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BACKGROUND: Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. AIM: To evaluate the impact of HCV treatment on such disparities. METHODS: In a retrospective cohort study, we analysed 6069 patients with HCV-related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. RESULTS: The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%-15%, 20% vs. 10%-17% and 10% vs. 5%-7%, respectively; all p < 0.0001). Treatment rate with direct-acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10-year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non-U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). CONCLUSION: DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.
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Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Humanos , Estados Unidos/epidemiología , Antivirales/uso terapéutico , Hepacivirus , Respuesta Virológica Sostenida , Estudios Retrospectivos , Hepatitis C Crónica/tratamiento farmacológico , Detección Precoz del Cáncer , Hepatitis C/tratamiento farmacológicoRESUMEN
PURPOSE: There are limited data on antiviral treatment utilization and its impact on long-term outcomes of hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after hepatic resection. We aimed to determine the utilization and impact of antivirals in HBV- and HCV-related HCC. METHODS: This cohort study included 1,906 participants (1,054 HBV-related HCC and 852 HCV-related HCC) from 12 international sites. All participants had HBV- or HCV-related HCC and underwent curative surgical resection. The primary outcome was the utilization of antiviral therapy, and the secondary outcome was long-term overall survival (OS). RESULTS: The mean (±standard deviation [SD]) age was 62.1 (±11.3) years, 74% were male, and 84% were Asian. A total of 47% of the total cohort received antiviral therapy during a mean (±SD) follow-up of 5.0 (±4.3) years. The overall antiviral utilization for participants with HBV-related HCC was 57% and declined over time, from 65% before 2010, to 60% from 2010 to 2015, to 47% beyond 2015, P < .0001. The overall utilization of antivirals for HCV-related HCC was 35% and increased over time, from 24% before 2015 to 74% from 2015 and beyond, P < .0001. The 10-year OS was lower in untreated participants for both HBV (58% v 61%) and HCV participants (38% v 82%; both P < .0001). On multivariable Cox regression analysis adjusted for relevant confounders, antiviral therapy initiated before or within 6 months of HCC diagnosis was independently associated with lower mortality in both HBV- (adjusted hazard ratio [aHR], 0.60 [95% CI, 0.43 to 0.83]; P = .002) and HCV-related HCC (aHR, 0.18 [95% CI, 0.11 to 0.31]; P < .0001). CONCLUSION: Antiviral therapy is associated with long-term survival in people with HBV- or HCV-related HCC who undergo curative resection but is severely underutilized.
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Carcinoma Hepatocelular , Hepatitis B , Hepatitis C , Neoplasias Hepáticas , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Carcinoma Hepatocelular/patología , Virus de la Hepatitis B , Neoplasias Hepáticas/patología , Hepacivirus , Estudios de Cohortes , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Antivirales/uso terapéutico , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Lateral flow assays (LFAs) provide a simple and quick option for diagnosis and are widely adopted for point-of-care or at-home tests. However, their sensitivity is often limited. Most LFAs only allow 50 µL samples while various sample types such as saliva could be collected in much larger volumes. Adapting LFAs to accommodate larger sample volumes can improve assay sensitivity by increasing the number of target analytes available for detection. Here, a simple agglutination system comprising biotinylated antibody (Ab) and streptavidin (SA) is presented. The Ab and SA agglutinate into large aggregates due to multiple biotins per Ab and multiple biotin binding sites per SA. Dynamic light scattering (DLS) measurements showed that the agglutinated aggregate could reach a diameter of over 0.5 µm and over 1.5 µm using poly-SA. Through both experiments and Monte Carlo modeling, we found that high valency and equivalent concentrations of the two aggregating components were critical for successful agglutination. The simple agglutination system enables antigen capture from large sample volumes with biotinylated Ab and a swift transition into aggregates that can be collected via filtration. Combining the agglutination system with conventional immunoassays, an agglutination assay is proposed that enables antigen detection from large sample volumes using an in-house 3D-printed device. As a proof-of-concept, we developed an agglutination assay targeting SARS-CoV-2 nucleocapsid antigen for COVID-19 diagnosis from saliva. The assay showed a 10-fold sensitivity enhancement when increasing sample volume from 50 µL to 2 mL, with a final limit of detection (LoD) of 10 pg mL-1 (â¼250 fM). The assay was further validated in negative saliva spiked with gamma-irradiated SARS-CoV-2 and showed an LoD of 250 genome copies per µL. The proposed agglutination assay can be easily developed from existing LFAs to facilitate the processing of large sample volumes for improved sensitivity.
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Prueba de COVID-19 , COVID-19 , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , Anticuerpos , Biotina , AglutinaciónRESUMEN
Pandemic preparedness and response have relied primarily on market dynamics to drive development and availability of new health products. Building on calls for transformation, we propose a new value proposition that instead prioritises equity from the research and development (R&D) stage and that strengthens capacity to control outbreaks when and where they occur. Key elements include regional R&D hubs free to adapt well established technology platforms, and independent clinical trials networks working with researchers, regulators, and health authorities to better study questions of comparative benefit and real-world efficacy. Realising these changes requires a shift in emphasis: from pandemic response to outbreak control, from one-size-fits-all economies of scale to R&D and manufacture for local need, from de novo product development to last-mile innovation through adaptation of existing technologies, and from proprietary, competitive R&D to open science and financing for the common good that supports collective management and sharing of technology and know-how.
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Motivación , Salud Pública , Humanos , Pandemias/prevención & control , Investigación , Brotes de EnfermedadesRESUMEN
INTRODUCTION: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population. METHODS: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment. RESULTS: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77). CONCLUSION: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data.
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Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Humanos , Antivirales/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Resultado del Tratamiento , Hepacivirus/genética , Cirrosis Hepática/complicaciones , Inhibidores de Proteasas/efectos adversos , Respuesta Virológica SostenidaRESUMEN
BACKGROUND & AIMS: Chronic hepatitis B (CHB) disproportionately impacts foreign-born patients and those of Asian or Black race. Given the paucity of data, we aimed to study the impact of race and ethnicity on CHB patient characteristics and management. METHODS: A retrospective analysis of adult CHB patients using data recorded in the deidentified Optum Clinformatics Data Mart Database (January 2003âMarch 2021) was performed. We characterized and examined the rates of receiving adequate treatment evaluation (measuring hepatitis B virus DNA and alanine transaminase) and hepatitis B virus treatment among the racial and ethnic groups. RESULTS: The study cohort included 42,140 patients: age, 51.9 ± 15.1 years; 56.1% male; 47% Asian; 26% White; 11% Black; and 7% Hispanic. Thirty-three percent of White and 48% of Asian patients had an annual household income greater than $100,000 US compared with 16% for Black and 25% for Hispanic patients (P < .001), with similar disparities in educational levels. Approximately one third of White (29.3%), Black (35.1%), and Hispanic (35.4%), and half of Asian (49.9%) patients received adequate evaluation (P < .001). Among patients who met American Association for the Study of Liver Diseases treatment criteria, treatment rates were similar among White (60.8%; P = .09) and Black (62.8%; P = .48), but lower among Hispanic (54.7%; P = .03), as compared with Asian patients (65.4%). On multivariable logistic regression adjusted for age, sex, provider type, viral co-infection, and fatty liver disease, Hispanic patients were less likely to receive treatment (adjusted hazard ratio, 0.69; 95% CI, 0.53â0.91; P = .01) compared with Asian patients. CONCLUSIONS: Compared with Asian CHB patients, non-Asian patients were less likely to undergo adequate evaluation and Hispanic patients were less likely to receive treatment for CHB. Additional efforts are needed to improve CHB management, especially for non-Asian patients.
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Hepatitis B Crónica , Adulto , Humanos , Masculino , Estados Unidos/epidemiología , Persona de Mediana Edad , Anciano , Femenino , Estudios Retrospectivos , Hepatitis B Crónica/terapia , Negro o Afroamericano , Etnicidad , BlancoRESUMEN
Tenofovir disoproxil fumarate (TDF) is associated with a higher risk of nephrotoxicity compared with entecavir (ETV) or tenofovir alafenamide (TAF).1,2 One-fifth of transplant recipients develop chronic kidney disease (CKD) within 5 years after transplantation, contributed by the use of nephrotoxic immunosuppressive medications.3 Prior studies conducted in the nontransplant setting reported superior renal safety in TAF compared with TDF but data in liver transplant (LT) recipients have so far been limited to small case series.1,4-6 Therefore, the goals of this study were to examine changes in renal function in a large multicenter cohort of LT recipients with chronic hepatitis B who were treated with TAF, TDF, or ETV for the prevention of hepatitis B virus (HBV) reinfection or reactivation from receipt of a positive HBV core antibody graft.
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Hepatitis B Crónica , Trasplante de Hígado , Humanos , Alanina/uso terapéutico , Tenofovir/efectos adversos , Adenina/efectos adversos , Hepatitis B Crónica/tratamiento farmacológico , Riñón/fisiología , Antivirales/efectos adversos , Resultado del TratamientoRESUMEN
Exosomes are extracellular vesicles that share components of their parent cells and are attractive in biotechnology and biomedical research as potential disease biomarkers as well as therapeutic agents. Crucial to realizing this potential is the ability to manufacture high-quality exosomes; however, unlike biologics such as proteins, exosomes lack standardized Good Manufacturing Practices for their processing and characterization. Furthermore, there is a lack of well-characterized reference exosome materials to aid in selection of methods for exosome isolation, purification, and analysis. This review informs exosome research and technology development by comparing exosome processing and characterization methods and recommending exosome workflows. This review also provides a detailed introduction to exosomes, including their physical and chemical properties, roles in normal biological processes and in disease progression, and summarizes some of the on-going clinical trials.
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Exosomas , Vesículas Extracelulares , Exosomas/química , Exosomas/metabolismo , Desarrollo Industrial , Proteínas/metabolismoAsunto(s)
Vacunas contra la COVID-19/uso terapéutico , COVID-19/diagnóstico , COVID-19/terapia , Control de Enfermedades Transmisibles/métodos , Antivirales/uso terapéutico , COVID-19/prevención & control , Citidina/análogos & derivados , Citidina/uso terapéutico , Salud Global , Política de Salud , Accesibilidad a los Servicios de Salud , Humanos , Hidroxilaminas/uso terapéutico , Terapia por Inhalación de Oxígeno/métodos , Pandemias/prevención & control , Salud Pública , SARS-CoV-2 , Organización Mundial de la SaludRESUMEN
Omics experiments are ubiquitous in biological studies, leading to a deluge of data. However, it is still challenging to connect changes in these data to changes in cell functions because of complex interdependencies between genes, proteins, and metabolites. Here, we present a framework allowing researchers to infer how metabolic functions change on the basis of omics data. To enable this, we curated and standardized lists of metabolic tasks that mammalian cells can accomplish. Genome-scale metabolic networks were used to define gene sets associated with each metabolic task. We further developed a framework to overlay omics data on these sets and predict pathway usage for each metabolic task. We demonstrated how this approach can be used to quantify metabolic functions of diverse biological samples from the single cell to whole tissues and organs by using multiple transcriptomic datasets. To facilitate its adoption, we integrated the approach into GenePattern (www.genepattern.org-CellFie).
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Genoma , Redes y Vías Metabólicas , Animales , Redes y Vías Metabólicas/genética , Fenómenos Fisiológicos Celulares , Perfilación de la Expresión Génica , Transcriptoma/genética , Mamíferos/genéticaRESUMEN
The magnitude of the COVID-19 pandemic challenged societies around our globalized world. To contain the spread of the virus, unprecedented and drastic measures and policies were put in place by governments to manage an exceptional health care situation while maintaining other essential services. The responses of many governments showed a lack of preparedness to face this systemic and global health crisis. Drawing on field observations and available data on the first wave of the pandemic (mid-March to mid-May 2020) in Quebec (Canada), this article reviewed and discussed the successes and failures that characterized the management of COVID-19 in this province. Using the framework of Palagyi et al. on system preparedness toward emerging infectious diseases, we described and analyzed in a chronologically and narratively way: (1) how surveillance was structured; (2) how workforce issues were managed; (3) what infrastructures and medical supplies were made available; (4) what communication mechanisms were put in place; (5) what form of governance emerged; and (6) whether trust was established and maintained throughout the crisis. Our findings and observations stress that resilience and ability to adequately respond to a systemic and global crisis depend upon preexisting system-level characteristics and capacities at both the provincial and federal governance levels. By providing recommendations for policy and practice from a learning health system perspective, this paper contributes to the groundwork required for interdisciplinary research and genuine policy discussions to help health systems better prepare for future pandemics.
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COVID-19 , Pandemias , Canadá , Humanos , Pandemias/prevención & control , Quebec/epidemiología , SARS-CoV-2RESUMEN
BACKGROUND AND AIMS: Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. APPROACH AND RESULTS: We analyzed 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA < 20 IU/mL), biochemical (alanine aminotransferase [ALT] < 35/25 U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96 weeks after switch. Viral suppression (P < 0.001) and ALT normalization (P = 0.003) rates increased significantly after switch, with a trend for increasing complete response (Ptrend = 0.004), while the eGFR trend (Ptrend > 0.44) or mean eGFR (P > 0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR < 90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P = 0.029) but not after TAF switch (P = 0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1. CONCLUSIONS: Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.