased, especially among those with poor glycaemic control, but there was no increase in combination therapy for hypertension. Fewer cirrhotic patients achieved blood pressure control and individualised LDL-C targets, but they were more likely to achieve individualised HbA 1c targets than non-cirrhotics. Metformin and statins were underused in cirrhotic patients. Younger patients (18-44 years) were less likely to achieve individualised HbA 1c targets than middle-aged (45-64 years) and older ones (≥65 years)., Conclusions: From 2000 to 2020, glycaemic and lipid control improved significantly, whereas blood pressure control remained static among patients with NAFLD and T2D., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Prenatal alcohol (ethanol) exposure (PAE) results in brain growth restriction, in part, by reprogramming self-renewal and maturation of fetal neural stem cells (NSCs) during neurogenesis. We recently showed that ethanol resulted in enrichment of both proteins and pro-maturation microRNAs in sub-200-nm-sized extracellular vesicles (EVs) secreted by fetal NSCs. Moreover, EVs secreted by ethanol-exposed NSCs exhibited diminished efficacy in controlling NSC metabolism and maturation. Here we tested the hypothesis that ethanol may also influence the packaging of RNAs into EVs from cell-of-origin NSCs., Methods: Sex-specified fetal murine iso-cortical neuroepithelia from three separate pregnancies were maintained ex vivo, as neurosphere cultures to model the early neurogenic niche. EVs were isolated by ultracentrifugation from NSCs exposed to a dose range of ethanol. RNA from paired EV and cell-of-origin NSC samples was processed for ribosomal RNA-depleted RNA sequencing. Differential expression analysis and exploratory weighted gene co-expression network analysis (WGCNA) identified candidate genes and gene networks that were drivers of alterations to the transcriptome of EVs relative to cells., Results: The RNA content of EVs differed significantly from cell-of-origin NSCs. Biological sex contributed to unique transcriptome variance in EV samples, where > 75% of the most variant transcripts were also sex-variant in EVs but not in cell-of-origin NSCs. WGCNA analysis also identified sex-dependent enrichment of pathways, including dopamine receptor binding and ectoderm formation in female EVs and cell-substrate adhesion in male EVs, with the top significant DEGs from differential analysis of overall individual gene expressions, i.e., Arhgap15, enriched in female EVs, and Cenpa, enriched in male EVs, also serving as WCGNA hub genes of sex-biased EV WGCNA clusters. In addition to the baseline RNA content differences, ethanol exposure resulted in a significant dose-dependent change in transcript expression in both EVs and cell-of-origin NSCs that predominantly altered sex-invariant RNAs. Moreover, at the highest dose, ~ 73% of significantly altered RNAs were enriched in EVs, but depleted in NSCs., Conclusions: The EV transcriptome is distinctly different from, and more sex-variant than, the transcriptome of cell-of-origin NSCs. Ethanol, a common teratogen, results in dose-dependent sorting of RNA transcripts from NSCs to EVs which may reprogram the EV-mediated endocrine environment during neurogenesis., (© 2023. The Author(s).)

Importance: Older patients living in nursing homes are at very high risk of mortality after getting COVID-19., Objective: To evaluate outcomes following oral antiviral treatment for COVID-19 among nonhospitalized older patients living in nursing homes., Design, Setting, and Participants: This is a territory-wide, retrospective cohort study conducted between February 16 and March 31, 2022, with the last follow-up date on April 25, 2022. Participants were patients with COVID-19 living in nursing homes in Hong Kong. Data analysis was performed from May to June 2022., Exposures: Molnupiravir, nirmatrelvir/ritonavir, or no oral antiviral treatment., Main Outcomes and Measures: The primary outcome was hospitalization for COVID-19, and the secondary outcome was risk of inpatient disease progression (ie, admission to intensive care unit, use of invasive mechanical ventilation, and/or death)., Results: Of 14 617 patients (mean [SD] age, 84.8 [10.2] years; 8222 women [56.2%]), 8939 (61.2%) did not use oral antivirals, 5195 (35.5%) used molnupiravir, and 483 (3.3%) used nirmatrelvir/ritonavir. Compared with patients who did not use oral antivirals, those who used molnupiravir and nirmatrelvir/ritonavir were more likely to be female and less likely to have comorbid illnesses and hospitalization in the past year. At a median (IQR) follow-up of 30 (30-30) days, 6223 patients (42.6%) were hospitalized and 2307 patients (15.8%) experienced inpatient disease progression. After propensity score weighting, both molnupiravir and nirmatrelvir/ritonavir were associated with a reduced risk of hospitalization (molnupiravir, weighted hazard ratio [wHR], 0.46; 95% CI, 0.37-0.57; P < .001; nirmatrelvir/ritonavir, wHR, 0.46; 95% CI, 0.32-0.65; P < .001) and inpatient disease progression (molnupiravir, wHR, 0.35; 95% CI, 0.23-0.51; P < .001; nirmatrelvir/ritonavir, wHR, 0.17; 95% CI, 0.06-0.44; P < .001). Nirmatrelvir/ritonavir was comparable to molnupiravir in achieving better clinical outcomes (hospitalization, wHR, 1.00; 95% CI, 0.75-1.33; P = .99; inpatient disease progression, wHR, 0.49; 95% CI, 0.20-1.20; P = .12)., Conclusions and Relevance: In this retrospective cohort study, the use of oral antivirals to treat COVID-19 was associated with a reduced risk of hospitalization and inpatient disease progression among patients living in nursing homes. The findings of this study of nursing home residents could be reasonably extrapolated to other frail older patients living in the community.

Objective: To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region., Methods: This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators., Results: A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%., Conclusion: This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry., (© 2023. The Author(s).)

Background & Aims: We examined the long-term incidence of hepatocellular carcinoma (HCC) and hepatic decompensation among chronic hepatitis B (CHB) patients who have achieved hepatitis B surface antigen (HBsAg) seroclearance., Methods: All adult CHB-monoinfected patients who cleared HBsAg between January 2000 and December 2020 were identified using a territory-wide database in Hong Kong. Patients who underwent liver transplantation and/or developed HCC before HBsAg seroclearance or less than 6 months follow-up were excluded. The primary and secondary endpoints were HCC and hepatic decompensation respectively., Results: We identified 9,769 patients with CHB who achieved HBsAg seroclearance (mean age 57 years, 60.0% male, 13.2% cirrhosis); most had compensated liver function at HBsAg loss. At a median (25 th -75 th percentile) follow-up of 4.6 (2.2-8.4) years, 106 (1.1%) patients developed HCC. Patients who developed HCC were older, more likely to be male and have cirrhosis, and had higher alanine aminotransferase and lower platelets at the time of HBsAg loss than patients without HCC. The cumulative incidence of HCC remained steady 0-7 and 8-12 years after HBsAg loss (p = 0.898) (crude annual incidence drop: -0.04%, 95% CI -0.13% to 0.04%, p = 0.265). Moreover, 124/9,640 (1.3%) patients developed hepatic decompensation. The growth in cumulative incidence of hepatic decompensation decelerated 8-12 years after HBsAg loss (p = 0.009) (crude annual incidence drop: -0.23%, 95% CI -0.40% to -0.06%, p = 0.012). In multivariable analysis, HBsAg loss for over 7 years was associated with a reduced risk of hepatic decompensation (adjusted subdistribution hazard ratio [aSHR] 0.55, 95% CI 0.31-0.97, p = 0.039) but not HCC (aSHR 1.35, 95% CI 0.83-2.19, p = 0.230)., Conclusion: HCC risk persists in patients after HBsAg loss, whereas the risk of hepatic decompensation decreases over time., Impact and Implications: Patients with chronic hepatitis B (CHB) still have a non-negligible risk of hepatocellular carcinoma (HCC) after 12 years of HBsAg seroclearance, especially among those with cirrhosis. The risk of developing hepatic decompensation decreases over time after HBsAg seroclearance. In clinical practice, although patients with CHB who cleared HBsAg have a more favourable clinical outcome than those who remain chronically infected, long-term HCC surveillance would still be necessary for patients with cirrhosis and other high-risk subgroups after HBsAg seroclearance., Competing Interests: Conflict of interest Terry Yip has served as an advisory committee member and a speaker for Gilead Sciences. Vincent Wong has served as a consultant or advisory committee member for AbbVie, Boehringer Ingelheim, Echosens, Intercept, Inventiva, Novo Nordisk, Pfizer, and TARGET PharmaSolutions; and a speaker for Abbott, AbbVie, Gilead Sciences, and Novo Nordisk. He has received a research grant from Gilead Sciences, and is a cofounder of Illuminatio Medical Technology Limited. Henry Chan has served as an Independent Non-Executive Director for Shanghai Henlius Biotech Inc; as an advisory board member for Aligos, Aptorum, Arbutus, Hepion, Janssen, Gilead, Glaxo-Smith-Kline, Roche, Vaccitech, Virion Therapeutics, and Vir Biotechnology; and as a speaker for Gilead, Roche, and Viatris. Grace Wong has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, AbbVie, Ascletis, Bristol-Myers Squibb, Echosens, Gilead Sciences, Janssen, and Roche. She has also received a research grant from Gilead Sciences. The other authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: We examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalization and deaths in a real-world cohort of nonhospitalized patients with coronavirus disease 2019 (COVID-19)., Methods: This was a territory-wide retrospective cohort study in Hong Kong. Nonhospitalized COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2022 were identified. Patients hospitalized on the day of the first clinic appointment or used both oral antivirals were excluded. The primary endpoint was hospitalization. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death., Results: Of 93 883 patients, 83 154 (88.6%), 5808 (6.2%), and 4921 (5.2%) were oral antiviral nonusers, molnupiravir users, and nirmatrelvir/ritonavir users, respectively. Compared with nonusers, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year. Molnupiravir users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1931 (2.1%) patients were hospitalized and 225 (0.2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0.79; 95% confidence interval [CI], 0.65-0.95; P = .011) but not molnupiravir use (weighted hazard ratio 1.17; 95% CI, 0.99-1.39; P = .062) was associated with a reduced risk of hospitalization than nonusers. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared with nonusers., Conclusion: Use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalization in real-world nonhospitalized patients with COVID-19., Competing Interests: Potential conflicts of interest. T. Y. has served as an advisory committee member and a speaker for Gilead Sciences. G. L. has served as an advisory committee member for Gilead, Merck, and GSK; speaker for Merck, Pfizer, and Gilead; and received research grant from Gilead, Merck, and GSK. V. W. has served as a consultant or advisory committee member for 3V-BIO, AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Merck, Novo Nordisk, Pfizer, ProSciento, Sagimet Biosciences, and TARGET PharmaSolutions; and a speaker for Bristol-Myers Squibb, Abbott, AbbVie, Echosens, Gilead Sciences, Merck, and Novo Nordisk. He has received a research grant from Gilead Sciences and is a cofounder of Illuminatio Medical Technology Limited. H. C. has served as an Independent Non-Executive Director for Shanghai Henlius Biotech Inc; as an advisory board member for Aligos, Aptorum, Arbutus, Hepion, Janssen, Gilead, Glaxo-Smith-Kline, Roche, Vaccitech, Virion Therapeutics, and Vir Biotechnology; and as a speaker for Gilead, Roche, and Viatris. G. W. has served as an advisory committee member for Gilead Sciences and Janssen, and as a speaker for Abbott, Abbvie, Ascletis, Bristol-Myers Squibb, Echosens, Gilead Sciences, Janssen, and Roche. She has also received a research grant from Gilead Sciences. D. H. is an advisory committee member for Roche (personal fees). E. H. reports grants from Merck and GSK; is an advisory committee member for Merk, Gilead, Sanofi Pasteur, and GSK; and speaker for Merck and Gilead sciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fibroblast growth factor 9 (FGF9) modulates cell proliferation, differentiation and motility for development and tissue repair in normal cells. Growing evidence shows that abnormal activation of FGF9 signaling is associated with tumor malignancy. We have previously reported that FGF9 increases MA-10 mouse Leydig tumor cell proliferation, in vitro , and tumor growth, in vivo . Also, FGF9 promotes the tumor growth and liver metastasis of mouse Lewis lung cancer cells, in vivo . However, the effects of FGF9 in the early stage of tumorigenesis remains elusive. In this study, TM3 mouse Leydig progenitor cells, that are not tumorigenic in immunocompromised mice, were used as a model cell line to investigate the role of FGF9 in tumorigenesis. The results demonstrated that FGF9 significantly induced cell proliferation and activated the MAPK, PI3K and PLCγ signaling pathways in TM3 cells. The percentage of the cell number in G1 phase was reduced and that in S and G2/M phases was increased after FGF9 stimulation in TM3 cells. Cyclin D1, cyclin A1, CDK2, CDK1, and p21 expressions and the phosphorylation level of Rb were all induced in FGF9-treated TM3 cells. In addition, FGF9 increased the expression of FGF receptor 1-4 in TM3 cells, suggesting the positive feedback loop between FGF9 and FGFRs. Furthermore, in the allograft mouse model, FGF9 promoted the tumorigenesis of TM3 cells characterized by higher expression of tumor markers, such as tumor necrosis factor alpha (TNFα) and α-fetoprotein (AFP), in the subcutaneously inoculated TM3 cell tissue. Conclusively, FGF9 induced cell cycle to increase cell proliferation of TM3 cells through FAK, MAPK, PI3K/Akt and PLCγ signaling pathways, in vitro , and promoted the tumorigenesis of TM3 cell allograft tissue, in vivo , which is a potential marker for tumor as well as a target for cancer therapeutic strategies., Competing Interests: None., (AJCR Copyright © 2022.)

Importance: Some patients treated with nirmatrelvir-ritonavir have experienced rebound of COVID-19 infections and symptoms; however, data are scarce on whether viral rebound also occurs in patients with COVID-19 receiving or not receiving molnupiravir., Objective: To examine the incidence of viral rebound in patients with COVID-19 who were treated with the oral antiviral agents nirmatrelvir-ritonavir and molnupiravir., Design, Setting, and Participants: This cohort study identified 41 255 patients with COVID-19 who were hospitalized from January 1, 2022, to March 31, 2022, in Hong Kong and assessed 12 629 patients with serial cycle threshold (Ct) values measured. Patients were followed up until the occurrence of the clinical end point of interest, death, date of data retrieval (July 31, 2022), or up to 30 days of follow-up, whichever came first., Exposures: Molnupiravir or nirmatrelvir-ritonavir treatment., Main Outcomes and Measures: Viral rebound, defined as a Ct value greater than 40 that decreased to 40 or less., Results: Of 12 629 patients (mean [SD] age, 65.4 [20.9] years; 6624 [52.5%] male), 11 688 (92.5%) were oral antiviral nonusers, 746 (5.9%) were molnupiravir users, and 195 (1.5%) were nirmatrelvir-ritonavir users. Compared with nonusers, oral antiviral users were older, had more comorbidities, and had lower complete vaccination rates. The mean (SD) baseline Ct value was slightly higher in nirmatrelvir-ritonavir users (22.2 [6.0]) than nonusers (21.0 [5.4]) and molnupiravir users (20.9 [5.4]) (P = .04). Viral rebound occurred in 68 nonusers (0.6%), 2 nirmatrelvir-ritonavir users (1.0%), and 6 molnupiravir users (0.8%). Among 76 patients with viral rebound, 12 of 68 nonusers, 1 of 6 molnupiravir users, and neither of the nirmatrelvir-ritonavir users died of COVID-19., Conclusions and Relevance: In this cohort study, viral rebound was uncommon in patients taking molnupiravir or nirmatrelvir-ritonavir and was not associated with increased risk of mortality. Given these findings, novel oral antivirals should be considered as a treatment for more patients with COVID-19 in the early phase of the infection.