Nasal Spray of Neutralizing Monoclonal Antibody 35B5 Confers Potential Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern: A Small-Scale Clinical Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), especially the Delta and Omicron variants, have been reported to show significant resistance to approved neutralizing monoclonal antibodies (mAbs) and vaccines. We previously identified a mAb named 35B5 that harbors broad neutralization to SARS-CoV-2 VOCs. Herein, we explored the protection efficacy of a 35B5-based nasal spray against SARS-CoV-2 VOCs in a small-scale clinical trial. METHODS: We enrolled 30 healthy volunteers who were nasally administered the modified 35B5 formulation. At 12, 24, 48, and 72 hours after nasal spray, the neutralization efficacy of nasal mucosal samples was assayed with pseudoviruses coated with SARS-CoV-2 spike protein of the wild-type strain or the Alpha, Beta, Delta, or Omicron variants. RESULTS: The nasal mucosal samples collected within 24 hours after nasal spray effectively neutralized SARS-CoV-2 VOCs (including Delta and Omicron). Meanwhile, the protection efficacy was 60% effective and 20% effective at 48 and 72 hours after nasal spray, respectively. CONCLUSIONS: A single nasal spray of 35B5 formation conveys 24-hour effective protection against SARS-CoV-2 VOCs, including the Alpha, Beta, Delta, or Omicron variants. Thus, 35B5 nasal spray might be potential in strengthening SARS-CoV-2 prevention, especially in high-risk populations. CLINICAL TRIALS REGISTRATION: 2022-005-02-KY.

The role of pyroptosis in incomplete immune reconstitution among people living with HIV：Potential therapeutic targets.

Globally, HIV infection causes significant morbidity and mortality, and is a major public health problem. Despite the fact that widespread use of antiretroviral therapy (ART) has substantially altered the natural history of HIV infection from originally being a universally lethal disease to now being a chronic medical condition for those taking appropriate treatment, approximately 10-40% of people living with HIV (PLWH) who take effective ART and maintain long-term viral suppression fail to achieve normalization of CD4 + T-cell counts. This phenomenon is referred to as incomplete immune reconstitution or immunological non-response. Although the precise mechanisms underlying this outcome have not been elucidated, recent evidence indicates that excessive pyroptosis may play a crucial role in the development of incomplete immune reconstitution. Pyroptosis is characterized by the formation of pores in the cell membrane, cell rupture, and secretion of intracellular contents and pro-inflammatory cytokines, including IL-1ß and IL-18. This excessive inflammation-induced programmed cell death leads to a massive loss of CD4 + T-cells, and inflammatory consequences that may promote and sustain incomplete immune reconstitution. Herein, we review the possible pathways activated in HIV infection by inflammasomes that act as switches of pyroptosis, and the role of pyroptosis in HIV, as well as the relevance of CD4 + T-cells in incomplete immune reconstitution. We also highlight the possible mechanisms of pyroptosis involved in incomplete immune reconstitution, thus paving the way for the development of potential targets for the treatment of incomplete immune reconstitution.

Severe anemia, severe leukopenia, and severe thrombocytopenia of amphotericin B deoxycholate-based induction therapy in patients with HIV-associated talaromycosis: a subgroup analysis of a prospective multicenter cohort study.

BACKGROUND: This study's objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis. METHODS: A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020. RESULTS: Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level < 100 g/L (OR = 5.846, 95% CI: 2.765 ~ 12.363), serum creatinine level > 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level < 100 × 109 /L (OR = 2.935, 95% CI: 1.075 ~ 8.016) was identified as the independent risk factor associated with the development of severe thrombocytopenia. There was no difference in progression to severe anemia, severe leukopenia, and severe thrombocytopenia between the patients with or without fungal clearance at 2 weeks. 10 mg on the first day of amphotericin B deoxycholate was calculated to be independent risk factors associated with the development of severe anemia (OR = 2.621, 95% CI: 1.107 ~ 6.206). The group receiving a starting amphotericin B dose (10 mg, 20 mg, daily) exhibited the highest fungal clearance rate at 96.3%, which was significantly better than the group receiving a starting amphotericin B dose (5 mg, 10 mg, 20 mg, daily) (60.9%) and the group receiving a starting amphotericin B dose (5 mg, 15 mg, and 25 mg, daily) (62.9%). CONCLUSION: The preceding findings reveal risk factors for severe anemia, severe leukopenia, and severe thrombocytopenia. After treatment with Amphotericin B, these severe adverse events are likely unrelated to fungal clearance at 2 weeks. Starting amphotericin B deoxycholate at a dose of 10 mg on the first day may increase the risk of severe anemia but can lead to earlier fungal clearance. TRIAL REGISTRATION: ChiCTR1900021195. Registered 1 February 2019.

Willingness to take long-acting injectable pre-exposure prophylaxis among men who have sex with men who participated in the CROPrEP study: a cross-sectional online study.

INTRODUCTION: Evidence on the willingness of men who have sex with men (MSM) with oral pre-exposure prophylaxis (PrEP) experience, especially those with suboptimal adherence, to take long-acting injectable PrEP (LAI-PrEP) is critical to guide future LAI-PrEP implementation. OBJECTIVE: The objective was to assess the willingness of MSM with oral PrEP experience to take LAI-PrEP. METHODS: MSM who participated in the China Real-world Study of Oral PrEP (CROPrEP) were enrolled in this study. Information on the willingness of MSM to take LAI-PrEP and potential correlates was collected using a structured online questionnaire. The main outcomes were the willingness of MSM to take LAI-PrEP and its association with HIV-related behaviours, sexually transmitted infections, and oral PrEP history. Logistic regression was used to identify correlates of the willingness of MSM to take LAI-PrEP. RESULTS: A total of 612 former CROPrEP participants (FCPs) were included in this study. There were 315 (51.5%) daily oral PrEP (D-PrEP) users and 297 (48.5%) event-driven oral PrEP (ED-PrEP) users at the last follow-up. Most FCPs (77.8%) were willing to take free LAI-PrEP. FCPs with no less than two sexual male partners (aOR = 1.54, [95% CI: 1.04, 2.29], P = 0.031), those with male partners with unknown HIV statuses (aOR = 2.04, [95% CI: 1.31, 3.18], P = 0.002), those with recreational drug use (aOR = 1.58, [95% CI: 1.05, 2.40], P = 0.030), and those with HSV-2 positivity (aOR = 2.15, [95% CI: 1.30, 3.57], P = 0.003) were more willing to take LAI-PrEP, while ED-PrEP users (aOR = 0.66, [95% CI: 0.45, 0.98], P = 0.037) and FCPs with suboptimal oral PrEP adherence (aOR = 0.58, [95% CI: 0.36, 0.94], P = 0.026) were less willing to take LAI-PrEP. CONCLUSION: LAI-PrEP has good prospects for expanding PrEP coverage. However, FCPs with suboptimal oral PrEP adherence are less likely to take LAI-PrEP. Further intervention and implementation efforts are needed to improve the willingness of MSM to use LAI-PrEP, and sexual health should be considered during the discussion about PrEP initiation.

Psychoanalysis of COVID-19 Patient Narratives: A Descriptive Study.

Background and Objectives: COVID-19 patients are a psychologically vulnerable patient group who suffer from both physical symptoms and psychological problems. The present study is a psychoanalytic investigation of COVID-19 patients utilizing Lacan's desire theory. We aimed to explore the manner in which patients' desire is presented in their lived experience narratives and sought to discover factors which directly impacted on this process. Materials and Methods: In-depth semi-structural interviews were conducted with 36 COVID-19 patients in China. During each interview, participants narrated their lived experiences of COVID-19 infection. Emotions, metaphors, and behaviors in patient narratives were collated as the main points for psychoanalysis. Results: Our findings demonstrated that the desire for being a healthy person made patients emotionally sensitive to the social environment. Anxiety and obsessive behaviors emerged in the process, which reveals their desire for that which they lack. Furthermore, public fear with respect to COVID-19 was somehow converted to psychological pressure on COVID-19 patients. Thus, these patients attempted to "de-identify" their identity as "patients". Positive responses of COVID-19 patients to the external world included admiring medical personnel, government, and country, while negative responses included interpersonal conflicts or complaints about discrimination. Following the rules of the Other, COVID-19 patients were influenced by the Other's desire in constructing their own image of a healthy person. Conclusions: This study revealed COVID-19 patients' psychological need to rid themselves of the identity of "patient" at the individual and social level. Our findings have clinical implications in helping COVID-19 patients to reshape their identity and to live a normal life.

Distribution of nontuberculous mycobacteria in patients with and without HIV/AIDS in Chongqing.

INTRODUCTION: In this study, the distribution of nontuberculous mycobacteria (NTM) strains in patients with and without HIV/AIDS in Chongqing, China was evaluated. METHODS: A retrospective study was performed in January-December 2020 at Chongqing Public Health Medical Center. NTM strains were assessed by a multi locus phylogenetic analysis. The distribution of NTM strains in HIV/AIDS and non-HIV/AIDS groups was compared. CD4+ cell counts, imaging changes, and characteristics of mycobacterial species were determined. RESULTS: In total, 324 patients with NTM infection (50 patients with HIV/AIDS and 274 patients without HIV/AIDS) were included. The most common etiological agent was M. abscessus (29%), followed by M. paraintracellulare (12%) and M. colombiense (11%). Predominant NTM species were M. avium (26%), M. colombiense (24%), and M. kansasii (18%) in patients with HIV/AIDS and were M. abscessus (32%), M. paraintracellulare (13%), M. fortuitum (10%), and M. intracellulare (10%) in patients without HIV/AIDS. For a CD4+ cell count of <200/µl, the predominant species were M. aviumin the HIV/AIDS group and M. abscessus in the non-HIV/AIDS group. With respect to radiologic characteristics, different NTM strains were associated with distinct imaging manifestations; for example, M. marseillense, M. kansasii, and M. parasenchytosis were more likely to induce cavities. Imaging cavities, bronchiectasis, and acinar-like changes were more common in the non-HIV/AIDS groups. CONCLUSIONS: The infection rates of HIV and NTM in Chongqing are high, while M. abscessus, M. paraintracellulare, and M. colombiense are the main pathogens causing NTM diseases in Chongqing, and NTM strains differed significantly between patients with and without HIV/AIDS. Monitoring these indicators can help develop prevention strategies.

Comparison of HIV DNA decay and immune recovery between early and chronic HIV-infected individuals 96 weeks after ART.

OBJECTIVES: Although antiretroviral therapy (ART) has prolonged the lives of HIV-infected individuals, HIV reservoir remains the main stumbling block to HIV cure. Presently, early ART initiation is one of the effective measures to reduce the HIV reservoir. The effects of ART in Chinese individuals with acute and early HIV infection (AEHI) and chronic HIV infection (CHI) were analyzed in this study. METHODS: We performed virological and immunological parameter analysis in 29 AEHI and 19 CHI individuals who were initiated into ART in Beijing, China. The HIV DNA, CD4+ T-cell and CD8+ T-cell counts, and CD4/CD8 ratios between the two groups were compared using statistical analyses. RESULTS: At weeks 48 and 96, the total HIV DNA was significantly lower in the AEHI group than that the CHI group (2.48 [2.26-2.66] vs. 3.06 [2.79-3.33] log10 copies/106 peripheral blood mononuclear cells (PBMCs), p < 0.01 at week 48 and 2.17 [1.85-2.45] vs. 2.92 [2.73-3.24] log10 copies/106  PBMCs, p < 0.01 at week 96, respectively). The CD4/CD8 T-cell ratio in the AHI group at week 24 was significantly higher than that in the CHI group (0.71 [0.50-0.99] vs. 0.45 [0.34-0.65], p = 0.08). After 48 weeks of ART, there was still a negative correlation between the CD4/CD8 ratio and the HIV DNA level in the CHI group rather than the AEHI group. CONCLUSIONS: Early ART initiation could enhance an earlier immunological recovery in AEHI. Immunological normalization after ART initiation could provide important protection against the viral reservoir seeded in AEHI individuals.

Pretreatment drug resistance in people living with HIV: A large retrospective cohort study in Chongqing, China.

OBJECTIVES: The emergence of pretreatment drug resistance (PDR) caused by increased usage of antiretroviral therapy (ART) represents a significant challenge to HIV management. In this study, we evaluated the prevalence of PDR in people living with HIV (PLWH) in Chongqing, China. METHODS: We retrospectively collected the data of 1110 ART-naïve PLWH in Chongqing from January 1, 2018 to June 30, 2021. HIV-1 genotypes and drug resistance were analyzed using the HIV-1 pol sequence. Risk factors associated with PDR were evaluated via the logistic regression model. RESULTS: Nine genotypes were detected among 1110 participants, with CRF07_BC (55.68%) being the dominant genotype, followed by CRF01_AE (21.44%), CRF08_BC (14.14%), and other genotypes (8.74%). Of all the participants, 24.14% exhibited drug resistance mutations (DRMs). The predominant DRMs for non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were V179D/E/A/DIN (13.60%) and M184V/I (1.44%), respectively, whereas only two major DRMs (M46L and I54L) were identified for protease inhibitors (PIs). The total prevalence of PDR was 10.54%, with 2.43%, 7.66%, and 1.71% participants exhibiting PDR to NRTIs, NNRTIs, and PIs, respectively. Furthermore, female PLWH, delays in ART initiation, and the CRF08_BC genotype were associated with a higher risk of PDR. CONCLUSIONS: Our study provides the first large cohort data on the prevalence of PDR in Chongqing, China. HIV-1 genotypes are diverse and complex, with a moderate level of PDR, which does not reach the threshold for the initiation of a public health response. Nevertheless, continuous surveillance of PDR is both useful and advisable.

Diagnosis of pulmonary tuberculosis via identification of core genes and pathways utilizing blood transcriptional signatures: a multicohort analysis.

BACKGROUND: Blood transcriptomics can be used for confirmation of tuberculosis diagnosis or sputumless triage, and a comparison of their practical diagnostic accuracy is needed to assess their usefulness. In this study, we investigated potential biomarkers to improve our understanding of the pathogenesis of active pulmonary tuberculosis (PTB) using bioinformatics methods. METHODS: Differentially expressed genes (DEGs) were analyzed between PTB and healthy controls (HCs) based on two microarray datasets. Pathways and functional annotation of DEGs were identified and ten hub genes were selected. They were further analyzed and selected, then verified with an independent sample set. Finally, their diagnostic power was further evaluated between PTB and HCs or other diseases. RESULTS: 62 DEGs mostly related to type I IFN pathway, IFN-γ-mediated pathway, etc. in GO term and immune process, and especially RIG-I-like receptor pathway were acquired. Among them, OAS1, IFIT1 and IFIT3 were upregulated and were the main risk factors for predicting PTB, with adjusted risk ratios of 1.36, 3.10, and 1.32, respectively. These results further verified that peripheral blood mRNA expression levels of OAS1, IFIT1 and IFIT3 were significantly higher in PTB patients than HCs (all P < 0.01). The performance of a combination of these three genes (three-gene set) had exceeded that of all pairwise combinations of them in discriminating TB from HCs, with mean AUC reaching as high as 0.975 with a sensitivity of 94.4% and a specificity of 100%. The good discernibility capacity was evaluated d via 7 independent datasets with an AUC of 0.902, as well as mean sensitivity of 87.9% and mean specificity of 90.2%. In regards to discriminating PTB from other diseases (i.e., initially considered to be possible TB, but rejected in differential diagnosis), the three-gene set equally exhibited an overall strong ability to separate PTB from other diseases with an AUC of 0.999 (sensitivity: 99.0%; specificity: 100%) in the training set, and 0.974 with a sensitivity of 96.4% and a specificity of 98.6% in the test set. CONCLUSION: The described commonalities and unique signatures in the blood profiles of PTB and the other control samples have considerable implications for PTB biosignature design and future diagnosis, and provide insights into the biological processes underlying PTB.

Comparison of amphotericin B deoxycholate in combination with either flucytosine or fluconazole, and voriconazole plus flucytosine for the treatment of HIV-associated cryptococcal meningitis: a prospective multicenter study in China.

BACKGROUND: The most appropriate alternative to induction therapy for HIV-associated cryptococcal meningitis (CM) remains unclear when standard treatment is unavailable, inaccessible, intolerable, or ineffective. METHODS: A prospective, multi-centre cohort study was conducted to analyze the data of 156 HIV-infected patients with CM who were treated with amphotericin B deoxycholate (AmB-D) + flucytosine (5FC), voriconazole (VCZ) + 5FC, or AmB-D + Fluconazole (Flu) as induction regimens. Clinical efficacy, cumulative mortality, and adverse effects were compared among the three treatment groups. RESULTS: Fewer deaths occurred by week 4 and week 10 among patients receiving AmB-D + 5FC than among those receiving AmB-D + Flu [4 (5.1%) vs. 8 (16.0%) deaths by week 4; hazard ratio, 1.8; 95% confidence interval [CI], 1.0 to 3.3; p = 0.039; and 8 (10.3%) vs. 14 (28.0%) deaths by week 10; hazard ratio, 1.8; 95% CI, 1.1 to 2.7; p = 0.008, respectively]. AmB-D plus 5FC was found to result in significantly higher rates of cerebrospinal fluid (CSF) culture sterility (57.6% vs. 34% by week 2; 87.9% vs. 70% by week 10; p < 0.05 for both comparisons). However, the differences in CSF culture sterility and mortality between the VCZ + 5FC group and the AmB-D + 5FC group were not statistically significant. VCZ plus 5FC had a significantly advantageous effect on the incidence of new AIDS-defining illness and length of hospital stay, compared with AmB-D plus 5FC. Laboratory adverse events (grade 3 or 4), such as severe anemia, were less frequent with VCZ + 5FC use than with AmB-D combined with 5FC or Flu use. CONCLUSION: Our results suggest that AmB-D combined with 5FC remains the more efficacious induction regimen compared to AmB-D plus Flu, and that VCZ + 5FC might be a potential alternative when the standard regimen is not readily available, accessible, tolerated, or effective. CLINICAL TRIALS: Registration number, ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection.

During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection.

Central nervous system aspergillosis misdiagnosed as Toxoplasma gondii encephalitis in a patient with AIDS: a case report.

BACKGROUND: Patients with acquired immunodeficiency syndrome (AIDS) tend to suffer from several central nervous system (CNS) infections due to hypoimmunity. However, CNS aspergillosis (CNSAG) is extremely rare and difficult to diagnose. Thus, it is easily misdiagnosed. CASE PRESENTATION: We reported a 47-year-old male AIDS patient with ghosting vision and anhidrosis on the left head and face. He was accordingly diagnosed with Toxoplasma gondii encephalitis (TE) at other hospitals, for which he received regular anti-Toxoplasma gondii and anti-human immunodeficiency virus (anti-HIV) treatment. Then, the patient was transferred to our hospital due to a lack of any improvement with the prescribed treatment. The patient's neurological examination revealed no abnormalities at admission, only a slight change in the cerebrospinal fluid. His cranial magnetic resonance imaging (MRI) revealed multiple abnormal signals in the brain parenchyma, and his blood was positive for Toxoplasma gondii IgG antibody. The initial diagnosis at our hospital was also TE. Considering the poor efficacy of anti-TE treatment, cerebrospinal fluid metagenomics next-generation sequencing (mNGS) was performed, but no pathogenic bacteria were detected. However, Aspergillus fumigatus was detected in the cerebrospinal fluid via targeted next-generation sequencing (tNGS) and bronchoalveolar alveolar lavage fluid via mNGS. The diagnosis was accordingly revised to CNSAG combined with his other clinical manifestations. After administering voriconazole antifungal therapy, the patient's symptoms were relieved, with improved absorption of the intracranial lesions. CONCLUSIONS: The present case experience indicates the need for clinicians to strengthen their understanding of CNSAG. Moreover, for patients with diagnostic difficulties, early mNGS and tNGS (using biological samples with only a few pathogens) are helpful for early diagnosis and treatment, potentially allowing patients to achieve favorable outcomes.

Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.

BACKGROUND: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients. METHODS: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks. RESULTS: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started. CONCLUSIONS: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

The development and validation of a diagnostic scoring system to differentiate pulmonary tuberculosis from non-tuberculosis pulmonary infections in HIV-infected patients with severe immune suppression.

BACKGROUND: It remains challenging to differentiate tuberculosis (TB) from non-TB pulmonary infections in HIV-infected patients. Herein, we developed a scoring system aimed to rapidly determine the likelihood of TB or non-TB pathology in HIV-infected patients presenting with pulmonary infections. METHODS: We collected and collated data of hospitalized HIV-infected patients with pulmonary infections, followed by univariate and multivariate data analyses to determine risk variables that were significantly different between HIV/TB patients and HIV/non-TB patients. Subsequently, a regression coefficient was calculated for each variable, and a score was assigned to each variable in line with its regression coefficient. The sum of the scores for each variable in our scoring model was used to predict the likelihood of TB or non-TB pulmonary infection in each patient. Finally, we tested the diagnostic accuracy of the scoring system in our retrospective cohort, as well as in a prospective cohort. RESULTS: A total of 598 HIV-infected patients were enrolled in our retrospective cohort, among whom 288 had TB and 310 had non-TB pulmonary infections. Eight variables, including fever, highest body temperature, erythrocyte sedimentation rate (ESR), cervical lymphadenopathy, hilar and/or mediastinum lymphadenopathy, pulmonary cavitation, pleural effusion, and miliary nodules, were found to be mathematically significantly different via univariate analysis and multivariate logistic regression analysis. After regression coefficient calculation followed by score assignment, a receiver operating characteristic (ROC) curve was plotted, and the area under the curve (AUC) was calculated to be 0.902. When the total score for a patient is > 12, the sensitivity and specificity for TB prediction using our scoring system were 76.4% and 87.7% respectively in the retrospective cohort, and its diagnostic accuracy was 82.7% in the prospective cohort. CONCLUSIONS: Our results demonstrate that our proposed diagnostic scoring system could be helpful in differentiating pulmonary TB from non-TB pulmonary infections in HIV-infected patients.

Establishment of a novel scoring model for mortality risk prediction in HIV-infected patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) remains a leading cause of death in HIV-infected patients, despite advances in CM diagnostic and therapeutic strategies. This study was performed with the aim to develop and validate a novel scoring model to predict mortality risk in HIV-infected patients with CM (HIV/CM). METHODS: Data on HIV/CM inpatients were obtained from a Multicenter Cohort study in China. Independent risk factors associated with mortality were identified based on data from 2013 to 2017, and a novel scoring model for mortality risk prediction was established. The bootstrapping statistical method was used for internal validation. External validation was performed using data from 2018 to 2020. RESULTS: We found that six predictors, including age, stiff neck, impaired consciousness, intracranial pressure, CD4+ T-cell count, and urea levels, were associated with poor prognosis in HIV/CM patients. The novel scoring model could effectively identify HIV/CM patients at high risk of death on admission (area under curve 0.876; p<0.001). When the cut-off value of 5.5 points or more was applied, the sensitivity and specificity was 74.1 and 83.8%, respectively. Our scoring model showed a good discriminatory ability, with an area under the curve of 0.879 for internal validation via bootstrapping, and an area under the curve of 0.886 for external validation. CONCLUSIONS: Our developed scoring model of six variables is simple, convenient, and accurate for screening high-risk patients with HIV/CM, which may be a useful tool for physicians to assess prognosis in HIV/CM inpatients.

Multicentre derivation and validation of a prognostic scoring system for mortality assessment in HIV-infected patients with talaromycosis.

BACKGROUND: Although the widespread use of modern antiretroviral therapy (ART) has reduced the incidence of talaromycosis in people living with HIV, mortality remains as high as 20% in this population, even after appropriate antifungal treatment. OBJECTIVES: The objective of our study was to develop a risk assessment system for HIV-infected patients with comorbid talaromycosis, in order to provide these patients with appropriate, effective and potentially life-saving interventions at an early stage of their illness. PATIENTS/METHODS: This was a multicentre, retrospective cohort study conducted in China. We built a predictive model based on data from 11 hospitals, and a validated model using the data of 1 hospital located in an endemic area. RESULTS: Forward stepwise multivariate statistical calculations indicated that age, aspartate aminotransferase/alanine transaminase ratio and albumin levels, and BUN levels were valid, independent predictors of the risk of death in HIV-infected patients with talaromycosis. Our developed and validated risk scoring system is effective for the identification of HIV-infected patients with talaromycosis at high risk of death at hospital admission (p < .001; AUC = 0.860). In our study, our risk prediction model provided functional and robust discrimination in the validation cohort (p < .001; AUC = 0.793). CONCLUSION: The prognostic scoring system for mortality assessment developed in the present study is an easy-to-use clinical tool designed to accurately assist clinicians in identifying high-risk patients with talaromycosis.

Internet-Based HIV Self-Testing Among Men Who Have Sex With Men Through Pre-exposure Prophylaxis: 3-Month Prospective Cohort Analysis From China.

BACKGROUND: Routine HIV testing accompanied with pre-exposure prophylaxis (PrEP) requires innovative support in a real-world setting. OBJECTIVE: This study aimed to determine the usage of HIV self-testing (HIVST) kits and their secondary distribution to partners among men who have sex with men (MSM) in China, who use PrEP, in an observational study between 2018 and 2019. METHODS: In 4 major cities in China, we prospectively followed-up MSM from the China Real-world oral PrEP demonstration study, which provides daily or on-demand PrEP for 12 months, to assess the usage and secondary distribution of HIVST on quarterly follow-ups. Half of the PrEP users were randomized to receive 2 HIVSTs per month in addition to quarterly facility-based HIV testing. We evaluated the feasibility of providing HIVST to PrEP users. RESULTS: We recruited 939 MSM and randomized 471 to receive HIVST, among whom 235 (49.9%) were daily and 236 (50.1%) were on-demand PrEP users. At baseline, the median age was 29 years, 390 (82.0%) men had at least college-level education, and 119 (25.3%) had never undergone facility-based HIV testing before. Three months after PrEP initiation, 341 (74.5%) men had used the HIVST provided to them and found it very easy to use. Among them, 180 of 341 (52.8%) men had distributed the HIVST kits it to other MSM, and 132 (51.6%) among the 256 men who returned HIVST results reported that used it with their sexual partners at the onset of intercourse. Participants on daily PrEP were more likely to use HIVST (adjusted hazard ratio=1.3, 95% CI 1.0-1.6) and distribute HIVST kits (adjusted hazard ratio=1.3, 95% CI 1.1-1.7) than those using on-demand PrEP. CONCLUSIONS: MSM who used PrEP had a high rate of usage and secondary distribution of HIVST kits, especially among those on daily PrEP, which suggested high feasibility and necessity for HIVST after PrEP initiation. Assuming that fourth-generation HIVST kits are available, HIVST may be able to replace facility-based HIV testing to a certain extent. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800020374; https://www.chictr.org.cn/showprojen.aspx?proj=32481. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2019-036231.

The Optimal Timing of Antiretroviral Therapy Initiation in HIV-Infected Patients with Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Trial.

The optimal timing of antiretroviral therapy (ART) initiation in human immunodeficiency virus (HIV)-infected patients with cryptococcal meningitis (HIV/CM) is controversial. We designed a clinical trial to inves-tigate the optimal timing for ART initiation in HIV/CM patients. This will be a multicenter, prospective, and randomized clinical trial. Each enrolled patient will be randomized into either the early ART arm or the deferred ART arm. We will compare the mortality and incident rates of immune reconstitution inflammatory syndrome between the two arms. We hope to elucidate the optimal timing for ART initiation in HIV/CM patients.

A Peptide-Based Magnetic Chemiluminescence Enzyme Immunoassay for Serological Diagnosis of Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel ß-coronavirus, causes severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named coronavirus disease 2019 (COVID-19). To date, real-time reverse-transcription polymerase chain reaction (RT-PCR) is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. METHODS: In this study, we developed a peptide-based luminescent immunoassay that detected immunoglobulin (Ig)G and IgM. The assay cutoff value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. RESULTS: To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. CONCLUSIONS: Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.

Quercetin inhibits Pseudomonas aeruginosa biofilm formation via the vfr-mediated lasIR system.

Pseudomonas aeruginosa is one of the most common opportunistic pathogens that cause biofilm-associated infections. Biofilm formation is partially regulated by the quorum sensing (QS) system, and quercetin can inhibit QS, biofilm formation and virulence factors. We therefore speculated that quercetin would inhibit the formation of P. aeruginosa biofilm via the QS system. In this study, we successfully constructed lasI, rhlI and lasI/rhlI gene-knockout strains. The knockout of the lasI and lasI/rhlI genes resulted in decreases in adhesion, biofilm formation, swarming motility and the expression of biofilm-associated genes, whereas deletion of the rhlI gene had no obvious influence on these biofilm-related indicators with the exception of the swarming motility. After treatment with quercetin, the lasI- and lasI/rhlI-mutant strains exhibited increased adhesion, biofilm formation, swarming motility and biofilm-associated gene expression compared with the control group. However, quercetin still exerted an inhibitory effect on these physiological factors and the biofilm-associated gene expression in the rhlI-mutant strain. The knockout of QS genes reduced the production of pyocyanin and protease activity, but after the virulence factors of the QS-mutant strains treated with quercetin showed almost no differences compared with those of the control group. In addition, quercetin could significantly inhibit vfr gene expression regardless of the presence of QS genes. The results indicated that quercetin might inhibit the lasIR system through the vfr gene and ultimately the formation of P. aeruginosa biofilms.