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An increased risk for human infection with avian influenza A(H5N1) viruses is of concern. We developed an internally controlled, dual-target reverse transcription PCR for influenza A(H5) subtyping. This test could be used to detect influenza A(H5) in clinical samples.
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Gripe Aviar , Gripe Humana , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Humanos , Animales , Gripe Aviar/virología , Gripe Aviar/diagnóstico , Gripe Humana/virología , Gripe Humana/diagnóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Subtipo H5N1 del Virus de la Influenza A/genética , Subtipo H5N1 del Virus de la Influenza A/clasificación , Subtipo H5N1 del Virus de la Influenza A/aislamiento & purificación , Aves/virología , Reacción en Cadena de la Polimerasa Multiplex/métodos , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Virus de la Influenza A/genética , Virus de la Influenza A/clasificación , Virus de la Influenza A/aislamiento & purificaciónRESUMEN
BACKGROUND: Epstein-Barr Virus (EBV) is associated with lung disease in immunocompromised patients, particularly transplant recipients. EBV DNA testing of lower respiratory tract specimens may have diagnostic utility. METHODS: This was a retrospective, observational study of all patients with bronchoalveolar lavage (BAL) fluids submitted for EBV qPCR testing from February 2016 to June 2022 at the Stanford Clinical Virology Laboratory. RESULTS: There were 140 patients that underwent 251 EBV qPCR BAL tests (median 1; range 1 - 10). These patients had a mean age of 15.9 years (standard deviation, 15.1 years) and 50 % were female. Transplant recipients accounted for 67.1 % (94/140) of patients, including 67.0 % (63/94) solid organ transplant (SOT) and 33.0 % (31/94) hematopoietic cell transplant. Diagnostic testing was performed more commonly than surveillance testing [57.0 % (143/251) v. 43.0 % (108/251)]; 96.2 % (104/108) of surveillance samples were from lung transplant recipients. Excluding internal control failures, 34.7 % (83/239) of BAL had detectable EBV DNA, encompassing a wide range of viral loads (median=3.03 log10 IU/mL, range 1.44 to 6.06). Overall agreement of EBV DNA in BAL compared to plasma was 74.1 % [117/158; 95 % confidence interval (CI): 66.5 % to 80.7 %], with a kappa coefficient of 0.44 (95 % CI: 0.30 to 0.57). Only 20.1 % (48/239) of results were discussed in a subsequent clinical note, and one result (0.4 %; 1/239) changed clinical management. CONCLUSIONS: EBV qPCR testing on BAL offers limited clinical impact. Additional biomarkers are required to improve the diagnosis of EBV-associated lung diseases.
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IMPORTANCE: The COVID-19 pandemic has led to 775 million documented cases and over 7 million deaths worldwide as of March 2024 and is an ongoing health crisis. To limit viral spread within households and in the community, public health officials have recommended self-isolation, self-quarantine of exposed household contacts, and mask use. Yet, risk of household transmission (HHT) may be underestimated due to low frequency of sampling, and risk factors for HHT are not well understood. OBJECTIVES: To estimate the secondary attack rate of SARS-CoV-2 within households and to define the risk factors for new infections in household members who are in close contact with the index case. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, from March 2020-December 2021 we enrolled 60 households with index cases who tested positive for SARS-CoV-2. All household contacts and index cases were tested daily for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR) using self-collected anterior nares specimens. Households were followed until all study participants in the household tested negative for SARS-CoV-2 for seven consecutive days. We collected sex, age, race/ethnicity, comorbidities, and relationship to index case for secondary contacts, household level characteristics including primary income, household density, and square feet per person on property. We compared the sociodemographic variables between COVID-19 positive and negative household members and between households where secondary transmission did and did not occur. MAIN OUTCOMES AND MEASURES: Daily anterior nares swabs were tested for SARS-CoV-2 using RT-PCR, in order to assess duration of nasal shedding of SARS-CoV-2, as well as risk of transmission to secondary household contacts. RESULTS: Of the 163 participants in this study, 84 (51.5%) were women; median age (IQR) was 36.0 (17.0-54.0) years of age; 78 (47.8%) were white and 48 (29.5%) were Hispanic/LatinX. Of the fifty households with household contacts, at least one secondary case occurred in twenty-six households (52.0%) and forty-five household contacts (43.7%) were infected. Secondary attack rate was lowest among children of index cases (6/23, 26.1%). Modified Poisson regression identified that the risk of transmission to household contacts increases significantly with age (Risk ratio for each increase in years of age = 1.01, 95% CI = 1.00-1.02). Mixed effects regression models identified that participants with chronic diseases, such as asthma, diabetes, cancer, or cardiac disease, had higher Cts at baseline when compared to participants without chronic diseases (6.62, 95% CI: 1.46-11.77, p = 0.02) and show a slower rate of increase in Ct over time (-0.43, 95% CI: -0.77 to -0.09, p = 0.02). CONCLUSIONS AND RELEVANCE: This study suggests that HHT represents a key source of community-based infection of SARS-CoV-2. Allocation of resources for contact investigations and prevention interventions should focus on the individuals at highest risk of infection in households, especially those with higher density homes.
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COVID-19 , Composición Familiar , SARS-CoV-2 , Esparcimiento de Virus , Humanos , COVID-19/transmisión , COVID-19/epidemiología , COVID-19/virología , Femenino , Masculino , Adulto , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , Estudios Prospectivos , Adolescente , Niño , Adulto Joven , Factores de Riesgo , Preescolar , AncianoRESUMEN
Respiratory syncytial virus (RSV) causes a large burden of respiratory illness globally. It has two subtypes, RSV A and RSV B, but little is known regarding the predominance of these subtypes during different seasons and their impact on morbidity and mortality. Using molecular methods, we quantified RSV A and RSV B RNA in wastewater solids across multiple seasons and metropolitan areas to gain insight into the predominance of RSV subtypes. We determined the predominant subtype for each group using the proportion of RSV A to total RSV (RSV A + RSV B) in each wastewater sample (PA,WW) and conducted a comparative analysis temporally, spatially, and against clinical specimens. A median PA,WW of 0.00 in the first season and 0.58 in the second season indicated a temporal shift in the predominant subtype. Spatially, while we observed dominance of the same subtype, PA,WW was higher in some areas (PA,WW = 0.58-0.88). The same subtype predominated in wastewater and clinical samples, but clinical samples showed higher levels of RSV A (RSV A positivity in clinical samples = 0.79, median PA,WW = 0.58). These results suggest that wastewater, alongside clinical data, holds promise for enhanced subtype surveillance.IMPORTANCERespiratory syncytial virus (RSV) causes a large burden of respiratory illness globally. It has two subtypes, RSV A and RSV B, but little is known regarding the predominance of these subtypes during different seasons and their impact on morbidity and mortality. The study illustrates that information on subtype predominance can be gleaned from wastewater. As a biological composite sample from the entire contributing population, wastewater monitoring of RSV A and B can complement clinical surveillance of RSV.
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ARN Viral , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Estaciones del Año , Aguas Residuales , Aguas Residuales/virología , Humanos , Virus Sincitial Respiratorio Humano/genética , Virus Sincitial Respiratorio Humano/clasificación , Virus Sincitial Respiratorio Humano/aislamiento & purificación , Infecciones por Virus Sincitial Respiratorio/virología , ARN Viral/genética , Análisis Espacio-TemporalRESUMEN
Rift Valley fever virus (RVFV) is an adaptable arbovirus that can be transmitted by a wide variety of arthropods. Widespread urban transmission of RVFV has not yet occurred, but peri-urban outbreaks of RVFV have recently been documented in East Africa. We previously reported low-level exposure in urban communities and highlighted the risk of introduction via live animal influx. We deployed a slaughtered animal testing framework in response to an early warning system at two urban slaughterhouses and tested animals entering the meat value chain for anti-RVFV IgG and IgM antibodies. We simultaneously trapped mosquitoes for RVFV and bloodmeal testing. Out of 923 animals tested, an 8.5% IgG seroprevalence was identified but no evidence of recent livestock exposure was detected. Mosquito species abundance varied greatly by slaughterhouse site, which explained 52% of the variance in blood meals. We captured many Culex spp., a known RVFV amplifying vector, at one of the sites (p < 0.001), and this species had the most diverse blood meals. No mosquito pools tested positive for RVFV antigen using a rapid VecTOR test. These results expand understanding of potential RVF urban disease ecology, and highlight that slaughterhouses are key locations for future surveillance, modelling, and monitoring efforts.
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BACKGROUND: Screening with anti-Epstein-Barr virus (EBV) serology and endoscopy decreased nasopharyngeal carcinoma (NPC) mortality in Guangdong in a randomized trial. We conducted a secondary analysis of this trial using local incidence and cost data to optimize screening programs, hypothesizing that screening could be cost-effective in southern China. METHODS: Screening costs and life-years after NPC diagnosis were obtained from the Guangdong trial's intent-to-screen population (men and women aged 30-69). Seropositive subjects were rescreened annually for 5 years. Thereafter, we evaluated 12 screening strategies in Guangdong and Guangxi using a validated model. Strategies used combinations of serology, nasopharyngeal swab PCR (NP PCR), endoscopy, and MRI from trial subcohorts. Incidence data and costs were obtained from local cancer registries and the provincial healthcare system. RESULTS: In the intent-to-screen population, screening with serology and endoscopy was cost-effective (¥42,366/life-year, 0.52 GDP per capita). Screening for 5 to 15 years between ages 35 and 59 years met a willingness-to-pay threshold of 1.5 GDP/quality-adjusted life-years in all modeled populations. Despite doubling costs, adding MRI could be cost-effective via improved sensitivity. NP PCR triage reduced endoscopy/MRI referrals by 37%. One-lifetime screen could reduce NPC mortality by approximately 20%. CONCLUSIONS: EBV-based serologic screening for NPC is likely to be cost-effective in southern China. Among seropositive subjects, the preferred strategies use endoscopy alone or selective endoscopy triaged by MRI with or without NP PCR. These data may aid the design of screening programs in this region. IMPACT: These findings support population-based screening in southern China by defining the target population, cost-effectiveness, and optimized screening approach.
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Análisis Costo-Beneficio , Detección Precoz del Cáncer , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Femenino , Persona de Mediana Edad , China/epidemiología , Masculino , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/virología , Carcinoma Nasofaríngeo/economía , Adulto , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/economía , Neoplasias Nasofaríngeas/virología , Detección Precoz del Cáncer/economía , Detección Precoz del Cáncer/métodos , Anciano , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Tamizaje Masivo/economía , Tamizaje Masivo/métodosRESUMEN
In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We discovered PIP4K2C's roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays revealed that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced impairment of autophagic flux. Reversing this autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual inhibition of PIP4K2C and PIKfyve as a candidate strategy to combat emerging viruses.
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Despite having high analytical sensitivities and specificities, qualitative SARS-CoV-2 nucleic acid amplification tests (NAATs) cannot distinguish infectious from non-infectious virus in clinical samples. In this study, we determined the highest cycle threshold (Ct) value of the SARS-CoV-2 targets in the Xpert Xpress SARS-CoV-2/Flu/RSV (Xpert 4plex) test that corresponded to the presence of detectable infectious SARS-CoV-2 in anterior nasal swab samples. A total of 111 individuals with nasopharyngeal swab specimens that were initially tested by the Xpert Xpress SARS-CoV-2 test were enrolled. A healthcare worker subsequently collected anterior nasal swabs from all SARS-CoV-2-positive individuals, and those specimens were tested by the Xpert 4plex test, viral culture, and laboratory-developed assays for SARS-CoV-2 replication intermediates. SARS-CoV-2 Ct values from the Xpert 4plex test were correlated with data from culture and replication intermediate testing to determine the Xpert 4plex assay Ct value that corresponded to the presence of infectious virus. Ninety-eight of the 111 (88.3%) individuals initially tested positive by the Xpert Xpress SARS-CoV-2 test. An anterior nasal swab specimen collected from positive individuals a median of 2 days later (range, 0-9 days) tested positive for SARS-CoV-2 by the Xpert 4plex test in 39.8% (39/98) of cases. Of these samples, 13 (33.3%) were considered to contain infectious virus based on the presence of cultivable virus and replication intermediates, and the highest Ct value observed for the Xpert 4plex test in these instances was 26.3. Specimens that yielded Ct values of ≤26.3 when tested by the Xpert 4plex test had a likelihood of containing infectious SARS-CoV-2; however, no infectious virus was detected in specimens with higher Ct values.IMPORTANCEUnderstanding the correlation between real-time PCR test results and the presence of infectious SARS-CoV-2 may be useful for informing patient management and workforce return-to-work or -duty. Further studies in different patient populations are needed to correlate Ct values or other biomarkers of viral replication along with the presence of infectious virus in clinical samples.
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COVID-19 , Enfermedades Transmisibles , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , Nasofaringe , Técnicas de Diagnóstico Molecular/métodos , Prueba de COVID-19RESUMEN
The rapid emergence of divergent SARS-CoV-2 variants has led to an update of the COVID-19 booster vaccine to a monovalent version containing the XBB.1.5 spike. To determine the neutralization breadth following booster immunization, we collected blood samples from 24 individuals pre- and post-XBB.1.5 mRNA booster vaccination (â¼1 month). The XBB.1.5 booster improved both neutralizing activity against the ancestral SARS-CoV-2 strain (WA1) and the circulating Omicron variants, including EG.5.1, HK.3, HV.1, XBB.1.5 and JN.1. Relative to the pre-boost titers, the XBB.1.5 monovalent booster induced greater total IgG and IgG subclass binding, particular IgG4, to the XBB.1.5 spike as compared to the WA1 spike. We evaluated antigen-specific memory B cells (MBCs) using either spike or receptor binding domain (RBD) probes and found that the monovalent booster largely increases non-RBD cross-reactive MBCs. These data suggest that the XBB.1.5 monovalent booster induces cross-reactive antibodies that neutralize XBB.1.5 and related Omicron variants.
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In 2019-2020, dengue virus (DENV) type 4 emerged to cause the largest DENV outbreak in Paraguay's history. This study sought to characterize dengue relative to other acute illness cases and use phylogenetic analysis to understand the outbreak's origin. Individuals with an acute illness (≤7 days) were enrolled and tested for DENV nonstructural protein 1 (NS1) and viral RNA by real-time RT-PCR. Near-complete genome sequences were obtained from 62 DENV-4 positive samples. From January 2019 to March 2020, 799 participants were enrolled: 253 dengue (14 severe dengue, 5.5%) and 546 other acute illness cases. DENV-4 was detected in 238 dengue cases (94.1%). NS1 detection by rapid test was 52.5% sensitive (53/101) and 96.5% specific (387/401) for dengue compared to rRT-PCR. DENV-4 sequences were grouped into two clades within genotype II. No clustering was observed based on dengue severity, location, or date. Sequences obtained here were most closely related to 2018 DENV-4 sequences from Paraguay, followed by a 2013 sequence from southern Brazil. DENV-4 can result in large outbreaks, including severe cases, and is poorly detected with available rapid diagnostics. Outbreak strains seem to have been circulating in Paraguay and Brazil prior to 2018, highlighting the importance of sustained DENV genomic surveillance.
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Virus del Dengue , Dengue , Humanos , Virus del Dengue/genética , Dengue/diagnóstico , Dengue/epidemiología , Paraguay/epidemiología , Filogenia , Enfermedad Aguda , Genotipo , Brotes de EnfermedadesRESUMEN
Clinical diagnosis typically incorporates physical examination, patient history, and various laboratory tests and imaging studies, but makes limited use of the human system's own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis (Mal-ID) , an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to SARS-CoV-2, Influenza, and HIV, highlight antigen-specific receptors, and reveal distinct characteristics of Systemic Lupus Erythematosus and Type-1 Diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of human immune responses.
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We used a strand-specific RT-qPCR to evaluate viral replication as a surrogate for infectiousness among 242 asymptomatic inpatients with a positive severe acute respiratory coronavirus virus 2 (SARS-CoV-2) admission test. Only 21 patients (9%) had detectable SARS-CoV-2 minus-strand RNA. Because most patients were found to be noninfectious, our findings support the suspension of asymptomatic admission testing.
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COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , SARS-CoV-2/genética , Prueba de COVID-19 , Centros de Atención Terciaria , Técnicas de Laboratorio Clínico , ARN Viral/genéticaRESUMEN
This study reports that most patients with NSCLC had a significant increase in the nAb response to the currently circulating Omicron variants after bivalent booster vaccination and had Ab titers comparable to healthy participants. Interestingly, though the durability of the nAb response persisted in most of the healthy participants, patients with NSCLC had significantly reduced nAb titers after 4-6 months of vaccination. Our data highlight the importance of COVID-19 bivalent booster vaccination as the standard of care for patients with NSCLC given the evolution of new variants of concern.
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BACKGROUND: Cytomegalovirus (CMV) causes significant morbidity and mortality in immunocompromised patients, particularly transplant recipients. Quantitation of CMV DNA in peripheral blood is used to monitor prophylactic and pre-emptive approaches to prevent CMV disease, whereas CMV DNA testing of non-plasma specimens may aid in the diagnosis of end-organ disease. METHODS: The analytical performance of the FDA-approved Aptima CMV Quant Assay was evaluated using reference CMV (SeraCare) diluted in defibrinated human plasma, as well as negative bronchoalveolar lavage fluid and tissue. Agreement was determined using 100 clinical acid-citrate-dextrose (ACD) plasma specimens, 77 bronchoalveolar lavage (BAL) fluids, and 101 tissues previously tested using artus CMV qPCR. RESULTS: Aptima CMV lower limit of detection (LLOD) was 169 IU/mL for ACD plasma, 100 IU/mL for BAL, and 50 IU/mL for tissue. Positive percent agreement (PPA) was 100.0% (50/50; 95% CI: 92.9% - 100.0%) and negative percent agreement (NPA) was 94.0% (47/50; 95% CI: 83.5% - 98.8%) for ACD plasma. Bland-Altman analysis revealed a bias of 0.20 log10 IU/mL (Aptima - artus) with 95% limits of agreement of -0.53 to 0.93. For BAL fluids, PPA was 70.0% (14/20; 95% CI: 45.7% - 88.1%) and NPA was 82.4% (43/51; 95% CI: 69.1% - 91.6%). For tissues, PPA was 90.0% (45/50; 95% CI: 78.2% - 96.7%) and NPA was 94.0% (47/50; 95% CI: 83.5% - 98.8%). CONCLUSIONS: The Aptima CMV Quant Assay demonstrates high analytical sensitivity and good overall agreement using clinical plasma and tissue specimens.
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Infecciones por Citomegalovirus , Citomegalovirus , Humanos , Citomegalovirus/genética , Lavado Broncoalveolar , Infecciones por Citomegalovirus/diagnóstico , Líquido del Lavado Bronquioalveolar , Técnicas de Amplificación de Ácido Nucleico , Carga Viral , ADN , ADN Viral/genéticaRESUMEN
Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.
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Virus del Dengue , Dengue , Dengue Grave , Niño , Humanos , Linfocitos B , Células Asesinas NaturalesRESUMEN
Human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) initiation depends on interaction between viral 5'-leader RNA, RT and host tRNA3Lys. Therefore, we sought to identify co-evolutionary changes between the 5'-leader and RT in viruses developing RT-inhibitor resistance mutations. We sequenced 5'-leader positions 37-356 of paired plasma virus samples from 29 individuals developing the nucleoside RT inhibitor (NRTI)-resistance mutation M184V, 19 developing a non-nucleoside RT inhibitor (NNRTI)-resistance mutation and 32 untreated controls. 5'-Leader variants were defined as positions where ≥20â% of next-generation sequencing (NGS) reads differed from the HXB2 sequence. Emergent mutations were defined as nucleotides undergoing a ≥4-fold change in proportion between baseline and follow-up. Mixtures were defined as positions containing ≥2 nucleotides each present in ≥20â% of NGS reads. Among 80 baseline sequences, 87 positions (27.2â%) contained a variant; 52 contained a mixture. Position 201 was the only position more likely to develop a mutation in the M184V (9/29 vs 0/32; P=0.0006) or NNRTI-resistance (4/19 vs 0/32; P=0.02; Fisher's exact test) groups than the control group. Mixtures at positions 200 and 201 occurred in 45.0 and 28.8â%, respectively, of baseline samples. Because of the high proportion of mixtures at these positions, we analysed 5'-leader mixture frequencies in two additional datasets: five publications reporting 294 dideoxyterminator clonal GenBank sequences from 42 individuals and six National Center for Biotechnology Information (NCBI) BioProjects reporting NGS datasets from 295 individuals. These analyses demonstrated position 200 and 201 mixtures at proportions similar to those in our samples and at frequencies several times higher than at all other 5'-leader positions. Although we did not convincingly document co-evolutionary changes between RT and 5'-leader sequences, we identified a novel phenomenon, wherein positions 200 and 201 immediately downstream of the HIV-1 primer binding site exhibited an extraordinarily high likelihood of containing a nucleotide mixture. Possible explanations for the high mixture rates are that these positions are particularly error-prone or provide a viral fitness advantage.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , VIH-1/genética , Mutación , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , Nucleótidos/uso terapéutico , Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral/genéticaRESUMEN
Current HCV prevention efforts and treatment rates must improve for the United States (U.S.) to achieve WHO global elimination targets by 2030[1]. The current multi-day diagnosis and treatment paradigm for hepatitis C (HCV) infection leads to significant loss in the cascade of care, resulting in far fewer patients receiving treatment with direct acting antiviral agents (DAAs) than those diagnosed with HCV infection [2,3]. To achieve HCV elimination, a paradigm shift in access to HCV treatment is needed from current multi-day testing and treatment algorithms to same day diagnosis and treatment. This shift will require new tools, such as FDA-approved, CLIA-waived point-of-care (POC) antigen or nucleic acid tests (NAT) for HCV and HBV and NAT for HIV that do not require venous blood. Such a shift will also require better utilization of existing resources, expanding access to HCV treatment through availability of onsite treatment, removal of payer barriers to approval, adoption of minimal monitoring approaches during treatment, expanded access to available POC tests, and available specialist referral networks for patients who fail initial therapy, have advanced liver fibrosis, or have co-incident HIV or HBV infection. A same-day diagnosis and treatment paradigm will substantially contribute to HCV elimination by improving treatment rates for those diagnosed with HCV infection and expanding access to treatment in settings where patients have brief encounters with healthcare.
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As part of an epidemiologic survey, we screened remnant samples collected for STI testing for mpox virus. We identified two cases of presumed MPXV infection in pregnant, heterosexual cisgender women. Here, we describe their pregnancy and birth outcomes. Both patients required induction of labor and experienced labor complicated by chorioamnionitis.
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Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of blood-brain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.
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COVID-19 , Hepatitis C Crónica , Animales , Humanos , Ratones , Antivirales/farmacología , Citocinas , Inflamación/tratamiento farmacológico , Lapatinib/farmacología , SARS-CoV-2RESUMEN
What was the educational challenge?The complexity and variability of cross-sectional imaging present a significant challenge in imparting knowledge of radiologic anatomy to medical students.What was the solution?Recent advancements in three-dimensional (3D) segmentation and augmented reality (AR) technology provide a promising solution. These advances allow for the creation of interactive, patient-specific 3D/AR models which incorporate multiple imaging modalities including MRI, CT, and 3D rotational angiography can help trainees understand cross-sectional imaging.How was the solution implemented?To create the model, DICOM files of patient scans with slice thicknesses of 1 mm or less are exported to a computer and imported to 3D Slicer for registration. Once registered, the files are segmented with Vitrea software utilizing thresholding, region growing, and edge detection. After the creation of the models, they are then imported to a web-based interactive viewing platform and/or AR application.What lessons were learned that are relevant to a wider global audience?Low-resource 3D/AR models offer an accessible and intuitive tool to teach radiologic anatomy and pathology. Our novel method of creating these models leverages recent advances in 3D/AR technology to create a better experience than traditional high and low-resource 3D/AR modeling techniques. This will allow trainees to better understand cross-sectional imaging.What are the next steps?The interactive and intuitive nature of 3D and AR models has the potential to significantly improve the teaching and presentation of radiologic anatomy and pathology to a medical student audience. We encourage educators to incorporate 3D segmentation models and AR in their teaching strategies.