Association between chronic viral infection-related hospitalization and risk of cardiovascular disease: A population-based cohort study.

Chronic viral infection induces immunosenescence and systemic low-grade inflammation, leading to worsened long-term outcomes. We sought to explore the short- and long-term effects of chronic viral infection on cardiovascular disease (CVD). Based on UK Biobank data, exposed group was identified as individuals who had chronic virus infection-related hospitalization (IRH). Unexposed group was randomly selected, matched by 5-year age interval, sex, and Charlson comorbidity index at a ratio up to 1:10. Restricted cubic splines were used to model time-varying effects of IRH in nonproportional Cox models. A cut-off value of 5 years was recorded and used in piecewise Cox proportional hazards models as we estimated short- and long-term effects of IRH on CVD. A total of 2826 exposed participants and 28 212 matched unexposed participants were included. Chronic viral IRH was associated with increased risk of CVD (0-5 years: hazard ratio, 1.57 [95% confidence interval: 1.32, 1.87] and 5+ years: 1.31 [1.06, 1.61]). Elevated risk of stroke was only observed within the initial 5-year follow-up (0-5 years: 1.91 [1.30, 2.81]). The short- and long-term associations were observed in herpes or hepatitis virus IRH with risk of CVD (all p < 0.05). Subgroup analysis revealed long-term association between chronic viral IRH and CVD among female (5+ years: 1.68 [1.27, 2.22]) but not among male. The association between chronic viral infection and elevated CVD risk appeared to be stronger among individuals who did not take cholesterol-lowering medication, antithrombotic medication, or certain antihypertensive medications (all p for interaction < 0.05). The risk of CVD event remained persistently higher within and over 5 years following chronic viral IRH, especially in individuals infected with herpes and hepatitis virus.

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.

Effectiveness and cost-effectiveness of human papillomavirus vaccination strategies among men who have sex with men in China: a modeling study.

Introduction: The health and economic benefits of human papillomavirus (HPV) vaccination targeted at men who have sex with men (MSM) in developing settings have been rarely assessed. This study aimed to evaluate the effectiveness and cost-effectiveness of different HPV vaccination strategies among MSM in China. Methods: A Markov model was developed to simulate HPV transmission dynamics among a total of 30.73 million MSM in China. The corresponding natural history included 6 states: susceptible, infected with low-risk subtypes, high-risk subtypes, anogenital warts and anal cancer, and deaths from anal cancer. MSM were divided into three age groups with cut-off points of 27 and 45 years. Alternative vaccination strategies were built by allocating bivalent, quadrivalent, nine-valent, or no vaccine to each of the groups. We generated the prevented infections and deaths by vaccination compared with baseline (no vaccination) and calculated incremental cost-effectiveness ratios (ICERs) to determine the optimal strategy. Results: The model showed that in 10 years, at baseline, the existing cases of anogenital warts would reach 5,464,225 (IQR, 4,685,708-6,174,175); that of anal cancer would reach 1,922.95 (1,716.56-2,119.93), resulting in 940.55 (732.27-1,141.87) deaths. Under 50% vaccination coverage among one age group, the prevented cases of anogenital warts were maximized with quadrivalent vaccines allocated to MSM aged 27-45 years; that of anal cancer were maximized when offering nine-valent vaccines to the same group. Under 50% vaccination coverage among all groups, the lowest ICER (34,098.09 USD/QALY, 31,146.54-37,062.88) was reached when only quadrivalent vaccines were provided. Based on this strategy, when the annual vaccination rate increased by 30%, the ICER (33,521.75 USD/QALY, 31,040.73-36,013.92) would fall below three times China's per capita GDP. When the vaccine price decreased by 60%, the ICER was reduced to 7,344.44 USD/QALY (4,392.89-10,309.23), indicating good cost-effectiveness taking China's per capita GDP as a threshold. Conclusions: HPV vaccination can effectively reduce the prevalence and mortality of related diseases among MSM in China, especially quadrivalent vaccines for anogenital warts and nine-valent vaccines for anal cancer. MSM aged 27-45 years were the optimal group for vaccination. Annual vaccination and appropriate adjustment of vaccine price are necessary to further improve the cost-effectiveness.

Barriers and Facilitators to, and Experience of, Voluntary Medical Male Circumcision Among Men Who Have Sex with Men in China: A Mixed-Methods Study.

Voluntary medical male circumcision (VMMC) may be incorporated into HIV prevention services for men who have sex with men (MSM). We conducted a mixed-methods study to elucidate barriers and facilitators to, and experience of, VMMC among MSM. Participants were MSM aged 18 years and older who were enrolled in an ongoing multicenter randomized controlled trial (RCT) to evaluate VMMC to prevent HIV among MSM in China. RCT participants completed a questionnaire before and after VMMC to assess perceptions of and complications after the procedure. A subset of RCT participants were selected for in-depth interviews. Interviewees answered open-ended questions about barriers and facilitators to and experience of undergoing VMMC. Six-step thematic analysis incorporating inductive and deductive approaches was used to interpret interview responses. A total of 457 MSM completed the pre-VMMC survey, 115 circumcised MSM completed post-VMMC surveys, and 30 MSM completed an interview. Main barriers to VMMC uptake were concerns about pain, length of wound healing, cost, lack of knowledge about or misconceptions of VMMC, and stigma related to surgery. Facilitators to VMMC could be categorized as internal factors (foreskin) and external factors (motivation and follow-up care). Interestingly, the VMMC experiences of others could be transformed from a barrier into a facilitator to VMMC in some circumstances. After VMMC participants transitioned from a negative state of pain, remorse, difficulty sleeping, and discomfort to a positive state of symptom alleviation and personal hygiene improvement. Optimizing facilitators and addressing barriers may encourage VMMC among MSM. Joint efforts should be made by relevant stakeholders to improve the awareness and uptake of VMMC among MSM.

Voluntary Medical Male Circumcision and Incident HIV Infection Among Men Who Have Sex With Men in China (The CoM Study): Protocol for a Randomized Controlled Trial.

BACKGROUND: Systematic reviews and meta-analyses based on observational studies have shown voluntary medical male circumcision (VMMC) may reduce HIV risk among men who have sex with men (MSM). There is a lack of randomized controlled trial (RCT) data assessing the efficacy of VMMC. OBJECTIVE: The primary objective of this study was to assess the efficacy of VMMC for preventing HIV acquisition among MSM who primarily engage in insertive anal sex. METHODS: A multicenter RCT will be conducted among MSM in 8 cities in China. Eligible participants are men aged 18-49 years who self-report ≥2 male sex partners in the past 6 months, predominantly practice insertive anal sex, and are willing to undergo circumcision. Interested men who satisfy inclusion criteria will be tested for HIV 1 month before enrollment and at enrollment, and only those who are HIV negative will be enrolled. At baseline, all enrolled participants will be asked to report sociodemographic characteristics and sexual behaviors; provide a blood sample for HIV, syphilis, and herpes simplex virus type 2 testing; and provide a penile swab for human papillomavirus testing. Participants will be randomly assigned to the intervention or control group. Those in the intervention group will receive VMMC and undergo a web-based weekly follow-up assessment of postsurgery healing for 6 consecutive weeks. All participants will be tested for HIV at 3-, 6-, 9-, and 12-month follow-ups. All participants will also be asked to report sexual behaviors and undergo repeat herpes simplex virus type 2 and human papillomavirus testing at 6- and 12-month follow-ups. The primary end point is HIV seroconversion. Secondary end points are the safety and satisfaction with VMMC and the changes in sexual behaviors after VMMC. The grouped censored data will be analyzed by intention-to-treat approach. RESULTS: Recruitment for the RCT began in August 2020 and continued through July 2022. Data collection is expected to be completed by July 2023, and full data analysis is going to be completed by September 2023. CONCLUSIONS: This study will be the first RCT to assess the efficacy of VMMC in preventing HIV infection among MSM. Results from this trial will provide preliminary evidence for the potential efficacy of VMMC to reduce incident HIV infection among MSM. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000039436; https://www.chictr.org.cn/showproj.html?proj=63369. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47160.

Excess mortality and associated factors among people living with HIV initiating highly active antiretroviral therapy in Luzhou, China 2006-2020.

BACKGROUND: To estimate crude mortality, excess mortality, and standardized mortality rates (SMR) among people living with HIV (PLHIV) initiating highly active antiretroviral therapy (HAART) in Luzhou, China 2006-2020, and assess associated factors. METHODS: PLHIV initiating HAART in the HIV/AIDS Comprehensive Response Information Management System (CRIMS) in Luzhou, China 2006-2020 were included in the retrospective cohort study. The crude mortality, excess mortality, and SMR were estimated. Multivariable Poisson regression model was used for analyzing risk factors associated with excess mortality rates. RESULTS: The median age among 11,468 PLHIV initiating HAART was 54.5 years (IQR:43.1-65.2). The excess mortality rate decreased from 1.8 deaths/100 person-years (95% confidence interval [CI]:1.4-2.4) in 2006-2011 to 0.8 deaths/100 person-years (95%CI:0.7-0.9) in 2016-2020. SMR decreased from 5.4 deaths/100 person-years (95%CI:4.3-6.8) to 1.7 deaths/100 person-years (95%CI:1.5-1.8). Males had greater excess mortality with the eHR of 1.6 (95%CI:1.2-2.1) than females. PLHIV with CD4 counts ≥ 500 cells/µL had the eHR of 0.3 (95%CI:0.2-0.5) in comparison to those with CD4 counts < 200 cells/µL. PLHIV with WHO clinical stages III/IV had greater excess mortality with the eHR of 1.4 (95%CI:1.1-1.8). PLHIV with time from diagnosis to HAART initiation ≤ 3 months had the eHR of 0.7 (95%CI:0.5-0.9) compared to those with time ≥ 12 months. PLHIV with initial HAART regimens unchanged and viral suppression had the eHR of 1.9 (95%CI:1.4-2.6) and 0.1 (95%CI:0.0-0.1), respectively. CONCLUSIONS: The excess mortality and SMR among PLHIV initiating HAART in Luzhou, China decreased substantially from 2006 to 2020, but the mortality rate among PLHIV was still higher than general population. PLHIV who were male, with baseline CD4 counts less than 200 cells/µL, WHO clinical stages III/IV, time from diagnosis to HAART initiation ≥ 12 months, initial HAART regimens unchanged, and virological failure had a greater risk of excess deaths. Early and efficient HAART would be significant in reducing excess mortality among PLHIV.

Perception of and Vaccine Readiness towards Mpox among Men Who Have Sex with Men Living with HIV in China: A Cross-Sectional Study.

BACKGROUND: Men who have sex with men (MSM) living with HIV make up the majority of cases in the current Mpox outbreak. We aimed to investigate the perception of and vaccine readiness towards Mpox among MSM living with HIV in China. METHODS: This cross-sectional online study was conducted from 10 August to 9 September 2022. Participants responded to survey questions about their socio-demographic information, HIV status, sexual behaviors, knowledge of Mpox, and attitudes towards Mpox vaccines. RESULTS: A total of 577 MSM living with HIV participated in the study. A total of 37.6% expressed concerns about the Mpox epidemic in China, and 56.8% were willing to get the Mpox vaccine. Men who had > four sexual partners in the previous three months (aOR = 1.9 95% CI: 1.2-2.8 Ref: 0), had close contact with > four individuals in a day (3.1, 1.5-6.5 Ref: 0-3), were worried about the Mpox epidemic in China (1.6, 1.1-2.3 Ref: No), and believed that Mpox vaccines are safe (6.6, 2.7-16.4 Ref: No or not sure) and effective (1.9, 1.1-3.3 Ref: No) for people living with HIV were more likely to be willing to get the Mpox vaccine. MSM living with HIV with a high school education or below (0.5, 0.3-0.9 Ref: Postgraduate diploma), and sometimes (0.5, 0.3-0.8 Ref: Often), seldom, or never (0.5, 0.3-0.9 Ref: Often) followed news about Mpox were unwilling to get the Mpox vaccine. CONCLUSION: The ongoing Mpox pandemic has not attracted widespread concerns among MSM living with HIV in China. Having more sexual partners and close contacts, worrying about the Mpox epidemic, and believing in the vaccine's safety and efficacy were predictors of their willingness to get the Mpox vaccine. Efforts should be made to raise awareness of the potential risk of Mpox in this at-risk population. Public health strategies should fully address predictors of vaccination willingness.

Hesitancy to Undergo SARS-CoV-2 Rapid Antigen Testing in China: Nationwide Cross-sectional Study.

BACKGROUND: SARS-CoV-2 rapid antigen testing (RAT) could be a useful supplementary test to diagnose larger numbers of acute asymptomatic infections and alleviate the limitations of polymerase chain reaction testing. However, hesitancy to undergo SARS-CoV-2 RAT may compromise its implementation. OBJECTIVE: We aimed to understand the prevalence and correlates of hesitancy to undergo RAT among adults not infected with SARS-CoV-2 in mainland China. METHODS: A nationwide cross-sectional survey on hesitancy to undergo SARS-CoV-2 RAT was conducted among adults not infected with SARS-CoV-2 in mainland China between April 29, 2022, and May 10, 2022. Participants completed an online questionnaire that covered the following COVID-19-related factors: sociodemographic characteristics, experiences of COVID-19 restrictions and knowledge of COVID-19, and attitude toward COVID-19 and its screening. This study was a secondary analysis of data from the survey. We compared the characteristics of participants by hesitancy to undergo SARS-CoV-2 RAT. Thereafter, logistic regression with a sparse group minimax concave penalty was used to identify correlates of hesitancy to undergo RAT. RESULTS: We recruited 8856 individuals with diverse demographic, socioeconomic, and geographic characteristics in China. Eventually, 5388 participants (valid response rate of 60.84%; 52.32% [2819/5388] women; median age 32 years) were included in the analysis. Among the 5388 participants, 687 (12.75%) expressed hesitancy to undergo RAT and 4701 (87.25%) were willing to undergo RAT. Notably, those who were from the central region (adjusted odds ratio [aOR] 1.815, 95% CI 1.441-2.278) and those who received COVID-19 information from traditional media (aOR 1.544, 95% CI 1.279-1.863) were significantly more likely to report hesitancy to undergo RAT (both P<.001). However, those who were women (aOR 0.720, 95% CI 0.599-0.864), were older (aOR 0.982, 95% CI 0.969-0.995), had postgraduate education (aOR 0.612, 95% CI 0.435-0.858), had children (<6 years old) and elders (>60 years old) in the family (aOR 0.685, 95% CI 0.510-0.911), had better knowledge about COVID-19 (aOR 0.942, 95% CI 0.916-0.970), and had mental health disorders (aOR 0.795, 95% CI 0.646-0.975) were less likely to report hesitancy to undergo RAT. CONCLUSIONS: Hesitancy to undergo SARS-CoV-2 RAT was low among individuals who were not yet infected with SARS-CoV-2. Efforts should be made to improve the awareness and acceptance of RAT among men, younger adults, individuals with a lower education or salary, families without children and elders, and individuals who access COVID-19 information via traditional media. In a reopening world, our study could inform the development of contextualized mass screening strategies in general and the scale-up of RAT in particular, which remains an indispensable option in emergency preparedness.

Awareness and uptake of non-occupational post-exposure prophylaxis (nPEP) among gay, bisexual and other men who have sex with men in China: a cross-sectional study.

Non-occupational post-exposure prophylaxis (nPEP) is recommended to reduce the likelihood of HIV infection after potential exposure. However, little is known about this practice among Chinese gay, bisexual and other men who have sex with men (GBM). GBM were enrolled from both centers for disease prevention and control (CDCs) and community health centers in six cities in China. Multivariable logistics regression was used to assess factors associated with awareness of and willingness to use nPEP. A total of 516 eligible GBM were included, 67.2% of whom were aware of nPEP, 76.0% were willing to use nPEP, and 2.3% had ever used nPEP. GBM who had college or higher education, had disclosed sexual orientation, had increased number of male sex partners in the last 6 months, and had ever tested for HIV were more likely to be aware of nPEP. Willingness to use nPEP was significantly associated with college or higher education, STI history, gay app use, and awareness of nPEP prior to study. Uptake of nPEP is still low among MSM in China. Efforts are needed to improve awareness of and access to nPEP among GBM, especially those at higher risk of HIV infection.

Incidence and mortality of non-AIDS-defining cancers among people living with HIV: A systematic review and meta-analysis.

Background: Non-AIDS-defining cancers (NADCs) are now becoming a rising cause of morbidity among people living with HIV (PLHIV) in the highly active antiretroviral therapy (HAART) era. We conducted a systematic review and meta-analysis to estimate the summary risk of incidence and mortality of a wide range of NADCs among PLHIV compared with the general population. Methods: This systematic review and meta-analysis was registered in the PROSPERO (registration number CRD42020222020). We searched PubMed, EMBASE, Cochrane library, and Web of Science for relevant studies published before Jan 24, 2022. Cohort or registry linkage studies comparing the incidence or mortality of individual NADCs in PLHIV with that in the general population were included. Studies simply reporting outcomes of cancer precursor lesions or combined NADCs were excluded. We calculated pooled standardised incidence (SIRs) and standardised mortality ratios (SMRs) and their 95% confidence intervals (CIs) using random-effects models, and used robust variance estimation to account for non-independence in study-level effect sizes. Findings: We identified 92 publications arising from 46 independent studies including 7 articles out of 7 studies from developing countries. Among the 40 types of NADCs investigated, all of the 20 infection-related NADCs, cancers related with human papillomavirus infection in particular, and half of the 20 non-infection-related NADCs occurred in excess in PLHIV compared with the general population. This risk pattern was consistent in most WHO regions and in both high-income and low-and middle-income countries. The increased SIRs for various NADCs were more evident among PLHIV with advanced immunodeficiency, and was explored by HIV transmission route, and use of HAART. PLHIV had increased mortality for anal cancer (SMR 124·07, 95% CI 27·31-563·72), Hodgkin lymphoma (41·03, 2·91-577·88), liver cancer (8·36, 3·86-18·11), lung cancer (3·95, 1·52-10·26), and skin melanoma (3·95, 1·28-12·2). Interpretation: PLHIV had increased incidence and mortality for a wide spectrum of NADCs. Primary prevention and effective treatment for NADCs in this population is urgently needed. Funding: Natural Science Foundation of China Excellent Young Scientists Fund, Natural Science Foundation of China International/Regional Research Collaboration Project, National Science and Technology Major Project of China, Sanming Project of Medicine in Shenzhen, High Level Project of Medicine in Longhua, Shenzhen, Shenzhen Science and Technology Innovation Commission Basic Research Program, Special Support Plan for High-Level Talents of Guangdong Province, the Guangzhou Basic Research Program on People's Livelihood Science and Technology, the National Natural Science Foundation of China.

Oral Sexual Behavior Among HIV-Infected Men Who Have Sex with Men - China, February 2021.

What is already known about this topic?: Unprotected oral sex carries a risk of the transmission of sexually transmitted infections (STIs), especially if the individual has poor oral health. What is added by this report?: Most human immunodeficiency virus (HIV) infected men who have sex with men (MSM) had never used a condom when giving oral sex (89.30%, 718/804) or receiving oral sex (90.32%, 709/785). Among MSM with detectable viral loads who had ever received oral sex without a condom, 40.00% reported ejaculation in their partner's mouth. What are the implications for public health practice?: Unprotected oral sex is very common among HIV-infected MSM in China. The public health sectors in China should recommend condom use during oral sex among HIV-infected MSM, especially when in-mouth ejaculation is involved.

Stress hormone biosynthesis-based genes and lifestyle moderated the association of noise exposure with blood pressure in a cohort of Chinese tobacco factory workers: A cross-sectional analysis.

When evaluating noise-related cardiovascular risk, noise is generally solely assessed as the major stressor. However, cardiovascular effect of other simultaneous exposure events, such as unhealthy lifestyle and genetic variation, is easily neglected. The aim of this study is to estimate the combined effect of noise and lifestyle on blood pressure alteration, particularly under different genetic background. This study included 536 workers from a tobacco factory in Wuhan, China, who were divided into high exposure group and low exposure group according to noise measurement in their working area. All participants took annual physical examination and questionnaire survey to provide information on individual systolic and diastolic blood pressure (SBP and DBP) and lifestyle (smoking, drinking and physical activity). Single nucleotide polymorphism at genes related to stress hormone production were determined. Moderated moderation models were constructed to investigate the interaction effect of noise exposure and lifestyle factors on blood pressure with regard to different genetic background. We identified an expected trend in association between noise exposure and SBP among active smokers (P = 0.086). The moderated moderation analysis showed significant three-way interaction effect (COMT rs4680 × smoking status × noise exposure levels) on SBP or DBP (both P < 0.05). For COMT rs4680 GA+AA genotype carriers, active smoking significantly moderated the association between noise exposure and SBP or DBP (both P < 0.05). The results indicated that for COMT rs4680 A allele carriers, tobacco and noise exposure contribute collectively to blood pressure alteration, supporting that stress hormone production may play a certain role in the smoke-and-noise-induced cardiovascular effect.

Seasonal exposure to phthalates and inflammatory parameters: A pilot study with repeated measures.

Exposure to phthalates poses potential to damage multiple organs and system in the body. However, limited data are available regarding effects of seasonal exposure levels of phthalates and indicators reflecting inflammatory response. We designed a pilot study with repeated measures. We recruited 106 eligible habitants from Wuhan city, China. They completed questionnaires, physical examinations and provided urine specimens in winter and summer seasons. We found that urinary levels of low-molecular-weight phthalate metabolites were higher in summer than in winter (all P < 0.01). In winter, an interquartile range increase (1.264 µg/L) in 3-day moving average of high-molecular-weight phthalate metabolites corresponded to a 13.634% (95% CI: -22.331, -3.941) decrease in mean platelet volume, 25.879% (95% CI: -37.424, -12.204) for lymphocyte count or 10.862% (95% CI: -18.716, -2.125) for platelet count (P < 0.05 or P < 0.01). However, in summer, an interquartile range increase (1.215 µg/L) in urinary levels of high-molecular-weight phthalate metabolites corresponded to an 8.743% (95% CI: 4.217, 13.467) increase in platelet distribution width value or a 4.597% (95% CI: 2.335, 6.780) for mean platelet volume value at 3-day lag (both P < 0.01). In conclusion, phthalate exposure exhibited the potential for the activation of platelet function, particularly in winter. Seasonal variations of phthalate exposure should be considered when assessing health risk.

Metformin alleviates lead-induced mitochondrial fragmentation via AMPK/Nrf2 activation in SH-SY5Y cells.

As a widely acknowledged environmental pollutant, lead (Pb) exhibits neurological toxicity primarily due to the vulnerability of neural system. It is suggested that Pb could perturb mitochondrial function, triggering the following disturbance of cellular homeostasis. Here, we focused on the role of mitochondrial dynamics in Pb-induced cell damage. Pb exposure enhanced mitochondrial fragmentation and elevated p-Drp1 (s616) level in a reactive oxygen species (ROS) dependent manner, leading to cell death and energy shortage. By applying metformin, an AMP-activated protein kinase (AMPK) activator, these impairments could be alleviated via activation of AMPK, validated by experiments of pharmacological inhibition of AMPK. Further investigation confirmed that nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor managing antioxidative function, and its downstream antioxidant detoxifying enzyme were activated by metformin, resulting in the inhibition of the Pb-caused oxidative stress. Moreover, Nrf2 mediated the protection of metformin against mitochondrial fragmentation induced by Pb exposure, while knockdown of Nrf2 abrogated the protective effect. Finally, the treatment of Mdivi-1, a mitochondrial fission inhibitor, reversed Pb-triggered cell death, revealing that excessive mitochondrial fission is detrimental. To conclude, metformin could ameliorate Pb-induced mitochondrial fragmentation via antioxidative effects originated from AMPK/Nrf2 pathway activation, promoting energy supply and cell survival.

CypD deficiency confers neuroprotection against mitochondrial abnormality caused by lead in SH-SY5Y cell.

Mitochondrial permeability transition (MPT), which is mainly regulated by cyclophilin D (CypD) encoded by ppif gene, is an early event that occurs during mitochondrial stimuli exposure. Lead (Pb) induces MPT and subsequently causes mitochondrial abnormality, followed by events, including oxidative stress and cell death. Here, we generated a ppif-/- SH-SY5Y cell line to determine the role of CypD in Pb-induced mitochondrial abnormality. CypD deficiency significantly blocked mitochondrial permeability transition pore (MPTP) opening and inhibited mitochondrial membrane potential (MMP) collapse, as well as mitochondrial structure damage and fragmentation caused by Pb. Mitochondria fragmentation and MMP collapse, accompanying with Pb-induced downregulation of Glut1 and Glut3 and inactivation of AMPK signaling pathway, could impair the energy supply in wildtype cells. Meanwhile, ppif knockout can alleviate these impairments and maintain the energy supply. In addition, reactive oxygen species accumulation and cell death caused by Pb can also be attenuated by ppif knockout, thereby promoting cell survival. Our study tends to identify CypD as an important contributor to Pb-induced mitochondrial abnormality and provides a potential strategy to inhibit Pb neurotoxicity.