Gene set correlation enrichment analysis for interpreting and annotating gene expression profiles.

Pathway analysis, including nontopology-based (non-TB) and topology-based (TB) methods, is widely used to interpret the biological phenomena underlying differences in expression data between two phenotypes. By considering dependencies and interactions between genes, TB methods usually perform better than non-TB methods in identifying pathways that include closely relevant or directly causative genes for a given phenotype. However, most TB methods may be limited by incomplete pathway data used as the reference network or by difficulties in selecting appropriate reference networks for different research topics. Here, we propose a gene set correlation enrichment analysis method, Gscore, based on an expression dataset-derived coexpression network to examine whether a differentially expressed gene (DEG) list (or each of its DEGs) is associated with a known gene set. Gscore is better able to identify target pathways in 89 human disease expression datasets than eight other state-of-the-art methods and offers insight into how disease-wide and pathway-wide associations reflect clinical outcomes. When applied to RNA-seq data from COVID-19-related cells and patient samples, Gscore provided a means for studying how DEGs are implicated in COVID-19-related pathways. In summary, Gscore offers a powerful analytical approach for annotating individual DEGs, DEG lists, and genome-wide expression profiles based on existing biological knowledge.

SWEET: a single-sample network inference method for deciphering individual features in disease.

Recently, extracting inherent biological system information (e.g. cellular networks) from genome-wide expression profiles for developing personalized diagnostic and therapeutic strategies has become increasingly important. However, accurately constructing single-sample networks (SINs) to capture individual characteristics and heterogeneity in disease remains challenging. Here, we propose a sample-specific-weighted correlation network (SWEET) method to model SINs by integrating the genome-wide sample-to-sample correlation (i.e. sample weights) with the differential network between perturbed and aggregate networks. For a group of samples, the genome-wide sample weights can be assessed without prior knowledge of intrinsic subpopulations to address the network edge number bias caused by sample size differences. Compared with the state-of-the-art SIN inference methods, the SWEET SINs in 16 cancers more likely fit the scale-free property, display higher overlap with the human interactomes and perform better in identifying three types of cancer-related genes. Moreover, integrating SWEET SINs with a network proximity measure facilitates characterizing individual features and therapy in diseases, such as somatic mutation, mut-driver and essential genes. Biological experiments further validated two candidate repurposable drugs, albendazole for head and neck squamous cell carcinoma (HNSCC) and lung adenocarcinoma (LUAD) and encorafenib for HNSCC. By applying SWEET, we also identified two possible LUAD subtypes that exhibit distinct clinical features and molecular mechanisms. Overall, the SWEET method complements current SIN inference and analysis methods and presents a view of biological systems at the network level to offer numerous clues for further investigation and clinical translation in network medicine and precision medicine.

Intra- vs. Interhost Evolution of SARS-CoV-2 Driven by Uncorrelated Selection-The Evolution Thwarted.

In viral evolution, a new mutation has to proliferate within the host (Stage I) in order to be transmitted and then compete in the host population (Stage II). We now analyze the intrahost single nucleotide variants (iSNVs) in a set of 79 SARS-CoV-2 infected patients with most transmissions tracked. Here, every mutation has two measures: 1) iSNV frequency within each individual host in Stage I; 2) occurrence among individuals ranging from 1 (private), 2-78 (public), to 79 (global) occurrences in Stage II. In Stage I, a small fraction of nonsynonymous iSNVs are sufficiently advantageous to rise to a high frequency, often 100%. However, such iSNVs usually fail to become public mutations. Thus, the selective forces in the two stages of evolution are uncorrelated and, possibly, antagonistic. For that reason, successful mutants, including many variants of concern, have to avoid being eliminated in Stage I when they first emerge. As a result, they may not have the transmission advantage to outcompete the dominant strains and, hence, are rare in the host population. Few of them could manage to slowly accumulate advantageous mutations to compete in Stage II. When they do, they would appear suddenly as in each of the six successive waves of SARS-CoV-2 strains. In conclusion, Stage I evolution, the gate-keeper, may contravene the long-term viral evolution and should be heeded in viral studies.

Deciphering the Exact Sequence of Endogenous Soluble B Cell Maturation Antigen and Unbiased Quantitation in Multiple Myeloma Patient Samples by LC-MS.

BACKGROUND: B-cell maturation antigen is a pivotal therapeutic target for multiple myeloma (MM). Membrane-bound BCMA can be cleaved by γ-secretase and shed as soluble BCMA (sBCMA). sBCMA can act as a neutralizing sink to compete with drug, as well as serve as a diagnostic/prognostic biomarker for MM. Antibody-capture based methods, such as enzyme-linked immunosorbent assay (ELISA) and immunoaffinity-liquid chromatography-multiple reaction monitoring (IA-LC-MRM), have been reported and well adopted to measure sBCMA in clinical samples. However, both methods are biased by capturing antibodies. METHODS: We have used various LC-MS workflows to characterize and quantify endogenous sBCMA in MM patient samples, including bottom-up peptide mapping, intact analysis, IA-based, and reagent-free (RF)-LC-MRM quantitation. RESULTS: We have confirmed that sBCMA contains a variable N-terminus and a C-terminus that extends to the transmembrane domain, ending at amino acid 61. Leveraging an in-house synthesized G-1-61 sBCMA recombinant standard, we developed a RF-LC-MRM method for unbiased sBCMA quantitation in MM patient samples. By comparing the results from RF-LC-MRM with ELISA and IA-LC-MRM, we demonstrated that RF-LC-MRM measures a more complete pool of endogenous sBCMA compared to the antibody-based methods. CONCLUSIONS: This work fills the knowledge gap of the exact sequence of endogenous sBCMA for the first time, which differs from the current commercially available standard. Additionally, this work highlights the necessity of identifying the actual sequence of an endogenous soluble target such as sBCMA, both for bioanalytical purposes and to underpin pharmacodynamic measurements.

Identification of a novel HIV-1 third-generation circulating recombinant form (CRF126_0755) in Guangdong, China.

The genetic recombination patterns and genetic distribution of HIV-1 are valuable for elucidating the epidemic and genetic diversity of HIV. Numerous HIV-1 circulating recombinant forms (CRFs) have recently emerged and disseminated rapidly. In China, at least 32 CRFs have been reported to account for more than 80% of all HIV infections. However, CRFs derived from the CRF07_BC and CRF55_01B lineages have never been recorded. Here, a novel third-generation CRF involving HIV-1 was identified in four HIV-1-infected patients in Guangdong, China, who had no epidemiological association with each other. Phylogenetic and recombinant analyses confirmed that these strains shared highly similar recombination patterns, with the CRF07_BC backbone substituted by a CRF55_01B segment; therefore, these strains were classified as CRF126_0755. This is the first study of a CRF derived from CRF07_BC and CRF55_01B. Bayesian phylogenetic inference suggested that CRF126_0755 originated in approximately 2005-2007. The present findings reveal that the genotype composition of HIV-1 has become more complex than that of other viruses and highlight the urgent need for continuous molecular screening and epidemic surveillance within HIV-1-infected populations to advance our understanding of viral transmission mechanisms.

Evaluation of the performance of a novel HIV-1 viral load assay for HIV quantification in China.

OBJECTIVES: Our objective was to assess the HIV-1 quantification performance of the Livzon HIV-1 viral load (VL) assay and the Roche Cobas HIV-1 assay to evaluate an HIV-1 VL testing reagent for application in China. METHOD: We compared the Livzon and Roche Cobas HIV-1 VL assays using ethylenediaminetetraacetic acid plasma samples collected between May 2021 and November 2021 from patients with HIV-1 and healthy controls. We used Cohen's κ coefficient to measure agreement of qualitative values and Pearson's correlation coefficient (r) values and the coefficient of determination (R2 ) to determine the linear relationship between the two assays. We performed a Bland-Altman analysis to assess VL quantification agreement. RESULTS: In total, 11 plasma samples from patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) and nine samples from healthy controls were undetectable on both assays. Overall agreement was seen in 419 of 500 specimens (91.40%), with a κ value of 0.59. Pearson's correlation coefficient between the two assays was 0.970. Using the Bland-Altman method, 95.14% (352/370) of paired VLs fell within the 95% confidence limits of agreement (-0.51 to 0.95 log10  copies/mL). Higher VLs had a better correlation and a smaller mean difference between the two assays. Pearson's correlation coefficient for the samples of subtype CRF01_AE, CRF07_BC, and CRF55_01B was 0.950, 0.935, and 0.952, respectively. CONCLUSION: The Livzon HIV-1 VL assay exhibits good precision and linearity and a high correlation with the Roche Cobas HIV-1 assay. The Livzon HIV-1 VL assay has salient advantages in terms of the lyophilized powder reagent, which gives the assay greater stability and sensitivity and can be readily used in low-resource areas.

Characteristics and clinical significance of plasma IL-18, sCD14, and sCD163 levels in patients with HIV-1 infection.

Biomarkers of monocyte-macrophages activation and inflammation in plasma such as interleukin-18 (IL-18), soluble leukocyte differentiation antigen 14 (sCD14), and sCD163 are associated with disease severity and prognosis in HIV-1 infected patients, however, their relationships with efficacy of antiretroviral therapy (ART) need further investigation. We aimed to characterize and explore the clinical significance of plasma IL-18, sCD14, and sCD163 in this population. This was a retrospective cohort study consisting of HIV-1 infected patients enrolled in a randomized, controlled, open-label, noninferiority trial (ALTERLL study), with follow-up time points including initiation of ART (baseline), 12-, 24- and 48-weeks of treatment. Plasma levels of IL-18, sCD14, and sCD163 were measured using the enzyme-linked immunosorbent assay method. Viral suppression was defined as HIV-1 RNA < 20 copies/ml. Among the 193 studied patients (median age of 29.0 years, 180 males), IL-18 and sCD163 had U-shaped regression curves and sCD14 had an inverted U-shaped regression curve while the virus was decreased and immune function recovered. Patients with higher levels of IL-18 or lower levels of sCD163 at baseline were less likely to achieve viral suppression at Week 12 or Week 24 of treatment, respectively. In multivariate analysis, baseline sCD163 ≤ 500 pg/ml (adjusted odds ratio 0.33, 95% confidence interval 0.16-0.68) was independently associated with a lower rate of viral suppression at Week 24 of treatment. In conclusion, we demonstrated different dynamic changes among IL-18, sCD14, and sCD163 after ART. Baseline sCD163 level could be a potential predictor of early virological response to ART. Further validation and mechanistic research are needed.

Drug resistance and genetic transmission characteristics of HIV-1 CRF59_01B in infected patients in Guangdong Province, China.

OBJECTIVES: To comprehensively analyse the prevalence of drug resistance and the transmission characteristics of CRF59_01B strains in infected patients in Guangdong, China. METHODS: CRF59_01B-infected individuals were recruited, and the HIV-1 pol region was amplified. Drug resistance-associated mutations (DRMs) and antiretroviral susceptibility were examined using the Stanford University HIV Drug Resistance Database to analyse pretreatment drug resistance (PDR) and acquired drug resistance (ADR). Genetic transmission networks were extracted from the maximum likelihood phylogenetic tree with Cluster Picker and visualized with Cytoscape. RESULTS: Two hundred and twenty-five CRF59_01B-infected individuals, comprising 35 ART-experienced and 190 ART-naive individuals, were recruited. No patients harboured PI DRMs, 5.33% (12/225) of the patients harboured NRTI DRMs and 11.11% (25/225) of the patients harboured NNRTI DRMs. The overall prevalence of strains with ADR was 51.43% (18/35), while the prevalence of strains with PDR was 2.63% (5/190). A total of 20 transmission networks, involving 25.78% (58/225) database-derived sequences, were identified. The networks ranged in size from 2 to 10 individuals, of which most (55.00%, 11/20) were made up of two individuals. Among the 225 study subjects, 9.78% (22/225) had 1 link and 16.00% (36/225) had ≥2 links. CONCLUSIONS: The overall prevalence of CRF59_01B strains with ADR among the ART-experienced patients was high. Although the overall prevalence of CRF59_01B strains with PDR among the ART-naive patients was low, it is necessary to remain vigilant regarding some important DRMs.

Prevalence of doravirine cross-resistance in HIV-infected adults who failed first-line ART in China, 2014-18.

OBJECTIVES: To evaluate the prevalence and characteristics of doravirine resistance and cross-resistance in patients who failed first-line ART in China. METHODS: From 2014 to 2108, 4132 patients from five provinces were tested for drug resistance by genotypic resistance testing. Drug resistance mutations were assessed using the Stanford HIVdb algorithm Version 9.0. Sequences classified as having low-level, intermediate and high-level resistance were defined as having drug resistance. RESULTS: Overall, the prevalence of doravirine and other NNRTIs cross-resistance was 69.5%, with intermediate and high-level resistance accounting for 56.4%. Doravirine resistance highly correlated with efavirenz (r = 0.720) and nevirapine (r = 0.721) resistance and moderately correlated with etravirine (r = 0.637) and rilpivirine (r = 0.692) resistance. The most frequent doravirine-associated resistance mutations were V106M (8.7%), K101E (6.8%) and P225H (5.1%). High-level resistance was mainly due to Y188L (3.2%) and M230L (2.7%). There were significant differences between genotypes and provinces. Compared with CRF01_AE, CRF07_BC (OR = 0.595, 95% CI = 0.546-0.648) and CRF08_BC (OR = 0.467, 95% CI = 0.407-0.536) were associated with lower risks of doravirine resistance. Conversely, genotype A (OR = 3.003, 95% CI = 1.806-4.991) and genotype B (OR = 1.250, 95% CI = 1.021-1.531) were associated with higher risks of doravirine resistance. The risk of doravirine resistance was significantly lower in Xinjiang compared with other provinces. CONCLUSIONS: In China, the prevalence of doravirine cross-resistance among patients who have failed first-line ART is high. Therefore, doravirine should not be used blindly without genotypic resistance testing and is not recommended for people who have failed first-line NNRTI-based ART.

Transmission networks of hepatitis C virus among HIV/HCV-coinfected patients in Guangdong, China.

BACKGROUND: Coinfection with hepatitis C virus (HCV) is common in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients due to shared routes of transmission. We aimed to investigate the characteristics of HCV subgenotypes among HIV/HCV-coinfected patients in Guangdong and explore the molecular transmission networks and related risk factors for HCV strains. METHODS: Plasma samples were obtained from 356 HIV/HCV-coinfected patients for HCV NS5B region sequencing. A neighbor-joining phylogenetic tree was constructed to affirm HCV subgenotypes. The transmission networks based on maximum likelihood phylogenetic tree were determined by Cluster Picker, and visualized using Cytoscape 3.2.1. RESULTS: A total of 302 HCV NS5B sequences were successfully amplified and sequenced from the 356 plasma samples. A neighbor-joining phylogenetic tree based on the 302 NS5B sequences revealed the profile of HCV subgenotypes circulating among HIV/HCV coinfection patients in Guangdong. Two predominant strains were found to be 6a (58.28%, 176/302) and 1b (18.54%, 56/302), followed by 3a (10.93%, 33/302), 3b (6.95%, 21/302), 1a (3.64%, 11/302), 2a (0.99%, 3/302) and 6n (0.66%, 2/302). A molecular transmission network of five major HCV genotypes was constructed, with a clustering rate of 44.04%. The clustering rates of subgenotypes 1a, 3a, 3b, 1b, and 6a were 18.18% (2/11), 42.42%, 52.38%, 48.21%, and 44.89%, respectively. Multivariate logistic regression analysis showed no significant effects from sex, age, transmission route, geographical region, baseline CD4 + T cell count or subgenotype (P > 0.05), except marital status. Married or cohabiting people (compared with unmarried people) had more difficulty forming transmission networks. CONCLUSIONS: In summary, this study, based on HCV NS5B subgenotypes, revealed the HCV subtype diversity and distribution among HIV/HCV-coinfected patients in Guangdong. Marital status inclined to be the factor influencing HCV transmission networks formation.

Predictive value of anti-Mullerian hormone for pregnancy outcomes following assisted reproductive techniques (ART) in Southwest China.

BACKGROUND: Anti-Müllerian hormone (AMH) is secreted by granulosa cells in preantral follicles and small antral follicles. There is limited information about whether serum AMH levels are related to pregnancy outcomes during in vitro fertilization and embryo transfer (IVF-ET). The aim of this study was to provide a theoretical basis for improving pregnancy outcomes. METHODS: A retrospective cohort study was conducted on infertile women who were treated at the Reproductive Centre of the Affiliated Hospital of Southwest Medical University between September 2018 and September 2019. The sample included 518 participants from Southwest China. The participants were divided into 2 groups according to their AMH level. Their data were retrieved from the medical records: days and dosage of gonadotropin (Gn) (one bottle equals 75 IU), the number of oocytes obtained, the number of oocytes in metaphase II (MII) and the number of high-quality embryos. The pregnancy outcomes were followed up and divided into two groups according to whether they were pregnant or not, with statistical analysis of the parameters related to the in vitro fertilization process performed separately. RESULTS: Compared to a lower AMH level (AMH ≤ 1.1), a higher AMH level (AMH > 1.1) resulted in less total Gn (bottle) (P = 0.00 < 0.05) and a lower starting Gn (IU) (P = 0.00 < 0.05), while the number of oocytes obtained,MII,cleavages and high-quality embryos were higher (P = 0.00 < 0.05). The participants' pregnancy outcomes (ectopic pregnancy, miscarriage, singleton, twin, multiple births) were found to not be predictable by AMH through ROC curves (P = 0.980, 0.093, 0.447, 0.146, 0.526, and 0.868 > 0.05). For participants in the pregnancy group, although AMH was lower in the nonpregnant participants(P = 0.868 > 0.05), the difference was not statistically significant, and the correlation coefficients between the two groups suggested no differences in the IVF process, except for the starting Gn (IU) (P = 0.038 < 0.05). CONCLUSION: AMH has clinical application value in predicting ovarian reserve function, providing guidance and suggestions for the specific formulation of ovulation promotion programs with assisted reproductive technology, but it cannot effectively predict the outcome of clinical pregnancy.

Preparation and Characterization of Water-borne Polyurethane Based on Benzotriazole as Pendant Group with Different N-Alkylated Chain Extenders and Its Application in Anticorrosion.

A series of novel anti-corrosive coatings were synthesized successfully. Water-borne polyurethane (WPU) was synthesized using polyethylene glycol and modified by grafting benzotriazole (BTA) as a pendant group (WPU-g-BTA) and N-alkylated amines (ethylene diamine (A), diethylene triamine (B), triethylene tetramine (C)) as side-chain extenders. Fourier-transform infrared spectroscopy, thermogravimetry, and dynamic mechanical analyses were used to characterize the structural and thermomechanical properties of the samples. A gas permeability analyzer (GPA) was used to evaluate molecular barrier properties. The corrosion inhibition performance of WPU-g-BTA-A, WPU-g-BTA-B, and WPU-g-BTA-C coatings in 3.5 wt% NaCl solution was determined by electrochemical measurements. WPU-g-BTA-C coating synthesized with a high cross-linking density showed superior anticorrosive performance. The as-prepared coatings exhibited a very low icorr value of 0.02 µA.cm-2, a high Ecorr value of -0.02 V, as well as excellent inhibition efficiency (99.972%) and impedance (6.33 Ω) after 30 min of exposure.

Prognostic roles of KL-6 in disease severity and lung injury in COVID-19 patients: A longitudinal retrospective analysis.

To investigate the dynamic changes of Krebs von den Lungen-6 (KL-6) among patients with coronavirus disease 2019 (COVID-19) and the role of KL-6 as a noninvasive biomarker for predicting long-term lung injury, the clinical information and laboratory tests of 166 COVID-19 patients were collected, and a correlation analysis between KL-6 and other parameters was conducted. There were 17 (10.2%, 17/166) severe/critical and 149 (89.8%, 149/166) mild COVID-19 patients in our cohort. Serum KL-6 was significantly higher in severe/critical COVID-19 patients than in mild patients (median 898.0 vs. 451.2 U/ml, p < .001). KL-6 was next confirmed to be a sensitive and specific biomarker for distinguishing mild and severe/critical patients and correlate to computed tomography lung lesions areas. Serum KL-6 concentration during the follow-up period (>100 days postonset) was well correlated to those concentrations within 10 days postonset (Pearson r = .867, p < .001), indicating the prognostic value of KL-6 levels in predicting lung injury after discharge. Finally, elevated KL-6 was found to be significantly correlated to coagulation disorders, and T cells subsets dysfunctions. In summary, serum KL-6 is a biomarker for assessing COVID-19 severity and predicting the prognosis of lung injury of discharged patients.

Transmitted drug resistance and transmission clusters among HIV-1 treatment-naïve patients in Guangdong, China: a cross-sectional study.

BACKGROUND: Transmitted drug resistance (TDR) that affects the effectiveness of the first-line antiretroviral therapy (ART) regimen is becoming prevalent worldwide. However, its prevalence and transmission among HIV-1 treatment-naïve patients in Guangdong, China are rarely reported. We aimed to comprehensively analyze the prevalence of TDR and the transmission clusters of HIV-1 infected persons before ART in Guangdong. METHODS: The HIV-1 treatment-naïve patients were recruited between January 2018 and December 2018. The HIV-1 pol region was amplified by reverse transcriptional PCR and sequenced by sanger sequencing. Genotypes, surveillance drug resistance mutations (SDRMs) and TDR were analyzed. Genetic transmission clusters among patients were identified by pairwise Tamura-Nei 93 genetic distance, with a threshold of 0.015. RESULTS: A total of 2368 (97.17%) HIV-1 pol sequences were successfully amplified and sequenced from the enrolled 2437 patients. CRF07_BC (35.90%, 850/2368), CRF01_AE (35.56%, 842/2368) and CRF55_01B (10.30%, 244/2368) were the main HIV-1 genotypes circulating in Guangdong. Twenty-one SDRMs were identified among fifty-two drug-resistant sequences. The overall prevalence of TDR was 2.20% (52/2368). Among the 2368 patients who underwent sequencing, 8 (0.34%) had TDR to protease inhibitors (PIs), 22 (0.93%) to nucleoside reverse transcriptase inhibitors (NRTIs), and 23 (0.97%) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Two (0.08%) sequences showed dual-class resistance to both NRTIs and NNRTIs, and no sequences showed triple-class resistance. A total of 1066 (45.02%) sequences were segregated into 194 clusters, ranging from 2 to 414 sequences. In total, 15 (28.85%) of patients with TDR were included in 9 clusters; one cluster contained two TDR sequences with the K103N mutation was observed. CONCLUSIONS: There is high HIV-1 genetic heterogeneity among patients in Guangdong. Although the overall prevalence of TDR is low, it is still necessary to remain vigilant regarding some important SDRMs.

Severe interstitial pneumonia caused by cetuximab: a case report and review of the literature.

Cetuximab is an IgG1 chimeric mAb against epidermal growth factor receptor, which can be used for chemotherapy failure or tolerance in patients with epidermal growth factor receptor expressed RAS wild-type metastatic colorectal cancer. We report on a patient who developed rapid-onset interstitial pneumonia while being treated with cetuximab plus XELOX (oxaliplatin, capecitabine) for metastatic colorectal cancer. A 75-year-old man patient was administered cetuximab plus XELOX regularly. After his cetuximab schedule was adjusted from 1 to 2 weeks, he rapidly developed interstitial pneumonia which led to acute respiratory distress syndrome. Our literature review indicated that, for patients with risk factors, a 2-week regimen of cetuximab might lead to interstitial pneumonia. Clinicians should closely monitor patients for adverse drug reactions to improve drug safety.

Genetic characteristics of HIV-1 CRF06_cpx and CRF56_cpx strains isolated in Guangzhou, China.

Strains of the HIV-1 circulating recombinant forms (CRFs) 06_cpx and 56_cpx were identified for the first time in Guangzhou, China. The nearly full-length genome (NFLG) sequence was amplified, and the PCR products were sequenced by the Sanger method. The CRF06_cpx and CRF56_cpx strains were identified using the Basic Local Alignment Search Tool (BLAST) and confirmed by neighbour-joining (NJ) phylogenetic analysis. Additionally, these strains were found to contain transmitted drug resistance mutations that have little effect on first-line efavirenz (EFV)-based treatment. Genetic analysis of the detailed sequence data will provide more information on the HIV-1 epidemic in China.

Nickel/Photo-Cocatalyzed Asymmetric Acyl-Carbamoylation of Alkenes.

An unprecedented asymmetric acyl-carbamoylation of pendant alkenes tethered on aryl carbamic chlorides with both aliphatic and aromatic aldehydes has been developed via the cooperative catalysis of a chiral nickel-PHOX complex and tetrabutylammonium decatungstate. This reaction represents the first example of merging hydrogen-atom-transfer photochemistry and asymmetric transition metal catalysis in difunctionalization of alkenes. Using this protocol, a variety of oxindoles bearing a challenging quaternary stereogenic center are furnished under mild conditions in highly enantioselective manner.

Characteristics of drug resistance in HIV-1 CRF55_01B from ART-experienced patients in Guangdong, China.

BACKGROUND: HIV-1 acquired drug resistance (ADR) has become a critical clinical and public health issue. Recently, HIV-1 CRF55_01B has been found more frequently in the MSM population. OBJECTIVE: To investigate the characteristics of HIV-1 drug resistance mutations (DRMs) and the extent of changes in drug susceptibility among ART-experienced CRF55_01B-infected adults of Guangdong. METHODS: ADR was tested for immediately in CRF55_01B-infected patients with virological failure. Demographic and epidemiological information was collected. DRMs and antiretroviral susceptibility were interpreted using the Stanford University HIV Drug Resistance Database HIVdb program. RESULTS: Overall, 162 (4.78%) CRF55_01B isolates were identified from 2013 to 2018. Among DRMs, M184V (43.83%) was the most frequent NRTI DRM, followed by K65R (23.46%), and V179E (98.77%) was the most frequent NNRTI DRM, followed by K103N (47.53%) and Y181C (14.81%). According to the HIVdb program, 79.01% of the CRF55_01B-infected patients carried mutations conferring low-level or higher drug resistance to any of the three classes of ART drugs. Among PI DRMs, only one mutation affording low-level resistance to nelfinavir was found (0.62%). Among NRTI DRMs, a high proportion of high-level resistance to lamivudine (58.64%) and emtricitabine (58.02%) was found. As regards NNRTIs, more than 75% of patients carried efavirenz and nevirapine DRMs. The percentages of high-level resistance were 70.99%, 63.58%, 22.22%, 17.90% and 4.32% for nevirapine, efavirenz, rilpivirine, doravirine and etravirine, respectively. CONCLUSIONS: High frequencies of DRMs and resistance were observed among CRF55_01B-infected patients failing ART in Guangdong, and interventions may be considered to minimize ecological contributions to ART.

Multicenter evaluation of Xpert HIV-1 viral load assay for HIV quantification in China.

New approaches to increase HIV-1 testing and HIV-1 viral load (VL) monitoring are needed for people living with HIV (PLHIV) in China. The Xpert HIV-1 VL assay was prequalified by the World Health Organization in 2017 but has not been evaluated in China. A multicenter evaluation was conducted to assess the accuracy of the Cepheid Xpert HIV-1 VL assay compared to the Abbott RealTime HIV-1 assay in China. Overall agreement was seen in 558 of 562 specimens (99.29%) with a κ value of 0.962. Pearson's coefficient between the two assays was 0.943. Analyzed by the Bland-Altman method, the mean bias was -0.54 log10 copies/mL, and 94.05% results fell within the 95% confidence limit of agreement (-1.248 to 0.168 log10 copies/mL). The coefficient of variation of the Cepheid Xpert HIV-1 VL assay ranged from 0.61% to 1.55%, as determined by testing eight positive plasma specimens with three different lots on different days. Due to its simplicity, random-access, rapid turnaround time, and accuracy, the Xpert HIV-1 VL assay can be used in local hospitals and clinics that bear the burden of identifying and treating HIV patients in China.

Naturally occurring antiviral drug resistance in HIV patients who are mono-infected or co-infected with HBV or HCV in China.

Drug resistance mutations (DRMs) may reduce the efficacy of antiviral therapy. However, the studies focused on naturally occurring, pre-existing DRMs among co-infected patients in China are limited. To investigate DRMs prevalence in treatment-naïve human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) mono- and co-infected patients in China, a total of 570 patients were recruited for this study. DRMs sequences were amplified and successfully sequenced in 481 of these patients, who were grouped into three cohorts: (i) The HBV cohort included 100 HIV/HBV co-infected and 110 HBV mono-infected patients who were sequenced for HBV; (ii) The HCV cohort included 91 patients who were HIV/HCV co-infected and 72 who were HCV mono-infected for HCV sequencing; and (iii) The HIV cohort included 39 HIV mono-infected, 22 HIV/HCV, and 47 HIV/HBV co-infected patients for HIV sequencing. Next-generation sequencing and Sanger sequencing were used in this study. The results showed that in the HCV cohort, HCV genotypes 6a (P < 0.001) and 3b (P = 0.004) were more prevalent in HIV/HCV co-infected patients, however, the prevalence of HBV and HIV genotypes were similar within the HBV and HIV cohorts. HBV DRMs prevalence was significantly higher in HIV/HBV co-infected than HBV mono-infected patients (8.0% vs 0.9%, P = 0.015), whereas HCV and HIV DRMs did not differ within the HCV and HIV cohort (P > 0.05). This study revealed that HBV DRMs were more prevalent in HIV/HBV co-infected patients in China, while DRMs in HCV and HIV patients did not differ. Further dynamic surveillance of DRMs may be needed.