Refining a noninvasive prediction model for neurosyphilis diagnosis by using Immunoassay to Detect serum anti-TP0435 (TP17) and TP0574 (TP47) IgG antibodies: Two-center Cross-sectional retrospective study in China.

OBJECTIVES: Invasive lumbar puncture (LP) is the conventional method for diagnosing neurosyphilis (NS). We investigated a noninvasive alternative method to detect serum Treponema pallidum specific antibodies against highly immunogenic antigens TP0171 (TP15), TP0435 (TP17), and TP0574 (TP47) by using luciferase immunosorbent assay (LISA). METHODS: 816 HIV-negative patients suspected of NS from Beijing and Guangzhou cohort were retrospectively selected and tested for serum anti-TP15, TP17, and TP47 IgG antibody. Two diagnostic prediction models were developed using stepwise logistic regression in Beijing cohort, and evaluated in Guangzhou cohort for external validation. RESULTS: Serum antibodies against TP15, TP17, and TP47 showed moderate capability for NS diagnosis in Beijing cohort and the corresponding AUCs were 0.722 (95% CI: 0.680-0.762), 0.780 (95% CI: 0.741-0.817), and 0.774 (95% CI: 0.734-0.811), respectively. An expanded NS prediction model integrated with anti-TP17 and anti-TP47 antibodies showed better performance than the base NS diagnostic model without anti-TP17 and anti-TP47 antibodies with the AUC of 0.874 (95% CI: 0.841-0.906) vs 0.845 (95% CI: 0.809-0.881) (p = 0.007) in the development cohort, and 0.934 (95% CI: 0.909-0.960) vs 0.877 (95% CI: 0.840-0.914) (p<0.001) in validation cohort, respectively. Decision curve analysis (DCA) revealed that the net benefit of the expanded model exceeded that of the base model when the threshold probability was between 0.10 and 0.95 in both the development and external validation cohorts. CONCLUSIONS: Serum antibodies against TP17 and TP47 exhibited promising diagnostic capability for NS and significantly enhanced predictive accuracy of model for NS diagnosis. Our study highlights the potential of serum treponemal antibody detection as a noninvasive method for NS diagnosis to substitute invasive LP in NS diagnosis.

Evaluating the clinical utility of semi-quantitative luciferase immunosorbent assay using Treponema pallidum antigens in syphilis diagnosis and treatment monitoring.

To assess the clinical applicability of a semi-quantitative luciferase immunosorbent assay (LISA) for detecting antibodies against Treponema pallidum antigens TP0171 (TP15), TP0435 (TP17), and TP0574 (TP47) in diagnosing and monitoring syphilis. LISA for detection of anti-TP15, TP17, and TP47 antibodies were developed and evaluated for syphilis diagnosis using 261 serum samples (161 syphilis, 100 non-syphilis). Ninety serial serum samples from 6 syphilis rabbit models (3 treated, 3 untreated) and 110 paired serum samples from 55 syphilis patients were used to assess treatment effects by utilizing TRUST as a reference. Compared to TPPA, LISA-TP15, LISA-TP17, and LISA-TP47 showed a sensitivity of 91.9%, 96.9%, and 98.8%, specificity of 99%, 99%, and 98%, and AUC of 0.971, 0.992, and 0.995, respectively, in diagnosing syphilis. Strong correlations (rs = 0.89-0.93) with TPPA were observed. In serial serum samples from rabbit models, significant differences in the relative light unit (RLU) were observed between the treatment and control group for LISA-TP17 (days 31-51) and LISA-TP47 (day 41). In paired serum samples from syphilis patients, TRUST titres and the RLU of LISA-TP15, LISA-TP17, and LISA-TP47 decreased post-treatment (P < .001). When TRUST titres decreased by 0, 2, 4, or ≥8-folds, the RLU decreased by 17.53%, 31.34%, 48.62%, and 72.79% for LISA-TP15; 8.84%, 17.00%, 28.37%, and 50.57% for LISA-TP17; 22.25%, 29.79%, 51.75%, and 70.28% for LISA-TP47, respectively. Semi-quantitative LISA performs well for syphilis diagnosis while LISA-TP17 is more effective for monitoring syphilis treatment in rabbit models and clinical patients.

Large-Scale Proteome Profiling Identifies Biomarkers Associated with Suspected Neurosyphilis Diagnosis.

Neurosyphilis (NS) is a central nervous system (CNS) infection caused by Treponema pallidum (T. pallidum). NS can occur at any stage of syphilis and manifests as a broad spectrum of clinical symptoms. Often referred to as "the great imitator," NS can be easily overlooked or misdiagnosed due to the absence of standard diagnostic tests, potentially leading to severe and irreversible organ dysfunction. In this study, proteomic and machine learning model techniques are used to characterize 223 cerebrospinal fluid (CSF) samples to identify diagnostic markers of NS and provide insights into the underlying mechanisms of the associated inflammatory responses. Three biomarkers (SEMA7A, SERPINA3, and ITIH4) are validated as contributors to NS diagnosis through multicenter verification of an additional 115 CSF samples. We anticipate that the identified biomarkers will become effective tools for assisting in diagnosis of NS. Our insights into NS pathogenesis in brain tissue may inform therapeutic strategies and drug discoveries for NS patients.

Diagnosis of neurosyphilis in HIV-negative patients with syphilis: development, validation, and clinical utility of a suite of machine learning models.

Background: The ability to accurately identify the absolute risk of neurosyphilis diagnosis for patients with syphilis would allow preventative and therapeutic interventions to be delivered to patients at high-risk, sparing patients at low-risk from unnecessary care. We aimed to develop, validate, and evaluate the clinical utility of simplified clinical diagnostic models for neurosyphilis diagnosis in HIV-negative patients with syphilis. Methods: We searched PubMed, China National Knowledge Infrastructure and UpToDate for publications about neurosyphilis diagnostic guidelines in English or Chinese from database inception until March 15, 2023. We developed and validated machine learning models with a uniform set of predictors based on six authoritative diagnostic guidelines across four continents to predict neurosyphilis using routinely collected data from real-world clinical practice in China and the United States (through the Dermatology Hospital of Southern Medical University in Guangzhou [659 recruited between August 2012 and March 2022, treated as Development cohort], the Beijing Youan Hospital of Capital Medical University in Beijng [480 recruited between December 2013 and April 2021, treated as External cohort 1], the Zhongshan Hospital of Xiamen University in Xiamen [493 recruited between November 2005 and November 2021, treated as External cohort 2] from China, and University of Washington School of Medicine in Seattle [16 recruited between September 2002 and April 2014, treated as External cohort 3] from United States). We included all these patients with syphilis into our analysis, and no patients were further excluded. We trained eXtreme gradient boosting (XGBoost) models to predict the diagnostic outcome of neurosyphilis according to each diagnostic guideline in two scenarios, respectively. Model performance was measured through both internal and external validation in terms of discrimination and calibration, and clinical utility was evaluated using decision curve analysis. Findings: The final simplified clinical diagnostic models included neurological symptoms, cerebrospinal fluid (CSF) protein, CSF white blood cell, and CSF venereal disease research laboratory test/rapid plasma reagin. The models showed good calibration with rescaled Brier score of 0.99 (95% CI 0.98-1.00) and excellent discrimination (the minimum value of area under the receiver operating characteristic curve, 0.84; 95% CI 0.81-0.88) when externally validated. Decision curve analysis demonstrated that the models were useful across a range of neurosyphilis probability thresholds between 0.33 and 0.66 compared to the alternatives of managing all patients with syphilis as if they do or do not have neurosyphilis. Interpretation: The simplified clinical diagnostic models comprised of readily available data show good performance, are generalisable across clinical settings, and have clinical utility over a broad range of probability thresholds. The models with a uniform set of predictors can simplify the sophisticated clinical diagnosis of neurosyphilis, and guide decisions on delivery of neurosyphilis health-care, ultimately, support accurate diagnosis and necessary treatment. Funding: The Natural Science Foundation of China General Program, Health Appropriate Technology Promotion Project of Guangdong Medical Research Foundation, Department of Science and technology of Guangdong Province Xinjiang Rural Science and Technology（Special Commissioner）Project, Southern Medical University Clinical Research Nursery Garden Project, Beijing Municipal Administration of Hospitals Incubating Program.

Role of microglia in HIV-1 infection.

The usage of antiretroviral treatment (ART) has considerably decreased the morbidity and mortality related to HIV-1 (human immunodeficiency virus type 1) infection. However, ART is ineffective in eradicating the virus from the persistent cell reservoirs (e.g., microglia), noticeably hindering the cure for HIV-1. Microglia participate in the progression of neuroinflammation, brain aging, and HIV-1-associated neurocognitive disorder (HAND). Some methods have currently been studied as fundamental strategies targeting microglia. The purpose of this study was to comprehend microglia biology and its functions in HIV-1 infection, as well as to look into potential therapeutic approaches targeting microglia.

Characteristics of CD8+ Stem Cell-Like Memory T Cell Subset in Chronic Hepatitis C Virus Infection.

The dysfunction of memory CD8+ T cell cannot be reverted by successful clearance of hepatitis C virus (HCV) after direct-acting antivirals (DAAs) therapy, increasing the risk of reinfection with HCV. Stem cell-like memory T cells (Tscm) with superior properties of long-lasting, self-renewing, and multipotency contribute to the maintenance of immune function. We investigated the impact of HCV infection on CD8+ Tscm, and their possible role in disease progression, by using DAA-naive HCV-infected and human immunodeficiency virus (HIV)/HCV-coinfected cohorts. The distribution of memory CD8+ T cell subsets and the level of T cell immune activation were determined by flow cytometry. Associations between CD8+ Tscm and other memory T cell subsets, HCV viral load, as well as the level of T cell immune activation were analyzed. We observed that the proportion of CD8+ Tscm increased in both HCV and HIV/HCV individuals. The proportion of CD8+ Tscm had positive and negative correlation with CD8+ Tcm (central memory T cells) and CD8+ Tem (effector memory T cell), respectively, representing the contribution of CD8+ Tscm in T cell homeostasis. In addition, higher frequency of CD8+ Tscm indicated lower HCV viral load and less T cell immune activation in HCV infection, which suggested that CD8+ Tscm is likely associated with effective control of HCV replication for protective immunity. Considering the characteristics of Tscm, our current findings provide implications for Tscm-based vaccine design and immunotherapy development to achieve HCV elimination.

Factors Associated With Neurosyphilis in Patients With Syphilis Treatment Failure: A Retrospective Study of 165 HIV-Negative Patients.

Background: In recent years, the incidence of syphilis has increased year by year. Our study is to explore the risk factors for the development of neurosyphilis in patients who failed syphilis treatment. Methods: A total number of 165 patients with complete medical records and who agreed to undergo lumbar puncture were divided into 47 neurosyphilis cases and 118 non-neurosyphilis cases according to the diagnostic criteria of neurosyphilis, and the differences in clinical characteristics and laboratory features between the two groups were analyzed. Significant variables were entered into multivariable logistic regression models. Results: (1) There were statistical differences (p < 0.05) between the neurosyphilis (NS) group and the non-neurosyphilis (NNS) group in terms of the higher proportion of male and serum rapid plasma reagin (RPR) > 1:32 and the elevated cerebrospinal fluid white blood cell (CSF WBC) and CSF protein in the neurosyphilis group compared with the non-neurosyphilis group. (2) Male gender, serum RPR titers >1:32 at lumbar puncture, CSF WBC >8 × 106/L were significantly associated with neurosyphilis. Conclusion: For patients who have failed syphilis treatment, lumbar puncture should be performed to exclude neurosyphilis, to enable early diagnosis and treatment, and to prevent irreversible damage of neurosyphilis, especially if the patient is male and has a serum RPR>1:32 and elevated CSF WBC at lumbar puncture, which are risk factors for neurosyphilis.

The benefits of psychosocial interventions for mental health in men who have sex with men living with HIV: a systematic review and meta-analysis.

OBJECTIVE: Men who have sex with men (MSM) living with HIV are more likely to suffer from mental health problems. They should be given adequate attention to treat and improve their mental health disorders. This meta-analysis aimed to assess whether psychosocial interventions reliably improve psychological well-being among MSM living with HIV. METHOD: Cochrane Library, EMBASE, PsycINFO, and PubMed were searched for psychosocial intervention randomized controlled trials evaluating mental health (e.g., depression, anxiety, self-efficacy). The effect size was pooled using the random-effects model, and continuous outcomes were reported using standardized mean difference (SMD) values . RESULTS: A total of 12 studies including 1782 participants were included in the meta-analysis. Psychosocial interventions in contrast to control groups significantly reduced depression (SMD, - 0.28; 95% CI - 0.52 - - 0.03) at the follow-up assessment and improved quality of life (SMD 0.43, 95% CI 0.23-0.63) after treatment. Psychosocial interventions also had a significant effect on measures of self-efficacy (SMD 2.22, 95% CI 0.24-4.20), and this effect was sustained until long-term follow-up (SMD 0.55, 95% CI 0.02-1.08). Subgroup analyses revealed that improvements in depression were more significant when participants possessed higher education and treatment providers used cognitive behavioral therapy (CBT). CONCLUSIONS: The findings of this study indicate that psychosocial interventions benefit the mental health of MSM living with HIV. It is necessary to conduct more research to explore characteristics that may affect treatment outcomes in the future. TRIAL REGISTRATION: This research was prospectively registered in PROSPERO ( CRD42021262567 ).

Improving the Acceptability of Human Papillomavirus Vaccines Among Men Who Have Sex With Men According to the Associated Factors: A Systematic Review and Meta-analysis.

Objectives: To investigate the acceptability of human papillomavirus (HPV) vaccination among men who have sex with men (MSM) and its associated factors. Methods: We searched studies written in English in PubMed, EMBASE, and Web of Science with no geographical or time restrictions. We evaluated the quality of the included literature. We calculated the pooled acceptability and performed meta-analysis of selected studies, including factors associated with the acceptability among MSM, using Review Manager (v5.3). Results: The acceptability among the 15 studies (n = 8,658) was 50% (95% CI: 0.27-0.72). The meta-analysis of seven articles (n = 4,200) indicated that having a college or higher degree (OR = 1.62, 95% CI: 1.35-1.95), disclosure of sexual orientation to healthcare professionals (HCPs; OR = 2.38, 95% CI: 1.47-3.86), vaccination with at least one dose for hepatitis A or B (OR = 2.10, 95% CI: 1.42-3.10), awareness of HPV (OR = 1.85, 95% CI: 1.21-2.83), knowledge of HPV (SMD = 0.28, 95% CI: 0.16-0.39), perceived susceptibility to HPV infection (SMD = 0.31, 95% CI: 0.11-0.50), and perceived severity of HPV-related disease (SMD = 0.40, 95% CI: 0.28-0.51) can promote acceptance of HPV vaccines. Meanwhile, people who have had unprotected anal sex or have more sex partners tend to have low acceptance of HPV vaccines. Conclusions: HPV education should be actively promoted according to the factors that influence the acceptability of HPV vaccines among the MSM population. HPV education should be especially aimed at people with low academic qualifications and people with risky sexual behaviors, and should emphasize the aspects of susceptibility to and severity of HPV-related disease. More intervention trials should be conducted to increase the credibility of the results.

Identification of the factors associated with post-treatment asymptomatic neurosyphilis in HIV-negative patients with serological non-response syphilis: a retrospective study.

Some syphilis patients do not exhibit an appropriate serological response after treatment despite the absence of any clinical evidence of treatment failure or reinfection. This condition is called "serofast syphilis" or "serological non-response syphilis." This study explored the incidence of asymptomatic neurosyphilis (ANS) and related factors in 324 asymptomatic patients with serological non-response syphilis. We analyzed descriptive statistics stratified by the presence of asymptomatic neurosyphilis for the basic characteristics of samples. Bivariate analysis was conducted to assess correlations between outcomes and potential predictors. Variables significant in the bivariate analysis (p<0.1) were entered into multivariable logistic regression models. All p-values were two-sided with a significance threshold of p<0.05. The results indicated that 89 of 324 patients had ANS (incidence of 27.5%), and the greatest risk factors were a < fourfold decrease in serum rapid plasma reagin (RPR) titers after treatment and current serum RPR titers >1:32. Our findings suggest that ANS is common among syphilis patients, and patients with a fourfold decrease in serum RPR titers after treatment and current serum RPR titers >1:32 are more likely to develop ANS.

Syphilitic infection impairs immunity by inducing both apoptosis and pyroptosis of CD4+ and CD8+ T lymphocytes.

Syphilis is an important health problem worldwide; however, few studies have probed the impact of syphilitic infection on T cell turnover. The mechanisms behind the frequency of T cell subset changes and the associations between these subsets during syphilitic infection remain unclear. Herein, we used a cell-staining method and flow cytometry to explore changes in T cell subpopulations and potential contribution of apoptosis and pyroptosis that triggered therein. We investigated caspase-1-mediated pyroptosis and caspase-3-mediated apoptosis of CD4+ and CD8+ T cells, the major effector lymphocytes with pivotal roles in the pathogenesis of infectious diseases. We found that the levels of caspase-1 and caspase-3 increased in both the circulation and intracellularly in CD4+ and CD8+ T cells. Caspase-1 showed a continual increase from early latent stage infection through to phase 2 disease, whereas caspase-3 increased through to phase 1 disease but declined during phase 2. In addition, serum levels and intracellular expression of caspase-1 and caspase-3 were positively correlated. Overall, this study increases our understanding of how syphilitic infection influences CD4+ and CD8+ T-cell turnover, which may help with designing novel and effective strategies to control syphilis infection and prevent its transmission.

CD4+ T Memory Stem Cells Correlate with Disease Progression in Chronically HIV-1-Infected Patients.

Recently identified T memory stem (Tscm) cells have stem-cell-like properties, including long lifespan, self-renewal capacity, and multipotency to differentiate into other memory T cell types. In the study of simian immunodeficiency virus (SIV) infection, selective depletion of CCR5+CD4+ Tscm cells and the high proliferation rate of these cells are believed to be responsible for the pathogenesis of SIV-infected rhesus macaques. Here, we conducted a cohort study to investigate the influence of chronic human immunodeficiency virus (HIV)-1 infection on CD4+ Tscm cell homeostasis, and the effect of antiretroviral therapy (ART) on CD4+ Tscm cells. Chronic HIV-1 infection resulted in a decrease of the CD4+ Tscm cell proportion in HIV-1 patients. The decreased number of CD4+ Tscm cells in HIV-1 patients correlated positively with that of circulating CD4+ T cells. Further, the depletion of CD4+ Tscm cells was inversely correlated with an increased level of T cell immune activation during chronic HIV-1 infection. Prolonged ART recovered the CD4+ Tscm cells, and the dynamic change of CD4+ Tscm cells was in parallel with CD4+ T cell restoration and a decrease in the level of T cell immune activation. We propose that the abnormity of CD4+ Tscm cells may contribute to the pathogenesis and disease progression in HIV-1-infected individuals.

Hepatitis C therapy with interferon-α and ribavirin reduces the CD4 cell count and the total, 2LTR circular and integrated HIV-1 DNA in HIV/HCV co-infected patients.

This study investigated whether treatment with IFN-α and ribavirin (RBV) reduces 2LTR circular HIV DNA in addition to the total and integrated HIV DNA. Two groups of patients were enrolled. Group 1 comprised HIV/HCV co-infected patients who were treated with highly active antiretroviral therapy (HAART), IFN-α and RBV for 48 weeks. After the 48 weeks of treatment, IFN-α and RBV treatment was discontinued and HAART was continued. Group 2 comprised HIV-infected patients who were treated with HAART. Real-time polymerase chain reaction (RT-PCR) was used to quantify the levels of HIV-1 DNA. We found that compared with Group 2 patients, Group 1 patients exhibited an obvious decrease in the CD4 cell count and the total DNA, 2LTR circular DNA, and integrated HIV DNA after 48 weeks of treatment. After the discontinuation of IFN-α and RBV treatment in Group 1 patients, the levels of HIV DNA recovered. Therefore, we concluded that treatment with IFN-α and ribavirin (RBV) reduces 2LTR circular HIV DNA.