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Background: We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. Methods: This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150 mg plus lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate (TDF) 300 mg (ANV/3TC/TDF), or cobicistat (Cobi) 150 mg boosted EVG plus emtricitabine (FTC) 200 mg, and tenofovir alafenamide (TAF) 10 mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Findings: Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n = 381) or EVG/Cobi/FTC/TAF (n = 381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI -1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05 kg, ETD -0.90 kg, 95% CI, -1.43 to -0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. Interpretation: In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Funding: Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.
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Antiretroviral therapy (ART) is an effective treatment for people living with HIV (PLHIVs), requiring an extended period to achieve immune reconstitution. Metabolic alterations induced by ART are crucial for predicting long-term therapeutic responses, yet comprehensive investigation through large-scale clinical studies is still lacking. Here, we collected plasma samples from 108 PLHIVs to the untargeted plasma metabolomics study, based on the longitudinal metabolomics design. Cross-sectional analyzes were performed at pre- and post-ART to explore the metabolic transformation induced by the therapy. Subsequently, delta values between pre- and post-ART measurements were calculated to quantify metabolic alterations. Then, the optimal set of metabolic traits and clinical signatures were further identified and applied to construct random forest model for predicting the future therapeutic responses to ART. We found distinct ART-induced metabolic transformation among PLHIVs. After confounder-adjustments, five metabolites exhibited significant associations with future immune response: tetracosatetraenoic acid (24:4n-6) (pre-ART) (odds ratio [OR]: 0.978, 95% confidence interval [CI]: 0.955~0.997), 1-(3,4-dihydroxyphenyl)-5-hydroxy-3-decanone (pre-ART) (OR: 1.298, 95% CI: 1.061~1.727), beta-PC-M6 (change) (OR: 0.967, 95% CI: 0.938~0.993), d-Galactaro-1,4-lactone (change) (OR: 1.032, 95% CI: 1.007~1.063), Annuionone C (change) (OR: 1.100, 95% CI: 1.030~1.190). The addition of plasma metabolites to clinical markers accurately predicted immune response to ART with an area under curve of 0.91. Notably, most disrupted metabolites were significantly correlated with blood lipids, suggesting that metabolic transformation might contribute to dyslipidemia among PLHIVs. This study highlights the distinct metabolic transformation post-ART among PLHIVs and reveals the potential role of metabolic transformation as key determinants of ART efficacy.
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Infecciones por VIH , Metabolómica , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/sangre , Masculino , Femenino , Adulto , Estudios Transversales , Persona de Mediana Edad , Metaboloma/efectos de los fármacos , Fármacos Anti-VIH/uso terapéutico , Estudios Longitudinales , Plasma/química , Antirretrovirales/uso terapéutico , Biomarcadores/sangre , Terapia Antirretroviral Altamente ActivaRESUMEN
INTRODUCTION: Toxoplasma gondii can cause symptomatic toxoplasmosis in immunodeficient hosts, including in people living with human immunodeficiency virus (PLWH), mainly because of the reactivation of latent infection. We assessed the prevalence of toxoplasmosis and its associated risk factors in PLWH in the Asia-Pacific region using data from the TREAT Asia Human Immunodeficiency Virus (HIV) Observational Database (TAHOD) of the International Epidemiology Databases to Evaluate AIDS (IeDEA) Asia-Pacific. METHODS: This study included both retrospective and prospective cases of toxoplasmosis reported between 1997 and 2020. A matched case-control method was employed, where PLWH diagnosed with toxoplasmosis (cases) were each matched to two PLWH without a toxoplasmosis diagnosis (controls) from the same site. Sites without toxoplasmosis were excluded. Risk factors for toxoplasmosis were analyzed using conditional logistic regression. RESULTS: A total of 269/9576 (2.8%) PLWH were diagnosed with toxoplasmosis in 19 TAHOD sites. Of these, 227 (84%) were reported retrospectively and 42 (16%) were prospective diagnoses after cohort enrollment. At the time of toxoplasmosis diagnosis, the median age was 33 years (interquartile range 28-38), and 80% participants were male, 75% were not on antiretroviral therapy (ART). Excluding 63 out of 269 people without CD4 values, 192 (93.2%) had CD4 ≤200 cells/µL and 162 (78.6%) had CD4 ≤100 cells/µL. By employing 538 matched controls, we found that factors associated with toxoplasmosis included abstaining from ART (odds ratio [OR] 3.62, 95% CI 1.81-7.24), in comparison to receiving nucleoside reverse transcriptase inhibitors plus non-nucleoside reverse transcriptase inhibitors, HIV exposure through injection drug use (OR 2.27, 95% CI 1.15-4.47) as opposed to engaging in heterosexual intercourse and testing positive for hepatitis B virus surface antigen (OR 3.19, 95% CI 1.41-7.21). Toxoplasmosis was less likely with increasing CD4 counts (51-100 cells/µL: OR 0.41, 95% CI 0.18-0.96; 101-200 cells/µL: OR 0.14, 95% CI 0.06-0.34; >200 cells/µL: OR 0.02, 95% CI 0.01-0.06), when compared to CD4 ≤50 cells/µL. Moreover, the use of prophylactic cotrimoxazole was not associated with toxoplasmosis. CONCLUSIONS: Symptomatic toxoplasmosis is rare but still occurs in PLWH in the Asia-Pacific region, especially in the context of delayed diagnosis, causing advanced HIV disease. Immune reconstitution through early diagnosis and ART administration remains a priority in Asian PLWH.
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Infecciones por VIH , Toxoplasmosis , Humanos , Masculino , Factores de Riesgo , Adulto , Femenino , Toxoplasmosis/epidemiología , Toxoplasmosis/complicaciones , Infecciones por VIH/epidemiología , Infecciones por VIH/complicaciones , Asia/epidemiología , Estudios Retrospectivos , Estudios de Casos y Controles , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , ToxoplasmaRESUMEN
BACKGROUND: Interferon-gamma release assay (IGRA) for tuberculosis (TB) remains limited in its ability to discriminate between active TB (ATB) and latent TB infection (LTBI). Activation markers on host T and NK cells are currently considered to be promising markers in the diagnosis of ATB. METHODS: This prospective observational study enrolled 213 participants and the participants were divided into ATB, LTBI, other lung-related diseases (ORD), and health control (HC) groups. CD69 and HLA-DR on T and NK cells were detected in QFT-TB assay, and a composite scoring system (TB-Flow) was created for the diagnosis of ATB. RESULTS: The expression of activation markers (CD69 and HLA-DR) were significantly increased in ATB. HLA-DR on NK cells, CD69 on T cells, and QFT-TB in the differential diagnosis of ATB and HC were all of good diagnostic value (AUC>0.90). In addition, the TB-Flow greatly improved the efficiency of differential diagnosis between ATB and LTBI (AUC=0.90, 95%CI: 0.84-0.96), with sensitivity and specificity of 79.17 % (95%CI: 64.60%-89.04 %) and 88.68 % (95%CI: 76.28%-95.31 %). CONCLUSIONS: CD69 and HLA-DR on host T and NK cells are promising markers in distinguishing different TB infection status. Our blood-based TB-Flow scoring system can distinguish ATB from LTBI with good diagnostic efficacy.
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Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV-associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.
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The primary objective of this study is to investigate and develop a rapid and effective method for the immobilization of Sr in the event of a nuclear leakage incident. Coal gangue, an underutilized form of solid waste from the coal industry, can be used as a raw material for curing Sr due to its high content of silica-alumina oxides. In the present study, Sr was successfully solidified in cancrinite synthesized using a hydrothermal method with coal gangue as raw material. A stable cancrinite phase was formed at a relative alkali concentration of more than 6 M. When the Sr/Al(Si) ratio was <1/6, cancrinite was the only stable phase that varied with the hydrothermal temperature and time. When the Sr/Al(Si) ratio increased to 1/2, the cancrinite phase completely disappeared, and a new strontium feldspar phase (SrAl2Si2O8) appeared. PCT leaching experiments showed that when Sr/Al(Si) < 1/6, the Sr leaching rate of Sr-cancrinite samples obtained by hydrothermal synthesis at 180 °C for 24 h was very low.
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Introduction: Highly active antiretroviral therapy (HAART) was piloted in 2002 and was scaled up in 2003 in mainland China. The aim of this study was to evaluate the mortality and its possible predictors based on the long-term initial antiretroviral therapy (ART) cohort among HIV positive children and adolescents. Methods: This prospective open-labeled multicenter cohort study was conducted from January 2008 to July 2021. The participants were recruited from six representative sites in mainland China. A total of 609 participants with an HIV-positive serostatus and <18 years old were recruited and each participant was informed consent at the time of enrollment. Mortality and annual hazard were calculated, and predictors for death were analyzed using Cox regression models generating hazard ratios (HR). Results: The results showed that the mortality was 0.721 per hundred person-years, and the annual hazard was less than 0.10 over time. Both CD4+T cell count and CD4+T cell percentage declined in the death group during the follow-up. The Cox regression model showed that the baseline low CD4+T cell count level (Low vs. High: aHR = 8.309, 95% CI: (1.093, 63.135)) and age >5 years old at HIV diagnosis (6-12 vs. 0-5: aHR = 3.140, 95%CI: (1.331, 27.411)); 13-18 vs. 0-5: aHR = 5.451, 95%CI: (1.434, 20.724)) were possible risk factors for death. Conclusion: The longitudinal cohort study demonstrated the efficacy of China's ART program among HIV-positive children and adolescents which could be beneficial to other countries with limited resources.
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BACKGROUND: Low-level viremia (LLV) has been identified as a potential precursor to virologic failure (VF), yet its clinical implications, particularly within the context of Integrase Strand Transfer Inhibitors (INSTIs)-based regimens, remain insufficiently explored. The study aimed to investigate the relationship between LLV and VF within ART-naïve patients on INSTIs-based regimens in China. METHODS: A longitudinal cohort study was conducted with ART-naïve patients aged ≥ 18 years at Beijing Ditan Hospital, under the Chinese National Free Antiretroviral Treatment Program (NFATP). The LLV was defined as a viral load (VL) ranging from 50 to 199 copies/mL after six months of ART initiation, and VF as a VL ≥ 200 copies/mL. Sensitive analyses were also performed, defining LLV as 50-999 copies/mL and VF as exceeding 1000 copies/mL. Multivariate logistic regression, Kaplan-Meier (KM) curve, and Generalized Estimating Equation (GEE) models were used to evaluate the risk factors associated with LLV and VF events. RESULTS: The study involved 830 ART-naïve patients, comprising 600 in the INSTIs group and 230 in the protease inhibitors (PIs) group. LLV events were observed in 10.4% of patients on PIs-based regimens and and 3.2% on INSTIs-based regimens (P < 0.001). INSTIs-based regimens demonstrated a protective effect against LLV events (aHR = 0.27, 95% CI 0.137-0.532). VF events occurred in 10.9% of patients on PIs-based regimens and 2.0% on INSTIs-based regimens, respectively (P < 0.001). The occurrence of LLV events significantly increased the risk of VF by 123.5% (95% CI 7.5%-364.4%), while the integrase inhibitors were associated with a 76.9% (95% CI 59.1%-86.9%) reduction in VF risk. CONCLUSION: Our findings indicate that INSTIs-based regimens are critical protective factors against LLV and subsequent VF. These results underscore the importance of HIV viral load monitoring to ensuring effective treatment outcomes, highlighting the necessity for prompt and precise monitoring to refine HIV treatment methodologies.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Estudios Longitudinales , Incidencia , Viremia/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Insuficiencia del Tratamiento , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacología , Estudios de Cohortes , Carga Viral , Inhibidores de Integrasa , Integrasas/farmacología , Integrasas/uso terapéuticoRESUMEN
BACKGROUND: In HIV-1 infection, more than 95% of CD4+T cells die of caspase-1 mediated pyroptosis. What governs the increased susceptibility of CD4+T cells to pyroptosis is poorly understood. METHODS: Blood samples were obtained from 31 untreated HIV-infected patients (UNT), 29 antiretroviral therapy treated HIV-infected patients (ART), and 21 healthy control donors (HD). Plasma levels of IL-18 and IL-1ß, caspase-1 expression, mitochondrial mass (MM) and mitochondrial fusion/fisson genes of CD4+T subsets were measured. RESULTS: A significantly higher IL-18 level in plasma and MM level of CD4+T cells were found in HIV-infected patients (UNT and ART) compared to HD, and the MMhigh phenotype was manifested, related to increased caspase-1 expression. Moreover, the increased MM was more pronounced in the early differentiated and inactivated CD4+T cells. However, higher MM was not intrinsically linked to T cell differentiation disorder or excessive activation of the CD4+T cells. Mechanistically, the increased MM was significantly correlated with an elevated level of expression of the mitochondrial fusion gene mitofusin1. CONCLUSION: An increase in MM was associated with heightened sensitivity of CD4+T cells to pyroptosis, even in early differentiated and inactivated CD4+T cells, in patients with HIV-1 infection, regardless of whether patients were on antiretroviral therapy or not. These new revelations have uncovered a previously unappreciated challenge to immune reconstitution with antiretroviral therapy.
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Infecciones por VIH , VIH-1 , Humanos , Caspasa 1 , Linfocitos T , Interleucina-18 , Infecciones por VIH/tratamiento farmacológicoRESUMEN
BACKGROUND: Existing research has provided evidence of changes in hepatitis delta virus (HDV) prevalence worldwide. This study aimed to investigate the prevalence and molecular characteristics of HDV to elucidate its spread in China. METHODS: A total of 3,000 samples were collected from 2,241 HBV monoinfections and 759 HBV/HIV-1 coinfections across 13 sites in northern, southern, western, and southwestern China. Serological and virological prevalence were determined by detecting anti-HDV antibodies and HDV RNA. RESULTS: The study revealed a 2.63% (95% CI: 2.06-3.21) seroprevalence of HDV among HBV infections in China, exhibiting regional variation. HDV seroprevalence was notably higher at 7.91% (95% CI: 5.98-9.83) in HBV and HIV-1 coinfections. Region and HIV-1 infection were identified as risk factors for HDV infection. Virological prevalence was 0.67% (95% CI: 0.38-0.96) in HBV infections and 2.24% (95% CI: 1.18-3.29) in HBV/HIV-1 coinfections. The predominant HDV genotype in China was HDV-2a, followed by HDV-1. Participants with anti-HDV positivity demonstrated significantly higher proportions of abnormal liver dysfunction and elevated HBV DNA load (P < 0.001) compared to anti-HDV-negative participants. CONCLUSIONS: This study highlights the HDV epidemic in China, sheds light on its geographical distribution and high-risk populations, and provides insights for developing strategies to manage the spread of HDV in the country.
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Coinfección , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis Delta/genética , Prevalencia , Estudios Seroepidemiológicos , Coinfección/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , China/epidemiología , Virus de la Hepatitis B/genéticaRESUMEN
Knee osteoarthritis (KOA) is not merely a medical condition-it is a prevalent and incapacitating ailment that significantly affects the quality of life for millions worldwide, especially as they age. The incidence of KOA increases year by year with increasing age. This study evaluated the therapeutic efficacy of combining arthroscopy with sodium hyaluronate (SH) in the treatment of wound healing of knee osteoarthritis (KOA) in elderly patients, with a focus on wound healing and overall joint function restoration. Randomized controlled trials (RCTs) evaluating the combination of arthroscopy and SH in geriatric KOA patients were identified through a systematic search of the scientific literature utilizing multiple databases and predefined search criteria. Ultimately, twelve investigations were included in the meta-analysis. Using Stata 15.1 software, data extraction and analysis were conducted using both fixed- and random-effects models, and a sensitivity analysis was conducted to assure the validity of the findings. Compared with arthroscopy alone, the combination of arthroscopy and SH significantly improved the efficiency rate, pain management (as measured by the Visual Analogue Scale), knee function (as measured by the Lysholm Knee Scoring Scale) and decreased levels of the pro-inflammatory cytokines IL-1 and IL-6. The meta-analysis revealed minimal heterogeneity between studies, and the sensitivity analysis validated the results' reliability. The incorporation of SH into arthroscopic procedures for elderly patients with KOA provides significant therapeutic benefits, including improved wound healing, reduced inflammation and enhanced joint function overall. These results support the use of this combined approach in the management of KOA in the elderly population and emphasize the need for additional research to optimize treatment protocols and comprehend long-term outcomes.
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Osteoartritis de la Rodilla , Anciano , Humanos , Artroscopía/métodos , Ácido Hialurónico/uso terapéutico , Osteoartritis de la Rodilla/tratamiento farmacológico , Osteoartritis de la Rodilla/cirugía , Manejo del Dolor/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Cicatrización de HeridasRESUMEN
SnTe-In2Te3 alloys ensure excellent electrical properties in the whole temperature region due to the resonant level. Nevertheless, temperature-sensitive resonance states and single phonon scattering restrict further improvement of thermoelectric performance. Consequently, it is anticipated that additional electrically independent scattering sources should be introduced to impede phonon transport. Here, the SnTe-In2Te3-GeMnTe2 alloy is prepared by further solidifying cubic GeMnTe2, which demonstrates multiple modulation effects. The highly redissolved Mn2+ promotes the valence band convergence, enhances the Seebeck coefficient at higher temperature, and balances the possible weakened resonance level effect at higher carrier concentrations, and a high average power factor (1.94 mW m-1 K-2) is realized over the entire temperature range. Additionally, compensatory vacancies, substitutions, and Ge/Mn precipitates are easily constructed with GeMnTe2 alloying, leading to a further reduction in lattice thermal conductivity, which reaches κl â¼ 0.6 W m-1 K-1 at 850 K. Ultimately, a high peak zT of â¼1.25 (850 K) and a zTave of 0.72 (300-850 K) are realized in (SnTe)2.91(In2Te3)0.03(Ge0.5Mn0.5Te)1.2, and the maximum thermoelectric conversion efficiency of â¼2.8% (ΔT â¼ 450 K) is achieved. The present results indicate multiple effects of GeMnTe2 in enhancing the thermoelectric performance of SnTe-In2Te3 alloys.
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Introduction: Nut quality detection is of paramount importance in primary nut processing. When striving to maintain the imperatives of rapid, efficient, and accurate detection, the precision of identifying small-sized nuts can be substantially compromised. Methods: We introduced an optimized iteration of the YOLOv5s model designed to swiftly and precisely identify both good and bad walnut nuts across multiple targets. The M3-Net network, which is a replacement for the original C3 network in MobileNetV3's YOLOv5s, reduces the weight of the model. We explored the impact of incorporating the attention mechanism at various positions to enhance model performance. Furthermore, we introduced an attentional convolutional adaptive fusion module (Acmix) within the spatial pyramid pooling layer to improve feature extraction. In addition, we replaced the SiLU activation function in the original Conv module with MetaAconC from the CBM module to enhance feature detection in walnut images across different scales. Results: In comparative trials, the YOLOv5s_AMM model surpassed the standard detection networks, exhibiting an average detection accuracy (mAP) of 80.78%, an increase of 1.81%, while reducing the model size to 20.9 MB (a compression of 22.88%) and achieving a detection speed of 40.42 frames per second. In multi-target walnut detection across various scales, the enhanced model consistently outperformed its predecessor in terms of accuracy, model size, and detection speed. It notably improves the ability to detect multi-target walnut situations, both large and small, while maintaining the accuracy and efficiency. Discussion: The results underscored the superiority of the YOLOv5s_AMM model, which achieved the highest average detection accuracy (mAP) of 80.78%, while boasting the smallest model size at 20.9 MB and the highest frame rate of 40.42 FPS. Our optimized network excels in the rapid, efficient, and accurate detection of mixed multi-target dry walnut quality, accommodating lightweight edge devices. This research provides valuable insights for the detection of multi-target good and bad walnuts during the walnut processing stage.
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Rapid and accurate methods for the diagnosis of tuberculous pleurisy (TP) are urgently needed. Activation markers of tuberculosis (TB)-reactive T cells are considered promising for the diagnosis of active TB (ATB). Different activation indexes may play different roles in the progression of TB, but there are few reports on T cell activation indicators, except for HLA-DR. Hence, we evaluated the expression of early (CD25 and CD69) and late (CD134) activation markers on TB antigen-stimulated CD4+ T cells in populations with different TB infection status and investigated their diagnostic value for ATB, particularly, for TP. Moreover, we compared the differences in the diagnostic efficacy among the indexes from peripheral blood (PB) and pleural fluid (PF) for TP. The expression of each activation marker was significantly increased in TB-infected populations (patients with ATB and latent TB infection vs. healthy individuals; patients with TP vs. non-TP) and was significantly higher in the PF than in the PB of patients with TP. The diagnostic performance of the coexpressed activation markers was superior to that of single expression markers in the differential diagnosis of ATB and non-TB, with CD25+CD134+ showing the best diagnostic efficiency (AUC: 0.93, 95% CI, 0.87-0.99; sensitivity: 86.7%, 95% CI, 72.5%-94.5%; and specificity: 94.0%, 95% CI, 82.5%-98.4%). Except for TB-IGRA, the activation indexes were more accurate than conventional laboratory methods for ATB diagnosis. In addition, the expression of CD25+CD134+ in PB and PF was the best values for differential diagnosis of TP and NTP, with AUCs of 0.87 (95% CI, 0.77-0.96) and 0.95 (95% CI, 0.90-1.00), respectively. Our study provides information on the diagnostic value of different activation markers for TB and shows that the expression of CD25+CD134+ on CD4+ T cells in PF can serve as a potential marker for TP diagnosis.
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Tuberculosis Latente , Mycobacterium tuberculosis , Tuberculosis Pleural , Humanos , Tuberculosis Pleural/diagnóstico , Linfocitos T CD4-Positivos , Sensibilidad y Especificidad , Tuberculosis Latente/diagnóstico , Antígenos HLA-DRRESUMEN
Background: Ainuovirine (ANV) is a new non-nucleoside reverse transcriptase inhibitor (NNRTI), which was initially synthesized in Korea and later further developed in both Korea and China. Methods: A randomized, double-blind, double-dummy, positive parallel group, non-inferiority, phase 3 trial was conducted in 7 sites across China. Eligible HIV-1-positive antiretroviral therapy (ART)-naïve adults aged 18-65 years were randomly assigned in a 1:1 ratio to receive tenofovir disoproxil fumarate and lamivudine (TDF+3TC) in combination with either ANV (ANV group) or efavirenz (EFV group) for up to 48 weeks. Subsequently, participants in both groups received one of the two drug combinations according to their choice until week 96 in an observational study under an open-label setting. The primary endpoint was the proportion of participants achieving HIV RNA <50 copies/mL at week 48, with non-inferiority pre-specified at a margin of 10%. The secondary efficacy endpoints were logarithmic changes in HIV RNA, percentage of participants with HIV RNA levels ≤400 copies/mL and changes in the CD4 T-cell count after 48 and 96 weeks of treatment, as well as the percentage of participants with HIV RNA levels <50 copies/mL at 96 weeks of treatment. Safety endpoints were the incidence of adverse events and laboratory abnormalities evaluated according to the Division of AIDS criteria. This study was registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR1800019041). Findings: Between November 27, 2018 and March 11, 2021, a total of 826 participants were screened, and 630 were finally enrolled and randomly assigned (1:1) to either ANV (n = 315) or EFV (n = 315) groups. The mean age was 30.6 ± 9.4 years and most participants were male (94.6%). At week 48, 274 (87.0%) of 315 participants in the ANV group and 288 (91.7%) of 314 in the EFV group achieved HIV-1 RNA <50 copies/mL and non-inferiority was established (difference: -4.7%, 95% CI: -9.6 to 0.1%). In the period, 293 participants continued to take the ANV regimen and 287 switched from the EFV to the ANV regimen. During the open-label period, 92.5% (271/293) of participants in the continued ANV group and 95.1% (273/287) in the ANV to EFV transfer group remained virologically suppressed (HIV-1 RNA <50 copies/mL) at week 96 (p = 0.189). The incidence of NNRTI treatment-related adverse events (TEAEs) at week 48 was 67.6% in 315 participants in the ANV group, which was significantly lower than in 91.4% of 314 participants in the EFV group (p < 0.001). The most common TEAEs (weeks 0-48) were dizziness (10.5%) and dyslipidemia (22.2%) in the ANV group vs. 51.0% and 34.4% in the EFV group, respectively, followed by transaminase elevation (9.2% vs. 29.0%), γ-glutamyl transferase elevation (8.3% vs. 19.1%), and rash (7.9% vs. 18.8%) (all p < 0.001). After switching from EFV to ANV, TEAEs in the former EFV participants were significantly reduced in the following observational period of 48-96 weeks. Interpretation: The week 48 results indicated that the efficacy of ANV was non-inferior to EFV when combined with two NRTIs. The per-protocol risk difference at week 48 for the primary endpoint also supported non-inferiority. TEAEs in ANV treated participants were less frequent with regard to liver toxicity, dyslipidemia, neuropsychiatric symptoms and rash compared to the EFV group during the first 48 weeks of therapy. The effects were maintained during the 48-96 weeks of therapy. Funding: Jiangsu Aidea Pharmaceutical Co., Ltd.
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Ag doping can effectively increase the carrier concentration ofp-type SnSe polycrystalline, thereby enhancing the thermoelectric (TE) performance. However, the key role of the transport valence band in Ag-doped SnSe remains unclear. Particularly, understanding the influence of evaluating the optimal balance between band convergence and carrier mobility on weighted mobility is a primary consideration in designing high-performance TE materials. Here, we strongly confirm through theoretical and experimental evidence that Ag-doped Sn0.98Se can promote the evolution of valence bands and achieve band convergence and density of states distortion. The significantly increased carrier concentration and effective mass result in a dramatic increase in weighted mobility, which favors the achievement of superior power factors. Furthermore, the Debye model reveals the reasons for the evolution of lattice thermal conductivity. Eventually, a superior average power factor and averagezTvalue are obtained in the Ag-doped samples in both directions over the entire test temperature range. This strategy of improving TE performance through band engineering provides an effective way to advance TEs.
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BACKGROUND: For most adults with HIV-1 and hepatitis B virus (HBV) coinfection, initial recommended treatment is a tenofovir-containing antiretroviral regimen, but no randomised studies have compared tenofovir disoproxil fumarate with tenofovir alafenamide. We aimed to investigate whether bictegravir, emtricitabine, and tenofovir alafenamide is non-inferior to dolutegravir, emtricitabine, and tenofovir disoproxil fumarate for viral suppression in individuals with HIV-1 and HBV coinfection at 48 and 96 weeks. METHODS: We did this randomised, double-blind, active-controlled, phase 3, non-inferiority trial at 46 outpatient centres in China, Dominican Republic, Hong Kong, Japan, Malaysia, South Korea, Spain, Taiwan, Thailand, Turkey, and the USA. Eligible participants were treatment-naive adults (aged ≥18 years) with plasma HIV-1 RNA of at least 500 copies per mL and plasma HBV DNA of at least 2000 IU/mL. Participants were randomly assigned (1:1) to receive daily oral bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or dolutegravir 50 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg, each with corresponding matching placebo. Randomisation was stratified by hepatitis B e antigen (HBeAg) status (positive vs negative), HBV DNA (<8 vs ≥8 log10 IU/mL), and CD4 count (<50 vs ≥50 cells per µL) at screening. All investigators, participants, and staff providing treatment, assessing outcomes, and collecting data were masked to study treatment for 96 weeks. Coprimary endpoints were the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL (defined by the US Food and Drug Administration snapshot algorithm) and plasma HBV DNA less than 29 IU/mL (using the missing-equals-failure approach) at week 48, with a prespecified non-inferiority margin of -12%. Coprimary endpoints were assessed in the full analysis set, which included all randomly assigned participants who received at least one dose of study drug and had at least one post-baseline HIV-1 RNA or HBV DNA result while on study drug. Safety endpoints were assessed in all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03547908. FINDINGS: Between May 30, 2018 and March 16, 2021, 381 participants were screened, of whom 243 initiated treatment (121 in the receive bictegravir, emtricitabine, and tenofovir alafenamide group; 122 in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group). At week 48, both endpoints met the criteria for non-inferiority: 113 (95%) of 119 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group and 111 (91%) of 122 participants in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group had HIV-1 RNA less than 50 copies per mL (difference 4·1, 95% CI -2·5 to 10·8; p=0·21), and 75 (63%) of 119 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus 53 (43%) of 122 participants in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group had HBV DNA suppression (difference 16·6, 5·9 to 27·3; nominal p=0·0023). Drug-related adverse events up to week 96 occurred in 35 (29%) of 121 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group and 34 (28%) of 122 participants in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group. One (1%) of 121 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group reported a serious adverse event (cryptococcal meningitis attributed to immune reconstitution inflammatory syndrome) that was deemed to be treatment-related. INTERPRETATION: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is an effective therapy for adults with HIV-1 and HBV coinfection starting antiviral therapy. FUNDING: Gilead Sciences.
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Highly active antiretroviral therapy (ART) can effectively inhibit virus replication and restore immune function in most people living with human immunodeficiency virus (HIV). However, an important proportion of patients fail to achieve a satisfactory increase in CD4+ T cell counts. This state is called incomplete immune reconstitution or immunological nonresponse (INR). Patients with INR have an increased risk of clinical progression and higher rates of mortality. Despite widespread attention to INR, the precise mechanisms remain unclear. In this review, we will discuss the alterations in the quantity and quality of CD4+ T as well as multiple immunocytes, changes in soluble molecules and cytokines, and their relationship with INR, aimed to provide cellular and molecular insights into incomplete immune reconstitution.
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Infecciones por VIH , VIH , Humanos , Recuento de Linfocito CD4 , Terapia Antirretroviral Altamente Activa/efectos adversos , Linfocitos T CD4-PositivosRESUMEN
The emerged strategy of manipulating the rhombohedral crystal structure provides another new degree of freedom for optimizing the thermoelectric properties of GeTe-based compounds. However, the concept is difficult to be effectively measured and often depends on heavy doping that scatters carriers severely. Herein, we synergistically manipulate lattice distortion and vacancy concentration to promote the excellent electrical transport of GeTe-Cu2Te alloys and quantify the interaxial angle-dependent density of state effective mass. Distinct from the conventional electronic coupling effect, about 2% substitution of Zr4+ significantly increases the interaxial angle, thereby enhancing the band convergence effect and improving the Seebeck coefficient. In addition, Ge-compensation attenuates the mobility deterioration, leading to improved power factor over the whole temperature range, especially exceeding â¼22 µW cm-1 K-2 at 300 K. Furthermore, the Debye-Callaway model elucidates low lattice thermal conductivity due to strong phonon scattering from Zr/Ge substitutional defects. As a result, the highest figure of merit zT of â¼1.6 (at 650 K) and average zTave of â¼0.9 (300-750 K) are obtained in (Ge1.01Zr0.02Te)0.985(Cu2Te)0.015. This work demonstrates the effective band modulation of Zr on GeTe-based materials, indicating that the modification of the interaxial angle is a deep pathway to improve thermoelectrics.