Evaluation of Stability, Inactivation, and Disinfection Effectiveness of Mpox Virus.

BACKGROUND: Mpox virus (MPXV) infections have increased in many countries since May 2022, increasing demand for diagnostic tests and research on the virus. To ensure personnel safety, appropriate and reliable measures are needed to disinfect and inactivate infectious samples; Methods: We evaluated the stability of infectious MPXV cultures stored at different temperatures and through freeze-thaw cycles. Heat physical treatment (56 °C, 70 °C, 95 °C), chemical treatment (beta-propiolactone (BPL)) and two commercialized disinfectants (Micro-Chem Plus (MCP) and ethanol) were tested against infectious MPXV cultures; Results: The results indicated that MPXV stability increases with lower temperatures. The MPXV titer was stable within three freeze-thaw cycles and only decreased by 1.04 log10 (lg) 50% cell culture infective dose (CCID50) per milliliter (12.44%) after twelve cycles. MPXV could be effectively inactivated at 56 °C for 40 min, 70 °C for 10 min, and 95 °C for 5 min. For BPL inactivation, a 1:1000 volume ratio (BPL:virus) could also effectively inactivate MPXV. A total of 2% or 5% MCP and 75% ethanol treated with MPXV for at least 1 min could reduce >4.25 lg; Conclusions: MPXV shows high stability to temperature and freeze-thaw. Heat and BPL treatments are effective for the inactivation of MPXV, while MCP and ethanol are effective for disinfection, which could help laboratory staff operate the MPXV under safer conditions and improve operational protocols.

Rapid Initiation of Antiretroviral Therapy with Coformulated Bictegravir, Emtricitabine, Tenofovir Alafenamide Versus Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in HIV-positive Men Who Have Sex with Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with HIV-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400-mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among HIV-positive men who have sex with men (MSM). METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV(400-mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/ml) at 48 weeks per FDA Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression; and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (p < 0.001), respectively, discontinued treatment due to adverse effects, death, or loss to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (p = 0.020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < 0.001). CONCLUSION: BIC/FTC/TAF was more efficacious and safer than EFV(400-mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

The immunogenicity of Alum+CpG adjuvant SARS-CoV-2 inactivated vaccine in mice.

The ongoing evolution and emergence of SARS-CoV-2 variants have raised concerns regarding the efficacy of existing vaccines and therapeutic agents. This study aimed to investigate the immunogenicity of an aluminum hydroxide (Alum) and CpG adjuvanted inactivated vaccine (IAV) candidate against SARS-CoV-2 in mice. A comparison was made between the immune response of mice vaccinated with the Alum+CpG adjuvant IAV and those vaccinated with the Alum adjuvant IAV. Mice immunized with Alum+CpG adjuvant IAV demonstrated high antibody titers and a durable humoral immune response, as well as a Th1-type cellular immune response. Notably, compared to Alum alone vaccine, the Alum+CpG adjuvant IAV induced significantly higher proportions of GC B cells in the splenocytes of immunized mice. Importantly, the changes in inflammatory cytokine levels in the sera of mice vaccinated with the Alum+CpG adjuvant IAV followed a similar trend to that of the Alum adjuvant IAV, which had been proven safe in clinical trials. Overall, our results demonstrate that Alum+CpG adjuvant has the potential to serve as a novel adjuvant, thereby providing valuable insights into the development of vaccine formulations.

Long-term effects of particulate matter on incident cardiovascular diseases in middle-aged and elder adults: The CHARLS cohort study.

BACKGROUND: Although there is evidence of long-term effects of particulate matter (PM) on cardiovascular diseases (CVD), researches about long-term effects of PM1 on CVD are limited. We aimed to examine the long-term effects and magnitude of PM, especially PM1, on incident CVD in China. METHODS: We included 6016 participants aged ≥ 45 years without CVD at baseline in 2011 from the China Health and Retirement Longitudinal Study. Personal PM (PM1, PM2.5, and PM10) concentrations were estimated using geocoded residential address. Generalized linear mixed models and SHapley Additive exPlanation were utilized to calculate the impacts and contributions of PM on CVD. Sensitivity analyses were used to check the robustness. RESULTS: After a follow up of 4-year, 481 (7.99 %) participants developed CVD. Per 10 µg/m3 uptick in 1-year average concentrations of PM1, PM2.5 and PM10 was associated with a 1.20 [95 % confidence interval (CI): 1.05-1.37], 1.13 (95 % CI: 1.11-1.15), and 1.10 (95 % CI: 1.06-1.13) fold risk of incident CVD, respectively. The 2-year average concentrations of PM1, PM2.5 and PM10 were associated with incident CVD, corresponding to a 1.03 (95 % CI: 0.96-1.10), 1.11 (95 % CI: 1.02-1.21), and 1.09 (95 % CI: 1.03-1.15) fold risk, respectively. The SHapley Additive exPlanation values of PM1, PM2.5, and PM10 were 0.170, 0.153, and 0.053, respectively, corresponding to the first, second, and fifth among all air pollutants. Effects of PM1, PM2.5 and PM10 on CVD remained statistically significant in two-pollutant models. The elderly, males, smokers and alcohol drinkers tended to have slightly higher effects, while the differences were not statistically significant (all P-values > 0.05) between subgroups. CONCLUSION: Long-term exposure to PM1, PM2.5, and PM10 was associated with an increased incidence of CVD. The smaller the particle size, the more important it was for incident CVD indicating that emphasis should be placed on small size of PM.

Role of Proviral HIV-1 DNA Genotyping for People Living with HIV (PLWH) Who Had Low-Level Viremia While Receiving Antiretroviral Therapy.

Objective: To analyze the antiretroviral resistance in people living with HIV (PLWH) who developed low-level viremia (LLV) during antiretroviral therapy (ART) via sequencing of their HIV-1 proviral DNA and RNA and comparisons of their proviral DNA genotyping data with their past and synchronous RNA genotyping data. Patients and Methods: PLWH with LLV while receiving ART for 6 months or longer from January 2020 to September 2021 were included. HIV-1 proviral DNA and RNA were extracted from white-blood cells and concentrated plasma by ultracentrifugation, respectively, and HIV-1 pol gene fragments were amplified and sequenced. The concordance in the detection of resistance-associated mutations (RAMs) were examined between proviral DNA vs past RNA genotyping and proviral DNA vs synchronous RNA genotyping. Results: Of the 150 PLWH with LLV, 117 proviral DNA pol sequences detected in 105 PLWH were successfully amplified and RAMs were present in 27.6% and the rate of RAMs conferring low-level or greater resistance to antiretrovirals examined was 17.1%. Fifty-six and 57 PLWH had results of past and synchronous RNA genotyping, respectively, for comparisons with those of proviral DNA genotyping; and the concordance rates were 76.8% and 75.4%, respectively. However, proviral DNA genotyping lost than gained partial information on antiretroviral resistance compared with past or synchronous RNA genotyping. Conclusion: We found that the concordance between proviral DNA and past and synchronous RNA genotyping was moderate. Proviral DNA genotyping lost than gained more information on antiretroviral resistance compared with past or synchronous RNA genotyping. To optimize ART in PLWH with LLV, antiretroviral resistance profile should be interpreted in combination with proviral DNA and RNA genotyping and a comprehensive review of previous treatment history.

Association Between Long-Term Exposure to Fine Particulate Matter Constituents and Progression of Cerebral Blood Flow Velocity in Beijing: Modifying Effect of Greenness.

Few studies have explored the effects of fine particulate matter (PM2.5) and its constituents on the progression of cerebral blood flow velocity (BFV) and the potential modifying role of greenness. In this study, we investigated the association of PM2.5 and its constituents, including sulfate (SO4 2-), nitrate (NO3 -), ammonium (NH4 +), organic matter (OM), and black carbon (BC), with the progression of BFV in the middle cerebral artery. Participants from the Beijing Health Management Cohort who underwent at least two transcranial Doppler sonography examinations during 2015-2020 were recruited. BFV change and BFV change rate were used to define the progression of cerebral BFV. Linear mixed effects models were employed to analyze the data, and the weighted quantile sum regression assessed the contribution of PM2.5 constituents. Additionally, greenness was examined as a modifier. Among the examined constituents, OM exhibited the strongest association with BFV progression. An interquartile range increase in PM2.5 and OM exposure concentrations was associated with a decrease of -16.519 cm/s (95% CI: -17.837, -15.201) and -15.403 cm/s (95% CI: -16.681, -14.126) in BFV change, and -10.369 cm/s/year (95% CI: -11.387, -9.352) and -9.615 cm/s/year (95% CI: -10.599, -8.632) in BFV change rate, respectively. Furthermore, stronger associations between PM2.5 and BFV progression were observed in individuals working in areas with lower greenness, those aged under 45 years, and females. In conclusion, reducing PM2.5 levels in the air, particularly the OM constituent, and enhancing greenness could potentially contribute to the protection of cerebrovascular health.

Causal Associations of Air Pollution With Cardiovascular Disease and Respiratory Diseases Among Elder Diabetic Patients.

Extensive researches have linked air pollutants with cardiovascular disease (CVD) and respiratory diseases (RD), however, there is limited evidence on causal effects of air pollutants on morbidity of CVD or RD with comorbidities, particularly diabetes mellitus in elder patients. We included hospital admissions for CVD or RD among elder (≥65 years) diabetic patients between 2014 and 2019 in Beijing. A time-stratified case-crossover design based on negative-control exposure was used to assess causal associations of short-term exposure to air pollutants with CVD and RD among diabetic patients with the maximum lag of 7 days. A random forest regression model was used to calculate the contribution magnitude of air pollutants. A total of 493,046 hospital admissions were recorded. Per 10 µg/m3 uptick in PM1, PM2.5, PM10, SO2, NO2, O3, and 1 mg/m3 in CO was associated with 0.29 (0.05, 0.53), 0.14 (0.02, 0.26), 0.06 (0.00, 0.12), 0.36 (0.01, 0.70), 0.21 (0.02, 0.40), -0.08 (-0.25, 0.09), and 4.59 (0.56, 8.61) causal effect estimator for admission of CVD among diabetic patients, corresponding to 0.12 (0.05, 0.18), 0.09 (0.05, 0.13), 0.05, 0.23 (0.06, 0.41), 0.10 (0.02, 0.19), -0.04 (-0.06, -0.01), and 3.91(1.81, 6.01) causal effect estimator for RD among diabetic patients. The effect of gaseous pollutants was higher than particulate pollutants in random forest model. Short-term exposure to air pollution was causally associated with increased admission of CVD and RD among elder diabetic patients. Gaseous pollutants had a greater contribution to CVD and RD among elder diabetic patients.

The assessment on cross immunity with smallpox virus and antiviral drug sensitivity of the isolated mpox virus strain WIBP-MPXV-001 in China.

Since May 2022, human mpox cases have increased unexpectedly in non-endemic countries. The first imported case of human mpox in Hong Kong was reported in September 2022. Here we report the isolation and identification of MPXV from the vesicle swabs of this patient. In this research, the vesicle swabs were inoculated in Vero and Vero E6 cells. In addition to observing cytopathic effects (CPEs) in Vero or Vero E6 cells, the isolated virus was identified as mpox virus (MPXV) using quantitative Real-Time PCR (RT-PCR), transmission electron microscopy, and high-throughput sequencing. The experiment also assessed the cross-protective efficacy of sera from the smallpox vaccinated population and preliminarily assessed the inhibitory effect of anti-smallpox virus drugs against MPXV. CPEs can be observed on Vero E6 cells at 24 h and Vero cells at 48 h. The virus particles could be observed by transmission electron microscope, showing typical orthopoxvirus morphology. In addition, F3L and ATI genes which from MPXV A39R, B2R, HA genes which from orthopoxvirus were confirmed by conventional PCR and Sanger sequencing. The next generation sequencing (NGS) suggests that the MPXV strain belongs to B.1 branch of the West African linage, and has a high identity with the sequence of the 2022 ongoing outbreak. PRNT50 results showed that 26.7% of sera from individuals born before 1981 who had been immunized with smallpox were positive, but no MPXV-neutralizing antibodies were found in sera from individuals born later. All four anti-smallpox virus drugs evaluated demonstrated inhibition of mpox virus.

Genetic characteristics of a novel HIV-1 recombinant lineage (CRF103_01B) and its prevalence in northern China.

During the routine surveillance of HIV-1 pretreatment drug resistance in Beijing, five men who have sex with men (MSM) and a woman were observed to get infected by newly identified CRF103_01B strain. To elucidate the genetic characteristics, the near full-length genome (NFLG) was obtained. Phylogenetic inference indicated that CRF103_01B NFLG was composed of six mosaic segments. Segments IV and V of CRF103_01B were located among the clusters subtype B and CRF01_AE (group 5), respectively. The CRF103_01B strain was deduced to originate from Beijing MSM population around 2002.3-2006.4 and continued to spread among MSM population at a low level, then to the general population via heterosexual contact in northern China. Molecular epidemiology surveillance of CRF103_01B should be reinforced.

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.

Identification of specific and shared epitopes at the extreme N-terminal VP1 of Coxsackievirus A4, A2 and A5 by monoclonal antibodies.

Hand, foot and mouth disease (HFMD) is caused by a variety of serotypes in species A of the Enterovirus genus, including recently re-emerged Coxsackievirus A2 (CV-A2), CV-A4 and CV-A5. For development of diagnostic reagents, for surveillance, and the development of multivalent vaccines against HFMD, the antigenicity of HFMD-associated enteroviruses warrants investigation. The purified virions of CV-A4 were inoculated into Balb/c mice and hybridomas were obtained secreting monoclonal antibodies (mAbs) directed against CV-A4 and cross-reacting with other closely related species A enteroviruses. The mAbs were characterized by ELISA, Western blotting and in vitro neutralizing assays. The majority of mAbs was non-neutralizing, with only 2% of the mAbs neutralizing CV-A4 specifically. Most of mAbs bound to linear VP1 epitopes of CV-A4. Interestingly, four types of mAbs were obtained which bound specifically to CV-A4 or were broadly to CV-A4/-A2, CV-A4/-A5 and CV-A4/-A2/-A5, respectively. Mapping with overlapping or single-amino-acid mutant peptides revealed that the four types of mAbs all bound to the first 15 amino acids at the N-terminus of the VP1. This region of picornaviruses is functionally important as it is involved in uncoating and releasing of viral RNA into the cytosol. The binding footprints of four type mAbs are composed of conserved and variable residues and are different from each other. The newly discovered broadly cross-reactive mAbs reflect the high homology of CV-A4/ CV-A2/CV-A5. The results also demonstrate that it is possible and beneficial to develop the diagnostic reagents to detect rapidly the main pathogens of enteroviruses associated with HFMD cause by CV-A4/CV-A2/CV-A5.

Long-term effects of PM2.5 components on hypertension: A national analysis in China.

BACKGROUND: Evidence is less about the associations between fine particulate matter (PM2.5) components and hypertension. We aimed to examine the long-term effects of PM2.5 components on prevalence of hypertension, diastolic blood pressure (DBP) and systolic blood pressure (SBP). METHODS: We included participants between March 1, and July 31, 2021, from 13 provinces in China. Geocoded residential address was used for exposure assignment. Mixed-effect regression was used to assess 3-year average concentrations of PM2.5 and its components (black carbon, organic matter, nitrate, ammonium, and sulfate) on prevalence of hypertension, DBP and SBP with covariate-adjusted. SHapley Additive exPlanation was used to compare the contribution of PM2.5 components to hypertension, DBP, and SBP. Sex and age subgroup were also analyzed. RESULTS: We enrolled a total of 113,159 participants aged ≥18 years. Long-term exposure to PM2.5 and its components (black carbon, organic matter, nitrate, ammonium, and sulfate) had associations with prevalence of hypertension, with the Odds Ratios and 95% confidence interval (CI) of 1.06 (95%CI: 1.03-1.09), 1.07 (95%CI: 1.04-1.09), 1.07 (95%CI: 1.04-1.10), 1.05 (95%CI: 1.01-1.08), 1.03 (95%CI: 1.00-1.06), and 1.03 (95%CI: 1.00-1.04), respectively. Effects of that except for black carbon on DBP with per interquartile upticks of concentration were 0.23 (95%CI: 0.11-0.35), 0.17 (95%CI: 0.04-0.29), 0.35 (95%CI: 0.21-0.48), 0.40 (95%CI: 0.28-0.52), and 0.25 (95%CI: 0.13-0.26), respectively. Ammonium was associated with SBP, corresponding to an increase of 0.18 (95%CI: 0.01-0.35). Males had higher risks of DBP (Z = 2.54-6.08, P < 0.001). Older people were substantially more affected by PM2.5 and its components. Nitrate showed the highest contribution to hypertension, DBP and SBP compared with other components. CONCLUSIONS: Long-term exposure to PM2.5 and its components had adverse consequences on prevalence of hypertension, DBP and SBP, especially for males and older people. Nitrate contributed the highest to hypertension, DBP and SBP. Findings may have implications for pollution and hypertension control.

NMDA receptors as therapeutic targets for depression treatment: Evidence from clinical to basic research.

Ketamine, functioning as a channel blocker of the excitatory glutamate-gated N-methyl-d-aspartate (NMDA) receptors, displays compelling fast-acting and sustained antidepressant effects for treatment-resistant depression. Over the past decades, clinical and preclinical studies have implied that the pathology of depression is associated with dysfunction of glutamatergic transmission. In particular, the discovery of antidepressant agents modulating NMDA receptor function has prompted breakthroughs for depression treatment compared with conventional antidepressants targeting the monoaminergic system. In this review, we first summarized the signalling pathway of the ketamine-mediated antidepressant effects, based on the glutamate hypothesis of depression. Second, we reviewed the hypotheses of the synaptic mechanism and network of ketamine antidepressant effects within different brain areas and distinct subcellular localizations, including NMDA receptor antagonism on GABAergic interneurons, extrasynaptic and synaptic NMDA receptor-mediated antagonism, and ketamine blocking bursting activities in the lateral habenula. Third, we reviewed the different roles of NMDA receptor subunits in ketamine-mediated cognitive and psychiatric behaviours in genetically-manipulated rodent models. Finally, we summarized the structural basis of NMDA receptor channel blockers and discussed NMDA receptor modulators that have been reported to exert potential antidepressant effects in animal models or in clinical trials. Integrating the cutting-edge technologies of cryo-EM and artificial intelligence-based drug design (AIDD), we expect that the next generation of first-in-class rapid antidepressants targeting NMDA receptors would be an emerging direction for depression therapeutics. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Causal effect of PM1 on morbidity of cause-specific respiratory diseases based on a negative control exposure.

BACKGROUND: Extensive studies have linked PM2.5 and PM10 with respiratory diseases (RD). However, few is known about causal association between PM1 and morbidity of RD. We aimed to assess the causal effects of PM1 on cause-specific RD. METHODS: Hospital admission data were obtained for RD during 2014 and 2019 in Beijing, China. Negative control exposure and extreme gradient boosting with SHapley Additive exPlanation was used to explore the causality and contribution between PM1 and RD. Stratified analysis by gender, age, and season was conducted. RESULTS: A total of 1,183,591 admissions for RD were recorded. Per interquartile range (28 µg/m3) uptick in concentration of PM1 corresponded to a 3.08% [95% confidence interval (CI): 1.66%-4.52%] increment in morbidity of total RD. And that was 4.47% (95% CI: 2.46%-6.52%) and 0.15% (95% CI: 1.44%-1.78%), for COPD and asthma, respectively. Significantly positive causal associations were observed for PM1 with total RD and COPD. Females and the elderly had higher effects on total RD, COPD, and asthma only in the warm months (Z = 3.03, P = 0.002; Z = 4.01, P < 0.001; Z = 3.92, P < 0.001; Z = 2.11, P = 0.035; Z = 2.44, P = 0.015). Contribution of PM1 ranked first, second and second for total RD, COPD, and asthma among air pollutants. CONCLUSION: PM1 was causally associated with increased morbidity of total RD and COPD, but not causally associated with asthma. Females and the elderly were more vulnerable to PM1-associated effects on RD.

Exploring the biological function of immune cell-related genes in human immunodeficiency virus (HIV)-1 infection based on weighted gene co-expression network analysis (WGCNA).

BACKGROUND: Acquired immunodeficiency syndrome (AIDS) is a chronic infectious disease characterized by consistent immune dysfunction. The objective of this study is to determine whether immune cell-related genes can be used as biomarkers for the occurrence of AIDS and potential molecular mechanisms. METHODS: A weighted gene co-expression network analysis was performed using the GSE6740 dataset from the Gene Expression Synthesis Database to identify the Hub gene, which contained microarray data from HIV-1 positive (HIV-1+) and HIV-1 negative (HIV-1-) individuals. The HIV-1+-related differentially expressed genes were then identified using the limma package. Subsequently, the characteristic immune cell-related genes were identified as diagnostic biomarkers for HIV-1+ using the random forest model (RF), support vector machine model, and generalized linear model. RESULTS: MEdarkgreen exhibited the strongest correlation with HIV clinical features of any of these modules. As the best model for diagnosing HIV-1±, RF was used to select four critical immune cell-related genes, namely, ARRB1, DPEP2, LTBP3, and RGCC, and a nomogram model was created to predict the occurrence of HIV-1 infection based on four key immune cell-related genes. Diagnostic genes were shown to be engaged in immune-related pathways, suggesting that immunological molecules, immune cells, and immune pathways all have a role in HIV-1 infection. The CTD database was explored for prospective medications or molecular compounds that might be utilized to treat HIV-1+ patients. = Moreover, in HIV-1+ individuals, the ceRNA network revealed that ARRB1, DPEP2, LTBP3, and RGCC could be regulated by lncRNAs through the corresponding miRNAs. Ultimately, RT-PCR results from clinical blood samples demonstrated that the four diagnostic genes were significantly downregulated in HIV-1+ patients. CONCLUSION: We screened four immune cell-related genes, ARRB1, DPEP2, LTBP3, and RGCC, which may be considered as the diagnostic markers for HIV-1/AIDS. Our findings reveal that immune related genes and pathways involved in HIV-1 pathogenesis were regulated on both genetic and epigenetic levels by constructing a ceRNA network associated with lncRNA.

Insights into the HIV-1 Latent Reservoir and Strategies to Cure HIV-1 Infection.

Since the first discovery of human immunodeficiency virus 1 (HIV-1) in 1983, the targeted treatment, antiretroviral therapy (ART), has effectively limited the detected plasma viremia below a very low level and the technique has been improved rapidly. However, due to the persistence of the latent reservoir of replication-competent HIV-1 in patients treated with ART, a sudden withdrawal of the drug inevitably results in HIV viral rebound and HIV progression. Therefore, more understanding of the HIV-1 latent reservoir (LR) is the priority before developing a cure that thoroughly eliminates the reservoir. HIV-1 spreads through both the release of cell-free particles and by cell-to-cell transmission. Mounting evidence indicates that cell-to-cell transmission is more efficient than cell-free transmission of particles and likely influences the pathogenesis of HIV-1 infection. This mode of viral transmission also influences the generation and maintenance of the latent reservoir, which represents the main obstacle for curing the infection. In this review, the definition, establishment, and maintenance of the HIV-1 LR, along with the state-of-the-art quantitative approaches that directly quantify HIV-1 intact proviruses, are elucidated. Strategies to cure HIV infection are highlighted. This review will renew hope for a better and more thorough cure of HIV infection for mankind and encourage more clinical trials to achieve ART-free HIV remission.

Benefits and Risks of Rapid Initiation of Antiretroviral Therapy: A Systematic Review and Meta-Analysis.

Objectives: To compare the benefits and risks between Rapid ART and standard/delayed treatment for HIV. Methods: Databases of PubMed, Cochrane Library, Embase and Web of science were searched from the inception to 28 October 2021. Two investigators independently screened studies related to Rapid ART, extracted data, and evaluated the literature quality. The risk of bias was assessed by Cochrane Collaboration Risk of Bias Tool and the statistical software Stata15.0 was used for meta-analysis. Results: Ten eligible studies were included in this meta-analysis, the results showed Rapid ART was superior to standard/delayed treatment in continuing care for at least 8 months (RR = 1.13, 95%CI: 1.03∼1.25, Z = 2.44, p = 0.015), and severe bacterial infection (RR = 0.42, 95%CI: 0.25∼0.70, Z = 3.33, p = 0.001). At 12 months following treatment, there was no statistically significant difference in viral load <100 copies/mL (RR = 1.05, 95%CI: 0.80∼1.39, Z = 0.35, p = 0.726), mortality (RR = 0.77, 95%CI: 0.47∼1.24, Z = 1.09, p = 0.277), or the incidence of adverse events (RR = 0.52, 95%CI: 0.16∼1.76, Z = 1.05, p = 0.294) compared with standard/delayed treatment. Conclusion: In comparison to standard/delayed treatment, rapid ART can reduce the incidence of TB and severe bacterial infections in HIV patients. Our findings suggest that rapid ART should be utilized when clinical conditions and the patient's physical state allow. Systematic Review Registration: [https://inplasy.com/?s=202210004], identifier [INPLASY202210004].

Efficacy of Coxsackievirus A2 vaccine candidates correlating to humoral immunity in mice challenged with a mouse-adapted strain.

BACKGROUND: In recent years, Coxsackievirus A2 (CV-A2) has become one of the main serotypes of enterovirus species A associated with hand, foot and mouth disease (HFMD) in China. It has also caused HFMD epidemics in many countries all over the world. Currently, there are no effective, preventive vaccines against it. METHODS: A CV-A2 strain was isolated in RD cells and then adapted to grow in Vero cells. This is in compliance with guidelines for cell substrates allowed for human vaccines by the Chinese regulatory authority. Groups of newborn Kunming mice were inoculated on day 3 and day 9 using two formulations of candidate vaccines, empty particles and full particles. They were then challenged on day 14 at a lethal dose with a mouse-adapted strain. RESULTS: The mice in the control group all died within 14 days post-challenge whereas most of the mice in the candidate vaccine groups survived. It was found that the titers of neutralizing antibodies was dose-dependent in sera of immunized mice. The results also showed that the vaccine candidates stimulated a strong humoral immune response and protected the mice from disease and death. The virus loads in tissues or organs were significantly reduced and pathological changes were either weak or not observed in the immunized groups compared with those in Al(OH)3 control group. Preliminary mapping of the nucleotide and amino acid residues potentially related to cell tropism of the vaccine strain and virulence of the challenge strain was performed. CONCLUSION: The results showed that the RD cell-isolated and Vero cell-adapted CV-A2 strain is a promising vaccine candidate. This active immunization-challenge mouse model mimics the vaccination and then exposure to wildtype viruses, compared with passive immunization-challenge model, and is invaluable for efficacy evaluation in studies on multivalent vaccines containing CV-A2 against HFMD.

Association between ambient air pollution and hospital admissions, length of hospital stay and hospital cost for patients with cardiovascular diseases and comorbid diabetes mellitus: Base on 1,969,755 cases in Beijing, China, 2014-2019.

BACKGROUND: Evidence on the effects of the air pollutants on the hospital admissions, hospital cost and length of stay (LOS) among patients with comorbidities remains limited in China, particularly for patients with cardiovascular diseases and comorbid diabetes mellitus (CVD-DM). METHODS: We collected daily data on CVD-DM patients from 242 hospitals in Beijing between 2014 and 2019. Generalized additive model was employed to quantify the associations between admissions, LOS, and hospital cost for CVD-DM patients and air pollutants. We further evaluated the attributable risk posed by air pollutants to CVD-DM patients, using both Chinese and WHO air quality guidelines as reference. RESULTS: Per 10 ug/m3 increase of particles with an aerodynamic diameter < 2.5 µm (PM2.5), particles with an aerodynamic diameter < 10 µm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbonic oxide (CO) and ozone (O3) corresponded to a 0.64% (95% CI: 0.57 to 0.71), 0.52% (95% CI: 0.46 to 0.57), 0.93% (95% CI: 0.67 to 1.20), 0.98% (95% CI: 0.81 to 1.16), 1.66% (95% CI: 1.18 to 2.14) and 0.53% (95% CI: 0.45 to 0.61) increment for CVD-DM patients' admissions. Among the six pollutants, particulate pollutants (PM2.5 and PM10) in most lag days exhibited adverse effects on LOS and hospital cost. For every 10 ug/m3 increase in PM2.5 and PM10, the absolute increase with LOS will increase 62.08 days (95% CI: 28.93 to 95.23) and 51.77 days (95% CI:22.88 to 80.66), respectively. The absolute increase with hospital cost will increase 105.04 Chinese Yuan (CNY) (95% CI: 49.27 to 160.81) and 81.76 CNY (95% CI: 42.01 to 121.51) in PM2.5 and PM10, respectively. Given WHO 2021 air quality guideline as the reference, PM2.5 had the maximum attributable fraction of 3.34% (95% CI: 2.94% to 3.75%), corresponding to an avoidable of 65,845 (95% CI: 57,953 to 73,812) patients with CVD-DM. CONCLUSION: PM2.5 and PM10 are positively associated with hospital admissions, hospital cost and LOS for patients with CVD-DM. Policy changes to reduce air pollutants exposure may reduce CVD-DM admissions and substantial savings in health care spending and LOS.