The immunogenicity of an HIV-1 gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy.

OBJECTIVE: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). DESIGN: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4+ T-cell counts greater than 500 cells/µl, and nadir CD4+ T-cell counts greater than 350 cells/µl. METHODS: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm c). The active and placebo vaccines were administered by intramuscular electroporation. RESULTS: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4+ and/or CD8+ T cells in arm A compared with arm C (P = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) (P = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements. CONCLUSION: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART.

[Spatial and temporal variation in normalized difference vegetation index of vegetation in Liaoning Province from the perspective of ecogeographic zoning]. / 生态地理分区视角下的辽宁省植被归一化植被指数的时空变化.

Normalized difference vegetation index (NDVI) is an important indicator reflecting vegetation cover and growth status. It is of significance for regional ecological conservation and natural resource management to investigate its spatial and temporal variation trends and response to ecological factors. We divided Liaoning Province into three ecological geographical regions, including northwest agro-pastoral zone, central agricultural zone, and eastern agroforestry zone. Based on remote sensing, vegetation, climate, topography and human activities, we used trend analysis and geographic probe model to examine the spatial and temporal trends of NDVI in Liaoning Province, and analyzed the intensity and interaction mechanism of each driver on the spatial distribution pattern of NDVI. The results showed that the annual average NDVI in Liaoning Province from 2001 to 2020 was 0-0.92, showing a distribution pattern of high in the east and low in the west, high in the inland and low in the coastal land. The overall trend of vegetation cover was increasing, and the NDVI increasing areas were mainly concentrated in the northwest agro-pastoral zone and the eastern agroforestry zone, the NDVI reduction areas were mainly concentrated at the border between the central agricultural zone and the eastern agroforestry zone, as well as in the coastal area of the eastern agroforestry zone. The annual average NDVI change varied among the three ecological-geographic zones. The NDVI of the northwest agro-pastoral zone from 2001 to 2020 were generally low, but showed a fluctuating trend of slow increase. The NDVI of the eastern agroforestry zone was high overall, and the interannual variation of NDVI was generally stable. The distribution of high and low NDVI in the central agricultural zone was staggered, and the interannual variation of NDVI showed a decreasing trend. Natural factors were the key drivers of NDVI changes in the three ecogeographic zones, with cumulative temperature and precipitation having the greatest influence. The interactions between the factors were all mutually and nonlinearly enhanced.

Prevalence and risk of residual viremia after ART in low- and middle-income countries: A cross-sectional study.

ABSTRACT: In order to design effective strategies to eradicate the HIV, an understanding of persistent viral reservoirs is needed. Many studies have demonstrated HIV residual viremia prevalence in high income countries, data from low- and middle-income countries (LMIC) are limited. We assessed the prevalence, and factors associated with residual viremia in people with HIV (PWH), who were virally-suppressed on antiretroviral therapy (ART) in LMIC. We also compared residual viremia prevalence between the LMIC and US.This is a cross-sectional, retrospective study that utilized stored specimen samples from the AIDS clinical trials group (ACTG) studies A5175 and A5208. The last available sample among participants with plasma HIV RNA < 400 copies/mL for ≥3 years were tested by the HIV molecular and monitoring core gag (HMMCgag) single copy assay (SCA). Residual viremia was defined as detectable if ≥1 copy/mL. Spearman's correlation and multivariable stepwise logistic regression were used to assess associations of various factors with SCA.A total of 320 participants, 246 (77%) from LMIC and 74 (23%) from US, were analyzed. Median (IQR) age was 33 (2840) years; baseline CD4 166 (88,230) cells/mm3; HIV RNA 5.0 (4.5, 5.3) log10 copies/mL; duration of viral suppression 3.4 (3.1, 4.0) years and 48% were male. In 85 participants with information available, 53% were subtype C, 42% subtype B and 5% other subtypes. Overall prevalence of residual viremia was 57% [95% CI, 52-63] with 51% [40-63] in US and 59% [53-65] in LMIC. Among participants with detectable SCA, the median (IQR) HIV RNA was 3.8 (2.2, 8.1) copies/mL. The multivariable model conducted in LMIC participants showed that higher baseline HIV RNA was associated with detectable residual RNA (OR 2.9, 95% CI 1.8, 4.6 for every log10 increase, P < .001). After including both US and LMIC in the final model, baseline HIV RNA remained significant. No difference in SCA detestability was found between US and LMIC sites (OR 1.1 [0.6, 2.0], P = .72) after adjusting for baseline RNA and parent study.The prevalence of residual viremia between both groups were not different and more than half of the participants had detectable viremia. Higher baseline HIV RNA was independently associated with residual viremia.

Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine.

OBJECTIVES: The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine. METHODS: A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed. RESULTS: Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics. CONCLUSIONS: Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

Effect of Oral Oseltamivir on Virological Outcomes in Low-risk Adults With Influenza: A Randomized Clinical Trial.

BACKGROUND: Duration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding. METHODS: From January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18-64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3. RESULTS: Of 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of -12.2% [-21.4%, -3.0%], P =; .010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34) in those with confirmed influenza infection. CONCLUSIONS: Oseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms. CLINICAL TRIALS REGISTRATION: NCT01314911.

RETRACTED: Residual pomegranate affecting the nonspecific immunity of juvenile Darkbarbel catfish.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of Editors-in-Chief and first Author. The article duplicates significant parts of a paper that had already appeared in Fish & Shellfish Immunology, Volume 93 (2019) 726-731, https://doi.org/10.1016/j.fsi.2019.06.052. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. The first author informed the journal that the article was published without the knowledge of the co-authors.

On-line pre-treatment, separation, and nanoelectrospray mass spectrometric determinations for pesticide metabolites and peptides based on a modular microfluidic platform.

In order to address time-consuming sample pre-treatment and separation prior to mass spectrometry (MS) identifications, highly integrated chips were developed, but damage to any functional unit in these chips would result in complete replacement. Herein, we propose a modular microfluidic platform comprising pre-treatment, liquid chromatography (LC) separation and nanoelectrospray ionization (nESI) chips for on-line enrichment, separation and nESI MS detection of pesticide metabolites and peptides. The pre-treatment chip is applicable in enriching pyridalyl and its metabolites, and it achieves optimal desalination efficiency, 98.5%, for polymerase chain reaction products. Additionally, the LC separation chip was fully characterised, and it demonstrated satisfactory separation efficiency, quantification ability and pressure durability. Finally, the modular microfluidic platform was used to identify the peptides in trypsin-digested casein. Four additional peptides were identified, indicating an improvement in detection ability compared with using off-line zip tips coupled with MS investigations. Because the proposed modular platform can significantly reduce manual work, it would be a potential tool to achieve high throughput and automatic MS identifications with low sample consumptions.

Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial.

BACKGROUND: Influenza continues to have a substantial socioeconomic and health impact despite a long established vaccination programme and approved antivirals. Preclinical data suggest that combining antivirals might be more effective than administering oseltamivir alone in the treatment of influenza. METHODS: We did a randomised, double-blind, multicentre phase 2 trial of a combination of oseltamivir, amantadine, and ribavirin versus oseltamivir monotherapy with matching placebo for the treatment of influenza in 50 sites, consisting of academic medical centre clinics, emergency rooms, and private physician offices in the USA, Thailand, Mexico, Argentina, and Australia. Participants who were aged at least 18 years with influenza and were at increased risk of complications were randomly assigned (1:1) by an online computer-generated randomisation system to receive either oseltamivir (75 mg), amantadine (100 mg), and ribavirin (600 mg) combination therapy or oseltamivir monotherapy twice daily for 5 days, given orally, and participants were followed up for 28 days. Blinded treatment kits were used to achieve masking of patients and staff. The primary endpoint was the percentage of participants with virus detectable by PCR in nasopharyngeal swab at day 3, and was assessed in participants who were randomised, had influenza infection confirmed by the central laboratory on a baseline nasopharyngeal sample, and had received at least one dose of study drug. Safety assessment was done in all patients in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01227967. FINDINGS: Between March 1, 2011, and April 29, 2016, 633 participants were randomly assigned to receive combination antiviral therapy (n=316) or monotherapy (n=317). Seven participants were excluded from analysis: three were not properly randomised, three withdrew from the study, and one was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 (40·0%) of 200 participants in the combination group had detectable virus at day 3 compared with 97 (50·0%) of 194 (mean difference 10·0, 95% CI 0·2-19·8, p=0·046) in the monotherapy group. The most common adverse events were gastrointestinal-related disorders, primarily nausea (65 [12%] of 556 reported adverse events in the combination group vs 63 [11%] of 585 reported adverse events in the monotherapy group), diarrhoea (56 [10%] of 556 vs 64 [11%] of 585), and vomiting (39 [7%] of 556 vs 23 [4%] of 585). There was no benefit in multiple clinical secondary endpoints, such as median duration of symptoms (4·5 days in the combination group vs 4·0 days in the monotherapy group; p=0·21). One death occurred in the study in an elderly participant in the monotherapy group who died of cardiovascular failure 13 days after randomisation, judged by the site investigator as not related to study intervention. INTERPRETATION: Although combination treatment showed a significant decrease in viral shedding at day 3 relative to monotherapy, this difference was not associated with improved clinical benefit. More work is needed to understand why there was no clinical benefit when a difference in virological outcome was identified. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

Three-dimensional hydrodynamic focusing microfluidic emitter: a strategy to inhibit sample ion expansion in nanoelectrospray ionization.

A microfluidic emitter based on three-dimensional hydrodynamic focusing was developed to generate a wrapped charged aerosol plume, in which the distribution of the sample ion in the nanoelectrospray could be regulated. Deposition patterns of the wrapped spray from the proposed three-dimensional hydrodynamic focusing nanoelectrospray emitter (3D HFNE) were collected under different conditions to ensure the wrapped configuration. Moreover, sample ion intensities as well as their ratios to a focusing background ion were studied as a function of different displacements from the center of the wrapped electrospray to confirm the inhibition of ion expansion. Furthermore, the proposed 3D HFNE indicated improved sensitivities compared with a reported nanoelectropray emitter as well as its commercial ESI counterpart, and this demonstrated its capacity for determining samples with low concentrations and infusion rates. In addition, the proposed 3D HFNE was compatible with various sample flow compositions (from 100% methanol to 100% water) and a broad infusion rate range (from 10 nL min(-1) to 15 µL min(-1)). Finally, its stability and durability were indicated to be acceptable for various determinations. Therefore, the 3D HFNE is a potential option to achieve on-line nanoelectrospray MS determinations using microfluidics with conventional mass spectrometers, considering its low cost and user-friendly properties.

Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention.

BACKGROUND: Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and isoniazid in human immunodeficiency virus (HIV)-infected individuals receiving a 4-week regimen to prevent tuberculosis. METHODS: Participants receiving daily rifapentine and isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8. RESULTS: Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29-44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8. CONCLUSIONS: The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression. CLINICAL TRIALS REGISTRATION: NCT 01404312.

Cardiovascular disease risk factors in HIV-infected women after initiation of lopinavir/ritonavir- and nevirapine-based antiretroviral therapy in Sub-Saharan Africa: A5208 (OCTANE).

BACKGROUND: Limited comparative, prospective data exist regarding cardiovascular risk factors in HIV-infected women starting antiretroviral therapy in Africa. METHODS: In 7 African countries, 741 women with CD4 <200 cells/mm were randomized to tenofovir/emtricitabine (TDF/FTC) plus either nevirapine (NVP, n = 370) or lopinavir/ritonavir (LPV/r, n = 371). Lipids and blood pressure (BP) were evaluated at entry, 48, 96, and 144 weeks. Multivariable linear and logistic regression models were used to evaluate mean risk factor changes and clinically relevant risk factor changes. RESULTS: At entry, both NVP and LPV/r groups were similar regarding age [mean = 33.5 (SD = 7.1) years], CD4 [129 (67) cells/mm], and HIV-1 RNA [5.1 (0.6) log10 copies/mL]. Nearly, all women had normal lipids and BP except for high-density lipoprotein (HDL)-cholesterol. Over 144 weeks, the LPV/r compared with NVP group had significantly greater mean lipid increases (eg, non-HDL: +29 vs. +13 mg/dL) and smaller HDL increases (+12 vs. +21 mg/dL). In contrast, the NVP compared with LPV/r group had greater mean increases in BP (eg, diastolic BP: +5 vs. -0.5 mm Hg). Significantly, more women assigned LPV/r had week 144 "abnormal" lipid levels (eg, HDL 29.7% vs. 14.8% and triglycerides 28.6% vs. 8.2%), and significantly, more women assigned NVP had "abnormal" BP (eg, diastolic BP 22.7% vs. 6.5%). Most differences remained significant when adjusted for baseline risk factor, age, CD4, and HIV-1 RNA. CONCLUSIONS: In HIV-infected women initiating antiretroviral therapy in Africa, LPV/r + TDF/FTC was associated with less favorable changes in lipids, and use of NVP + TDF/FTC was associated with less favorable changes in BP.

Low-frequency nevirapine (NVP)-resistant HIV-1 variants are not associated with failure of antiretroviral therapy in women without prior exposure to single-dose NVP.

BACKGROUND: Low-frequency nevirapine (NVP)-resistant variants have been associated with virologic failure (VF) of initial NVP-based combination antiretroviral therapy (cART) in women with prior exposure to single-dose NVP (sdNVP). We investigated whether a similar association exists in women without prior sdNVP exposure. METHODS: Pre-cART plasma was analyzed by allele-specific polymerase chain reaction to quantify NVP-resistant mutants in human immunodeficiency virus-infected African women without prior sdNVP who were starting first-line NVP-based cART in the OCTANE/A5208 trial 2. Associations between NVP-resistant mutants and VF or death were determined and compared with published results from women participating in the OCTANE/A5208 trial 1 who had taken sdNVP and initiated NVP-based cART. RESULTS: Pre-cART NVP-resistant variants were detected in 18% (39/219) of women without prior sdNVP exposure, compared to 45% (51/114) with prior sdNVP exposure (P < .001). Among women without prior sdNVP exposure, 8 of 39 (21%) with NVP-resistant variants experienced VF or death vs 31 of 180 (17%) without such variants (P = .65); this compares with 21 of 51 (41%) vs 9 of 63 (14%) among women with prior exposure (P = .001). CONCLUSIONS: The risk of VF on NVP-based cART from NVP-resistant variants differs between sdNVP-exposed and -unexposed women. This difference may be driven by drug-resistance mutations emerging after sdNVP exposure that are linked on the same viral genome. CLINICAL TRIALS REGISTRATION: NCT00089505.

Changes in HIV-1 subtypes B and C genital tract RNA in women and men after initiation of antiretroviral therapy.

BACKGROUND: Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. METHODS: HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. RESULTS: One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4(+) cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. CONCLUSIONS: The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

[A services value of different landscape types in Longitudinal Range-Gorge Region].

Based on the RS image of Longitudinal Range-Gorge Region (LRGR) in 2001, the study area was classified into seven first-class landscape types (forestland, grassland, farmland, wetland, water body, urban land, and glacier), and 26 second-class landscape types in consideration of climate belt, vegetation, and topography. By using GIS technology, the services value of different landscape types of LRGR were studied in regards to the study results on services value of Chinese terrestrial ecosystems. The results indicated that the total services value of LRGR was 5 302.35 x 10(8) yuan x a(-1), accounting for 9.47% of the whole country. The service value of soil conservation was the highest, which occupied 18.05% of the total services value, while the service values of gas adjustability and biodiversity protection ranked the second and third. Due to its distribution extent and services intensity per unit area, the forest landscape, which covered 66.11% of the total area, contributed most (85.34%) to the total service value of LRGR, followed by grassland and farmland landscapes.