Prevalence and Risk Factors of Low Bone Mineral Density in HIV/AIDS Patients: A Chinese Cross-Sectional Study.

INTRODUCTION: Our study aimed to investigate the prevalence and risk factors of low bone mineral density (BMD) among HIV/AIDS patients in China. METHODS: We performed a cross-sectional analysis of HIV-infected patients from October 2017 to August 2020. Demographic information, clinical data, and serum parameters were obtained. Univariable and multiple logistic regression analyses were performed. RESULTS: A total of 1143 patients were included. In the ART-naive group, low BMD was diagnosed in 19.2% (117/608), including osteoporosis in 1.0% (6/608) and osteopenia in 18.3% (111/608). In the ART group, low BMD was diagnosed in 32.2% (231/717), including osteoporosis in 2.4% (17/717) and osteopenia in 29.8% (214/717). Using multivariate analysis, we identified age older than 50 years, body mass index < 18.5 kg/m2, and treatment based on tenofovir disoproxil fumarate as independent risk factors for low BMD. Low high-density lipoprotein cholesterol was a protective factor for low BMD. Among low BMD participants, the most common number of low BMD sites for a patient to have was 4 (33.6%, 117/348). CONCLUSION: We confirmed a high prevalence of low BMD and osteoporosis in HIV/AIDS patients, and we identified age older than 50 years, low body mass index, and a treatment based on tenofovir disoproxil fumarate as risk factors for low BMD. Low high-density lipoprotein cholesterol had a protective effect against low BMD. Among low BMD patients, patients most commonly had 4 sites with low BMD, which has been associated with fracture risk. In addition, bone changes to L1 can present before low BMD diagnosis and may be a potentially useful indicator that low BMD is developing.

Longitudinal analysis of new-onset non-AIDS-defining diseases among people living with HIV: A real-world observational study.

OBJECTIVES: We aimed to analyze the incidence rates of new-onset diabetes, hypertriglyceridemia, hypercholesterolemia, liver injury, and renal injury during antiretroviral therapy (ART) among people living with HIV (PLWH) and determine the associated risk factors. METHODS: This study included PLWH enrolled from Beijing Ditan Hospital from November 11, 2004, to December 29, 2018. The incidence rates of new-onset diabetes, hypertriglyceridemia, hypercholesterolemia, liver injury, and renal injury were calculated and stratified based on ART regimen, CD4 count, and HIV-RNA. Risk factors were determined using Cox regression analysis. RESULTS: Overall, 6747 participants were included. Moreover, 4.5%, 43.3%, 25.4%, 11.2%, and 6.2% of patients developed new-onset diabetes, hypertriglyceridemia, hypercholesterolemia, liver injury, and renal injury, respectively, with incidence rates of 1.7, 26.9, 10.2, 3.9, and 5.5 per 100 person-years, respectively. Longitudinally, the incidence rates and percentages of these outcomes were highest in the first year of ART. The percentage of dyslipidemia was significantly higher in protease inhibitor (PI)-based regimen than in non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. However, the percentage of liver injury was significantly higher in NNRTI-based regimen than in PI-based regimen. In multivariate Cox regression analysis, low CD4 count (<200 cells/µL, adjusted hazard ratio [aHR] = 1.34, 95% confidence interval [CI] 1.15-1.57) and high HIV-RNA (>105 copies/mL, aHR = 1.26, 95% CI 1.08-1.48) were risk factors for hypertriglyceridemia. CONCLUSIONS: Clinical outcomes, including new-onset diabetes, dyslipidemia, and liver and renal injuries, are common in PLWH. Regular glucose, lipid, liver, and renal function monitoring is required during ART, especially in high-risk patients.

Two-step fitness selection for intra-host variations in SARS-CoV-2.

Spontaneous mutations introduce uncertainty into coronavirus disease 2019 (COVID-19) control procedures and vaccine development. Here, we perform a spatiotemporal analysis on intra-host single-nucleotide variants (iSNVs) in 402 clinical samples from 170 affected individuals, which reveals an increase in genetic diversity over time after symptom onset in individuals. Nonsynonymous mutations are overrepresented in the pool of iSNVs but underrepresented at the single-nucleotide polymorphism (SNP) level, suggesting a two-step fitness selection process: a large number of nonsynonymous substitutions are generated in the host (positive selection), and these substitutions tend to be unfixed as SNPs in the population (negative selection). Dynamic iSNV changes in subpopulations with different gender, age, illness severity, and viral shedding time displayed a varied fitness selection process among populations. Our study highlights that iSNVs provide a mutational pool shaping the rapid global evolution of the virus.

Altered T-Cell Subsets are Associated with Dysregulated Cytokine Secretion of CD4+ T Cells During HIV Infection.

BACKGROUND: CD4+ T cells play a critical role in the regulation of immunopathogenesis in HIV infection. Previous studies have shown contradictory results of the CD4+ T-cell responses in people living with HIV (PLHIV). METHODS: A cross-sectional study was performed on 40 healthy controls, 134 ART-naïve PLHIV, and 34 individuals who experienced 3-year ART with low baseline CD4 count from 4 August 2016 to 23 January 2019. We determined the frequencies of CD4+ T-cell subsets and described the cytokine secretion pattern of total and subsets of CD4+ T cells in these individuals. RESULTS: We found that CD4+ T cells in PLHIV displayed enhanced secretion of pro-inflammation cytokines and polyfunctionality due to HIV disease progression (r = -0.282, P = 0.0035 for IFN-γ; r = -0.412, P = 0.0002 for TNF-α; r = -0.243, P < 0.0001 for GM-CSF; r = -0.252, P = 0.0093 for IFN-γ+ TNF-α+ cells). However, the altered T-cell subsets, as presented by the loss of naïve cells and expansion of memory/effector population in PLHIV, were associated with discordant results in total and subsets of CD4+ T cells. As major cytokine-producing T subsets, effector/memory CD4 subsets showed impaired cytokine production (P < 0.05). We further demonstrated that 3-year ART treatment could improve CD4 counts by increasing the pool of naïve T cells but could not restore cytokine secretion in CD4+ T-cell subsets (P < 0.05). CONCLUSION: These data identified the impaired capacity of cytokine secretion in CD4+ T-cell subsets due to HIV disease progression, and the altered T-cell subsets were associated with pseudo-elevation of cytokine production in total CD4+ T cells. This study collectively suggested the importance of therapies that can preserve and/or enhance the function of CD4+ T cells in strategies of HIV remission.

COVID-19 reinfection in the presence of neutralizing antibodies.

After a short recovery period, COVID-19 reinfections could occur in convalescent patients, even those with measurable levels of neutralizing antibodies. Effective vaccinations and protective public health measures are recommended for the convalescent COVID-19 patients.

Early and consecutive RT-PCR tests with both oropharyngeal swabs and sputum could improve testing yield for patients with COVID-19: An observation cohort study in China.

OBJECTIVE: The real-time polymerase chain reaction (RT-PCR) test is recommended for the diagnosis of COVID-19 and provides a powerful tool to identify new infections and facilitate contact tracing. In fact, as the prevalence of COVID-19 decreases, this RT-PCR testing remains as the main preventive measure to avoid rebound. However, inconsistent results can lead to misdiagnoses in the clinic. These inconsistencies are due to the variability in (1) the collection times of biological samples post infection, and (2) sampling procedures. METHODS: We applied the Kaplan-Meier method and multivariate logistic regression on RT-PCR results from 258 confirmed patients with COVID-19 to evaluate the factors associated with negative conversion. We also estimated the proportion (%) of negative conversion among patients who had tested twice or more, and compared the proportions arising from oropharyngeal swabs, sputum, and combined double testing, respectively. MAIN RESULTS: The proportion of negative conversion was 6.7% on day 4, 16.4% on day 7, 41.0% at 2 weeks, and 61.0% at 3 weeks post-admission. We also found that 34.1% and 60.3% of subjects had at least one negative RT-PCR result on days 7 and 14 after the onset of symptoms, respectively. The proportion of negative conversions following sputum testing was higher than that from oropharyngeal swabs in the early stages but this declined after the onset of symptoms. CONCLUSION: In the absence of effective treatments or vaccines, efficient testing strategies are critical if we are to control the COVID-19 epidemic. According to this study, early, consecutive and combined double testing, will be the key to identify infected patients, particularly for asymptomatic and mild symptomatic cases. These strategies will minimize misdiagnosis and the ineffective isolation of infected patients.

Phylogenomic tracing of asymptomatic transmission in a COVID-19 outbreak.

SARS-CoV-2 has caused over 100 million deaths and continues to spread rapidly around the world. Asymptomatic transmission of SARS-CoV-2 is the Achilles' heel of COVID-19 public health control measures. Phylogenomic data on SARS-CoV-2 could provide more direct information about asymptomatic transmission. In this study, using a novel MINERVA sequencing technology, we traced asymptomatic transmission of COVID-19 patients in Beijing, China. One hundred and seventy-eight close contacts were quarantined, and 14 COVID-19 patients were laboratory confirmed by RT-PCR. We provide direct phylogenomic evidence of asymptomatic transmission by constructing the median joining network in the cluster. These data could help us to determine whether the current symptom-based screening should cover asymptomatic persons.

Specific Redistribution of Severe Acute Respiratory Syndrome Coronavirus 2 Variants in the Respiratory System and Intestinal Tract.

Intrahost analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic sequences identified 2 viral haplotypes comprised of 3 genetically linked mutations from the respiratory and intestinal tracts of a patient with coronavirus disease 2019. Spatiotemporal data suggest that this patient initially had dual infection of 2 SARS-CoV-2 variants, which subsequently redistributed into the 2 systems.

The clinical characteristics and outcome of cryptococcal meningitis with AIDS in a tertiary hospital in China: an observational cohort study.

BACKGROUND: Despite the profound impact of antiretroviral therapy in the control of AIDS mortality, central nervous system opportunistic infections remains a significant burden in AIDS patients. This retrospective study aims to elucidate the clinical characteristics, outcome and risk factors of cryptococcal meningitis (CM) poor prognosis in AIDS patients from a tertiary hospital in China. METHODS: Clinical data from 128 patients admitted in Beijing Ditan Hospital, Capital Medical University from November 2008 to November 2017 was collected. The cohort was stratified based on treatment outcome (effective 79%, and ineffective 21%), and Multivariate Logistic regression analysis used to identify risk factors of poor disease prognosis. RESULTS: Age, incidence of cerebral infarction, the proportion of consciousness disorder, and fasting plasma glucose was higher in the ineffective treatment group than the effective treatment group. The duration of treatment in the induction period of the ineffective group was significantly shorter than that of the effective group. Multivariate Logistic regression analysis indicated that the occurrence of cerebral hernia and consciousness disorder were risk factors for the prognosis of AIDS patients with CM infection, while the duration of treatment in the induction period was a indicative of a better prognosis in AIDS with CM infection complications. Finally, shunt decompression therapy correlated with a better disease outcome. CONCLUSIONS: This retrospective study exposes the main risk factors associated with worse disease prognosis in AIDS patients with CM infection complications.

Specific dynamic variations in the peripheral blood lymphocyte subsets in COVID-19 and severe influenza A patients: a retrospective observational study.

BACKGROUND: Both COVID-19 and influenza A contribute to increased mortality among the elderly and those with existing comorbidities. Changes in the underlying immune mechanisms determine patient prognosis. This study aimed to analyze the role of lymphocyte subsets in the immunopathogenesisof COVID-19 and severe influenza A, and examined the clinical significance of their alterations in the prognosis and recovery duration. METHODS: By retrospectively reviewing of patients in four groups (healthy controls, severe influenza A, non-severe COVID-19 and severe COVID-19) who were admitted to Ditan hospital between 2018 to 2020, we performed flow cytometric analysis and compared the absolute counts of leukocytes, lymphocytes, and lymphocyte subsets of the patients at different time points (weeks 1-4). RESULTS: We reviewed the patients' data of 94 healthy blood donors, 80 Non-severe-COVID-19, 19 Severe-COVID-19 and 37 severe influenza A. We found total lymphocytes (0.81 × 109/L vs 1.74 × 109/L, P = 0.001; 0.87 × 109/L vs 1.74 × 109/L, P < 0.0001, respectively) and lymphocyte subsets (T cells, CD4+ and CD8+ T cell subsets) of severe COVID-19 and severe influenza A patients to be significantly lower than those of healthy donors at early infection stages. Further, significant dynamic variations were observed at different time points (weeks 1-4). CONCLUSIONS: Our study suggests the plausible role of lymphocyte subsets in disease progression, which in turn affects prognosis and recovery duration in patients with severe COVID-19 and influenza A.

CD70 contributes to age-associated T cell defects and overwhelming inflammatory responses.

Aging is associated with immune dysregulation, especially T cell disorders, which result in increased susceptibility to various diseases. Previous studies have shown that loss of co-stimulatory receptors or accumulation of co-inhibitory molecules play important roles in T cell aging. In the present study, CD70, which was generally regarded as a costimulatory molecule, was found to be upregulated on CD4+ and CD8+ T cells of elderly individuals. Aged CD70+ T cells displayed a phenotype of over-activation, and expressed enhanced levels of numerous inhibitory receptors including PD-1, 2B4 and LAG-3. CD70+ T cells from elderly individuals exhibited increased susceptibility to apoptosis and high levels of inflammatory cytokines. Importantly, the functional dysregulation of CD70+ T cells associated with aging was reversed by blocking CD70. Collectively, this study demonstrated CD70 as a prominent regulator involved in immunosenescence, which led to defects and overwhelming inflammatory responses of T cells during aging. These findings provide a strong rationale for targeting CD70 to prevent dysregulation related to immunosenescence.

T-cell Immunoglobulin and ITIM Domain Contributes to CD8+ T-cell Immunosenescence.

Aging is associated with immune dysfunction, especially T-cell defects, which result in increased susceptibility to various diseases. Previous studies showed that T cells from aged mice express multiple inhibitory receptors, providing evidence of the relationship between T-cell exhaustion and T-cell senescence. In this study, we showed that T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), a novel co-inhibitory receptor, was upregulated in CD8+ T cells of elderly adults. Aged TIGIT+ CD8+ T cells expressed high levels of other inhibitory receptors including PD-1 and exhibited features of exhaustion such as downregulation of the key costimulatory receptor CD28, representative intrinsic transcriptional regulation, low production of cytokines, and high susceptibility to apoptosis. Importantly, their functional defects associated with aging were reversed by TIGIT knockdown. CD226 downregulation on aged TIGIT+ CD8+ T cells is likely involved in TIGIT-mediated negative immune suppression. Collectively, our findings indicated that TIGIT acts as a critical immune regulator during aging, providing a strong rationale for targeting TIGIT to improve dysfunction related to immune system aging.