How can we establish animal models of HIV-associated lymphoma?

Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV-associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Meta-analysis of minimally invasive arthroscopy with sodium hyaluronate for wound healing of knee osteoarthritis treatment in the elderly.

Knee osteoarthritis (KOA) is not merely a medical condition-it is a prevalent and incapacitating ailment that significantly affects the quality of life for millions worldwide, especially as they age. The incidence of KOA increases year by year with increasing age. This study evaluated the therapeutic efficacy of combining arthroscopy with sodium hyaluronate (SH) in the treatment of wound healing of knee osteoarthritis (KOA) in elderly patients, with a focus on wound healing and overall joint function restoration. Randomized controlled trials (RCTs) evaluating the combination of arthroscopy and SH in geriatric KOA patients were identified through a systematic search of the scientific literature utilizing multiple databases and predefined search criteria. Ultimately, twelve investigations were included in the meta-analysis. Using Stata 15.1 software, data extraction and analysis were conducted using both fixed- and random-effects models, and a sensitivity analysis was conducted to assure the validity of the findings. Compared with arthroscopy alone, the combination of arthroscopy and SH significantly improved the efficiency rate, pain management (as measured by the Visual Analogue Scale), knee function (as measured by the Lysholm Knee Scoring Scale) and decreased levels of the pro-inflammatory cytokines IL-1 and IL-6. The meta-analysis revealed minimal heterogeneity between studies, and the sensitivity analysis validated the results' reliability. The incorporation of SH into arthroscopic procedures for elderly patients with KOA provides significant therapeutic benefits, including improved wound healing, reduced inflammation and enhanced joint function overall. These results support the use of this combined approach in the management of KOA in the elderly population and emphasize the need for additional research to optimize treatment protocols and comprehend long-term outcomes.

Cellular and molecular insights into incomplete immune recovery in HIV/AIDS patients.

Highly active antiretroviral therapy (ART) can effectively inhibit virus replication and restore immune function in most people living with human immunodeficiency virus (HIV). However, an important proportion of patients fail to achieve a satisfactory increase in CD4+ T cell counts. This state is called incomplete immune reconstitution or immunological nonresponse (INR). Patients with INR have an increased risk of clinical progression and higher rates of mortality. Despite widespread attention to INR, the precise mechanisms remain unclear. In this review, we will discuss the alterations in the quantity and quality of CD4+ T as well as multiple immunocytes, changes in soluble molecules and cytokines, and their relationship with INR, aimed to provide cellular and molecular insights into incomplete immune reconstitution.

Roles of circular RNAs in osteogenic differentiation of bone marrow mesenchymal stem cells (Review).

Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts, chondrocytes, adipocytes and even myoblasts, and are therefore defined as pluripotent cells. BMSCs have become extremely important seed cells in gene therapy, tissue engineering, cell replacement therapy and regenerative medicine due to their potential in multilineage differentiation, self­renewal, immune regulation and other fields. Circular RNAs (circRNAs) are a class of non­coding RNAs that are widely present in eukaryotic cells. Unlike standard linear RNAs, circRNAs form covalently closed continuous loops with no 5' or 3' polarity. circRNAs are abundantly expressed in cells and tissues, and are highly conserved and relatively stable during evolution. Numerous studies have shown that circRNAs play an important role in the osteogenic differentiation of BMSCs. Further studies on the role of circRNAs in the osteogenic differentiation of BMSCs can provide a new theoretical and experimental basis for bone tissue engineering and clinical treatment.

A retrospective study of distribution of HIV associated malignancies among inpatients from 2007 to 2020 in China.

HIV-associated malignancies are responsible for morbidity and mortality increasingly in the era of potent antiretroviral therapy. This study aimed to investigate the distribution of HIV-associated malignancies among inpatients, the immunodeficiency and the effect of antiretroviral therapy (ART) on spectrum of HIV-associated malignancies. A total of 438 cases were enrolled from 2007 to 2020 in Beijing Ditan Hospital. Demographic, clinical and laboratory data, managements, and outcomes were collected and analyzed retrospectively. Of 438 cases, 433 were assigned to non-AIDS-defining cancers (NADCs) (n = 200, 45.7%) and AIDS-defining cancers (ADCs) (n = 233, 53.2%), 5 (1.1%) with lymphoma were not specified further. No significant change was observed in the proportion of NADCs and ADCs as time goes on. Of NADCs, lung cancer (n = 38, 19%) was the most common type, followed by thyroid cancer (n = 17, 8.5%). Patients with ADCs had lower CD4 counts(104.5/µL vs. 314/µL), less suppression of HIVRNA(OR 0.23, 95%CI 0.16-0.35) compared to those with NADCs. ART did not affect spectrum of NADCs, but affect that of ADCs (between patients with detectable and undetectable HIVRNA). ADCs remain frequent in China, and NADCs play an important role in morbidity and mortality of HIV positive population.

Estimation of renal function by three CKD-EPI equations in Chinese HIV/AIDS patients: A STROBE-compliant article.

ABSTRACT: Assessing renal function accurately is important for human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) patients. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recommended three equations to calculate estimated glomerular filtration rate (eGFR). There is evidence that eGFR based on the combination of serum creatinine and cystatin C is the most accurate of the three equations. But there is limited data on the comparison of three CKD-EPI equations in Chinese HIV/AIDS patients. The aim of our study was to compare the three CKD-EPI equations in Chinese HIV/AIDS population and assess renal function.Cross-sectional, single center, prospective study.One hundred seventy two Chinese adult HIV/AIDS patients were enrolled, including 145 (84.3%) males and 27 (15.7%) females. Mean age was 40(±12) years old. Overall mean eGFR based on serum creatinine, cystatin C and the combination of the 2 markers was 112.6(±19.0) mL/min/1.73 m2, 92.0(±24.2)mL/min/1.73 m2, and 101.7(±21.8)mL/min/1.73 m2, respectively (P = .000). The eGFR calculated by serum creatinine alone is higher than eGFR calculated by combination of serum creatinine and cystatin C, and eGFR calculated by cystatin C individual is lower than eGFR calculated by combination of the 2 markers.Of the 3 CKD-EPI equations, the CKD-EPIscr-cys equation may have the most accuracy in evaluating renal function in Chinese HIV/AIDS patients while the CKD-EPIscr equation may overestimate renal function and the CKD-EPIcys equation may underestimate renal function.

Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized, controlled, phase 3, non-inferiority TALENT study.

BACKGROUND: Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs. METHODS: We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%. RESULTS: At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group. CONCLUSIONS: The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx.

First Case of Coronavirus Disease 2019 in Childhood Leukemia in China.

We report the first case of coronavirus disease 2019 (COVID-19) comorbid with leukemia in a patient hospitalized in Beijing, China. The patient showed a prolonged manifestation of symptoms and a protracted diagnosis period of COVID-19. It is necessary to extend isolation time, increase the number of nucleic acid detections and conduct early symptomatic treatment for children with both COVID-19 and additional health problems.

Comparison of early and delayed removal of dressing following primary closure of clean and contaminated surgical wounds: A systematic review and meta-analysis of randomized controlled trials.

The usefulness of dressing a surgical wound beyond the first 24-48 h of surgery is currently a controversial issue. The aim of this meta-analysis was to compare the early and delayed removal of dressing following primary closure in the management of clean and contaminated surgical wounds. Systematic searches were conducted in various databases including Medline, Cochrane Controlled Register of Trials (CENTRAL), Scopus, and Embase from January, 1964 until October, 2019. We used the Cochrane risk of bias tool to assess the quality of published trials. We carried out a meta-analysis with random-effects model and reported pooled risk ratios (RR) with 95% confidence intervals (CIs). In total, we analysed 10 studies with 1,708 participants. All the studies were randomized controlled trials, while the majority of studies had unclear or high bias risks. Early dressing removal was favoured with respect to surgical site infection (pooled RR=0.89; 95% CI: 0.61 to 1.29), patient's perception on safety (pooled RR=0.60; 95% CI: 0.48 to 0.76) and comfort (pooled RR=0.95; 95% CI: 0.74 to 1.22), while the remaining outcomes favoured delayed dressing removal. However, none of the factors had statistically significant difference between two interventions except the patient's perception on safety. To summarize, delayed removal of dressing is not superior to early removal following primary closure of clean or clean-contaminated surgical wounds.

The stage-specific impairment of granulopoiesis in people living with HIV/AIDS (PLWHA) with neutropenia.

Neutropenia and impaired functions were common manifestation in antiretroviral therapy (ART) in both naïve and experienced PLWHA. Granulopoiesis can be divided into two phases: lineage determination and committed granulopoiesis. However, stage-specific impairment of granulopoiesis in PLWHA with neutropenia remains unclear. A total of 48 ART-naïve and 49 ART-experienced PLWHA from 2016 to 2018 were recruited and divided into non-, mild-, and moderate-to-severe-neutropenia groups according to their neutrophil counts. The bone marrow aspirates and peripheral blood were collected and analyzed by multicolor flow cytometry for granulocyte subsets, hematopoietic stem/progenitor cells (HSPC), apoptosis, and emigration and retention of different subsets. Compared with healthy donors, the percentages of circulating segmented neutrophils were significantly decreased along with an increase of immature neutrophils in both groups. ART-naïve patients with moderate to severe neutropenia exhibited decreased proportion and accelerated apoptosis of relative mature segmented neutrophils. In contrast, ART-experienced patients with neutropenia displayed decreased proportion of granulocyte macrophage progenitors, indicating a defect at a stage of lineage determination. Meanwhile, ART-experienced patients with neutropenia also the expression of CXCR4 segmented neutrophils, suggesting an increased retention of segmented neutrophils inn the bone marrow. ART-naïve patients with neutropenia is caused by increased apoptosis of relatively differentiated neutrophils at committed granulopoiesis, whereas impaired lineage determination and enhanced retention of segmented neutrophils contribute to in ART-experienced patients.

Interventions to improve the HIV continuum of care in China.

PURPOSE OF REVIEW: To describe HIV epidemic and interventions for improving HIV continuum of care in China. RECENT FINDINGS: The reported HIV epidemic has been continuously increasing, partially due to the expansion of active HIV testing campaign. Public health intervention programs have been effective in containing HIV spread among former plasma donors and people who inject drugs (PWID), but more infections occur among heterosexual men and women and young men who have sex with men. Of 1.25 million Chinese people are living with HIV, one-third do not know their status. About two-thirds of diagnosed individuals have used antiretroviral therapy (ART) and two-thirds of those on ART have achieved viral suppression, but some risk groups such as PWID have lower rates. The national free ART program has reduced adult and pediatric mortality and reduced heterosexual transmission. China faces great challenges to reduce HIV sexual transmission, improve the HIV continuum of care, and close the gaps to the UNAIDS Three "90" Targets.

The influence of age-associated comorbidities on responses to combination antiretroviral therapy in older people living with HIV.

INTRODUCTION: Multiple comorbidities among HIV-positive individuals may increase the potential for polypharmacy causing drug-to-drug interactions and older individuals with comorbidities, particularly those with cognitive impairment, may have difficulty in adhering to complex medications. However, the effects of age-associated comorbidities on the treatment outcomes of combination antiretroviral therapy (cART) are not well known. In this study, we investigated the effects of age-associated comorbidities on therapeutic outcomes of cART in HIV-positive adults in Asian countries. METHODS: Patients enrolled in the TREAT Asia HIV Observational Database cohort and on cART for more than six months were analysed. Comorbidities included hypertension, diabetes, dyslipidaemia and impaired renal function. Treatment outcomes of patients ≥50 years of age with comorbidities were compared with those <50 years and those ≥50 years without comorbidities. We analysed 5411 patients with virological failure and 5621 with immunologic failure. Our failure outcomes were defined to be in-line with the World Health Organization 2016 guidelines. Cox regression analysis was used to analyse time to first virological and immunological failure. RESULTS: The incidence of virologic failure was 7.72/100 person-years. Virological failure was less likely in patients with better adherence and higher CD4 count at cART initiation. Those acquiring HIV through intravenous drug use were more likely to have virological failure compared to those infected through heterosexual contact. On univariate analysis, patients aged <50 years without comorbidities were more likely to experience virological failure than those aged ≥50 years with comorbidities (hazard ratio 1.75, 95% confidence interval (CI) 1.31 to 2.33, p < 0.001). However, the multivariate model showed that age-related comorbidities were not significant factors for virological failure (hazard ratio 1.31, 95% CI 0.98 to 1.74, p = 0.07). There were 391 immunological failures, with an incidence of 2.75/100 person-years. On multivariate analysis, those aged <50 years without comorbidities (p = 0.025) and age <50 years with comorbidities (p = 0.001) were less likely to develop immunological failure compared to those aged ≥50 years with comorbidities. CONCLUSIONS: In our Asia regional cohort, age-associated comorbidities did not affect virologic outcomes of cART. Among those with comorbidities, patients <50 years old showed a better CD4 response.

Brief Report: Malignancies in Adults Living With HIV in Asia.

BACKGROUND: Hematological malignancies have continued to be highly prevalent among people living with HIV (PLHIV). This study assessed the occurrence of, risk factors for, and outcomes of hematological and nonhematological malignancies in PLHIV in Asia. METHODS: Incidence of malignancy after cohort enrollment was evaluated. Factors associated with development of hematological and nonhematological malignancy were analyzed using competing risk regression and survival time using Kaplan-Meier. RESULTS: Of 7455 patients, 107 patients (1%) developed a malignancy: 34 (0.5%) hematological [0.08 per 100 person-years (/100PY)] and 73 (1%) nonhematological (0.17/100PY). Of the hematological malignancies, non-Hodgkin lymphoma was predominant (n = 26, 76%): immunoblastic (n = 6, 18%), Burkitt (n = 5, 15%), diffuse large B-cell (n = 5, 15%), and unspecified (n = 10, 30%). Others include central nervous system lymphoma (n = 7, 21%) and myelodysplastic syndrome (n = 1, 3%). Nonhematological malignancies were mostly Kaposi sarcoma (n = 12, 16%) and cervical cancer (n = 10, 14%). Risk factors for hematological malignancy included age >50 vs. ≤30 years [subhazard ratio (SHR) = 6.48, 95% confidence interval (CI): 1.79 to 23.43] and being from a high-income vs. a lower-middle-income country (SHR = 3.97, 95% CI: 1.45 to 10.84). Risk was reduced with CD4 351-500 cells/µL (SHR = 0.20, 95% CI: 0.05 to 0.74) and CD4 >500 cells/µL (SHR = 0.14, 95% CI: 0.04 to 0.78), compared to CD4 ≤200 cells/µL. Similar risk factors were seen for nonhematological malignancy, with prior AIDS diagnosis showing a weak association. Patients diagnosed with a hematological malignancy had shorter survival time compared to patients diagnosed with a nonhematological malignancy. CONCLUSIONS: Nonhematological malignancies were common but non-Hodgkin lymphoma was more predominant in our cohort. PLHIV from high-income countries were more likely to be diagnosed, indicating a potential underdiagnosis of cancer in low-income settings.

Changes in renal function with long-term exposure to antiretroviral therapy in HIV-infected adults in Asia.

PURPOSE: Renal disease is common among people living with human immunodeficiency virus (HIV). However, there is limited information on the incidence and risk factors associated with renal dysfunction among this population in Asia. METHODS: We used data from the TREAT Asia HIV Observational Database. Patients were included if they started antiretroviral therapy during or after 2003, had a serum creatinine measurement at antiretroviral therapy initiation (baseline), and had at least 2 follow-up creatinine measurements taken ≥3 months apart. Patients with a baseline estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 were excluded. Chronic kidney disease was defined as 2 consecutive eGFR values ≤60 mL/min/1.73 m2 taken ≥3 months apart. Generalized estimating equations were used to identify factors associated with eGFR change. Competing risk regression adjusted for study site, age and sex, and cumulative incidence plots were used to evaluate factors associated with chronic kidney disease (CKD). RESULTS: Of 2547 patients eligible for this analysis, tenofovir was being used by 703 (27.6%) at baseline. Tenofovir use, high baseline eGFR, advanced HIV disease stage, and low nadir CD4 were associated with a decrease in eGFR during follow-up. Chronic kidney disease occurred at a rate of 3.4 per 1000 patient/years. Factors associated with CKD were tenofovir use, old age, low baseline eGFR, low nadir CD4, and protease inhibitor use. CONCLUSIONS: There is an urgent need to enhance renal monitoring and management capacity among at-risk groups in Asia and improve access to less nephrotoxic antiretrovirals.

miRNA-185 serves as a prognostic factor and suppresses migration and invasion through Wnt1 in colon cancer.

Colon cancer is one of the deadliest cancers worldwide; abnormal microRNA expression is common during colon cancer development. The aim of the present study was to elucidate the role played by miR-185 in this context. We used quantitative real-time PCR (qRT-PCR) to measure miR-185 expression levels in colon cancer cell lines. The effects of miR-185 on colon cancer cell proliferation and invasion were assessed using the MTT, colony-forming, wound-healing, and transwell assays. A luciferase activity assay was used to confirm the target of miR-185. Our data showed that miR-185 was significantly down-regulated in colon cancer cells and colonic cancer tissues compared with NCM460 normal colonic epithelial cells and adjacent normal tissues. A functional analysis revealed that ectopic expression of miR-185 significantly inhibited colon cancer cell proliferation, colony formation, migration, and invasion. In addition, western blot, qRT-PCR, and luciferase assays confirmed in colon cancer cells that Wnt1 was a downstream target of miR-185, in turn suppressing ß-catenin-mediated signaling. In conclusion, we found that miR-185 inhibits colon cancer cell proliferation and invasion by targeting Wnt1, and that it serves as a tumor suppressor, indicating that the modulation of miR-185 levels may potentially be therapeutic in colon cancer patients.

The Human Immunodeficiency Virus Care Continuum in China: 1985-2015.

Background: Human immunodeficiency virus (HIV) care continuum attrition is a major global public health challenge. Few studies have examined this problem in resource-limited settings. We aimed to assess cumulative, current, and historical achievement along China's HIV continuum of care. Methods: A nationwide, serial cross-sectional study of all individuals with HIV infection diagnosed in China between 1 January 1985 and 31 December 2015 was conducted using data from China's HIV/AIDS information systems. Biennial estimates of the number of persons living with HIV were also used. We defined 7 steps in HIV care continuum as infected (estimated), diagnosed, linked, retained, enrolled, receiving antiretroviral therapy (ART), and virally suppressed. Cumulative, 30-year performance, and biennial performance during the most recent 10 years were examined. Results: A total of 573529 persons diagnosed with HIV infection were included. Cumulatively, 94% were linked, 88% were retained, 73% were enrolled, 67% were receiving ART, and 44% were suppressed. Greatest attrition was observed for adolescents, minorities, and those who reported injecting drug use as their route of infection. Improvement was observed from 2005 to 2015. As of the end of 2015, 68% among those infected were diagnosed, 67% among diagnosed were receiving ART, and 65% among those receiving ART were virally suppressed. After adjusting for those without viral load testing, the proportion suppressed increased to 89%. Conclusions: Despite dramatic improvements, China faces serious challenges in achieving the Joint United Nations Programme on HIV/AIDS 90-90-90 targets, because of substantial attrition along its continuum of HIV care.

Regional Challenges in the Prevention of Human Immunodeficiency Virus Drug Resistance.

In diverse global regions with significant human immunodeficiency virus (HIV) burden, programmatic, cultural, and provider-, patient-, and virus-related factors may result in HIV drug resistance, with global implications. This article reviews such common and unique challenges in Russia, Latin America and the Caribbean, China, and India, to suggest potential solutions.

Distinct Mitochondrial Disturbance in CD4+T and CD8+T Cells From HIV-Infected Patients.

BACKGROUND: Mitochondrial dysfunction has frequently been found in HIV-infected patients regardless of whether they received antiretroviral therapy (ART). Accumulating evidence suggests that HIV-infected patients exhibit marked changes in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, adenosine triphosphate generation, mitochondrial mass (MM), mitochondrial DNA, etc. However, mitochondrial toxicity in CD4T and CD8T cells caused by different levels of HIV progression and ART is poorly understood. METHODS: Blood samples were obtained from 97 ART-naïve HIV-infected patients with different CD4T cell counts, 97 nucleoside-reverse transcriptase inhibitors-exposed HIV-infected patients, and 25 HIV-negative subjects. MMP, ROS, and MM in CD4T and CD8T cells were assessed by flow cytometry. RESULTS: In healthy subjects, the levels of MMP and MM in CD4T cells were higher than those in CD8T cells. HIV infection led to an increase in MM in CD4T and CD8T cells, but mainly influenced MMP in CD8T cells and ROS accumulation in CD4T cells. MM in CD4T and CD8T cells gradually increased after the loss of CD4T cells. Although the dynamic changes in MMP in CD4T cells were different from those in CD8T cells during highly active ART, MM in both CD4T and CD8T cells was significantly decreased after 2 years of therapy, but increased again after 3 years. CONCLUSIONS: HIV infection and antiretroviral therapy both led to mitochondrial disturbances in CD4T cells and CD8T cells; however, the abnormal changes in mitochondrial parameters in CD4+T cells were different from those in CD8T cells caused by HIV infection and antiretroviral therapy.