Inflammation as a therapeutic target for osteoarthritis: A literature review of clinical trials.

The burden of osteoarthritis (OA) is rapidly increasing with population aging, but there are still no approved disease-modifying drugs available. Accumulating evidence has shown that OA is a heterogeneous disease with multiple phenotypes, and it is unlikely to respond to one-size-fits-all treatments. Inflammation is recognized as an important phenotype of OA and is associated with worse pain and joint deterioration. Therefore, it is believed that anti-inflammatory treatments may be more effective for OA with an inflammatory phenotype. In this review, we summarized clinical trials that evaluated anti-inflammatory treatments for OA and discussed whether these treatments are more effective in inflammatory OA phenotypes compared to general OA patients.

Bone marrow lesions in osteoarthritis: biomarker or treatment target? A narrative review.

Osteoarthritis (OA) is a leading cause of pain, functional impairment, and disability in older adults. However, there are no effective treatments to delay and reverse OA. Magnetic resonance imaging (MRI) can assess structural abnormalities of OA by directly visualizing damage and inflammatory reactions within the tissues and detecting abnormal signals in the subchondral bone marrow region. While some studies have shown that bone marrow lesions (BMLs) are one of the early signs of the development of OA and predict structural and symptomatic progression of OA, others claimed that BMLs are prevalent in the general population and have no role in the progression of OA. In this narrative review, we screened and summarized studies with different designs that evaluated the association of BMLs with joint symptoms and structural abnormalities of OA. We also discussed whether BMLs may serve as an imaging biomarker and a treatment target for OA based on existing clinical trials.

Association of handgrip strength asymmetry and weakness with cognitive function: a nationally representative cohort study.

OBJECTIVE: To describe the association of handgrip strength asymmetry and weakness with cognitive function among Chinese middle-aged and older adults. STUDY DESIGN: We used data from four waves (2011, 2013, 2015, and 2018) of the China Health and Retirement Longitudinal Study. Handgrip strength was measured at baseline. Handgrip strength asymmetry was defined on the basis of the ratio of handgrip strength of the non-dominant hand to that of the dominant hand (i.e. non-dominant/dominant): a ratio of <0.9 defined as dominant handgrip strength asymmetry and >1.1 as non-dominant handgrip strength asymmetry. Weakness was defined as a handgrip strength of <28 kg for males or <18 kg for females. MAIN OUTCOME MEASURES: Cognitive function with its two core dimensions (episodic memory and mental status) at each wave was assessed and standardized. RESULTS: 9333 participants (48.3 % female, age 58.2 ± 9.0 years) were included. Non-dominant but not dominant handgrip strength asymmetry was significantly associated with poorer cognitive function at baseline (ß = -0.121, -0.092, and -0.132 for mental status, episodic memory, and global cognition, respectively). In longitudinal analyses over 2 years, dominant handgrip strength asymmetry significantly slowed cognitive decline (ß = -0.078 and -0.069 for mental status and global cognition, respectively), and non-dominant handgrip strength asymmetry accelerated cognitive decline (ß = 0.053 and 0.043 for episodic memory and global cognition, respectively). Weakness was associated with poorer cognitive function at baseline and cognitive decline over 2, 4, and 7 years (all P < 0.05). CONCLUSIONS: In middle-aged and older adults, non-dominant handgrip strength asymmetry and weakness were associated with poorer cognitive function and predicted accelerated cognitive decline. Dominant handgrip strength asymmetry may be beneficial for maintaining cognitive function.

Krill Oil for Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Knee osteoarthritis is disabling, with few effective treatments. Preliminary evidence suggested that krill oil supplementation improved knee pain, but effects on knee osteoarthritis remain unclear. Objective: To evaluate efficacy of krill oil supplementation, compared with placebo, on knee pain in people with knee osteoarthritis who have significant knee pain and effusion-synovitis. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled clinical trial in 5 Australian cities. Participants with clinical knee osteoarthritis, significant knee pain, and effusion-synovitis on magnetic resonance imaging were enrolled from December 2016 to June 2019; final follow-up occurred on February 7, 2020. Interventions: Participants were randomized to 2 g/d of krill oil (n = 130) or matching placebo (n = 132) for 24 weeks. Main Outcomes and Measures: The primary outcome was change in knee pain as assessed by visual analog scale (range, 0-100; 0 indicating least pain; minimum clinically important improvement = 15) over 24 weeks. Results: Of 262 participants randomized (mean age, 61.6 [SD, 9.6] years; 53% women), 222 (85%) completed the trial. Krill oil did not improve knee pain compared with placebo (mean change in VAS score, -19.9 [krill oil] vs -20.2 [placebo]; between-group mean difference, -0.3; 95% CI, -6.9 to 6.4) over 24 weeks. One or more adverse events was reported by 51% in the krill oil group (67/130) and by 54% in the placebo group (71/132). The most common adverse events were musculoskeletal and connective tissue disorders, which occurred 32 times in the krill oil group and 42 times in the placebo group, including knee pain (n = 10 with krill oil; n = 9 with placebo), lower extremity pain (n = 1 with krill oil; n = 5 with placebo), and hip pain (n = 3 with krill oil; n = 2 with placebo). Conclusions and Relevance: Among people with knee osteoarthritis who have significant knee pain and effusion-synovitis on magnetic resonance imaging, 2 g/d of daily krill oil supplementation did not improve knee pain over 24 weeks compared with placebo. These findings do not support krill oil for treating knee pain in this population. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000726459; Universal Trial Number: U1111-1181-7087.

Outdoor Artificial Light at Night and Reproductive Endocrine and Glucose Homeostasis and Polycystic Ovary Syndrome in Women of Reproductive Age.

BACKGROUND: Artificial light at night, a well-recognized circadian clock disrupter, causes disturbances in endocrine homeostasis. However, the association of artificial light at night with polycystic ovary syndrome (PCOS) is still unknown. This study examines the effects of outdoor artificial light at night on sex hormones, glucose homeostasis markers, and PCOS prevalence in Anhui Province, China. METHODS: We recruited 20,633 women of reproductive age from Anhui Medical University Reproductive Medicine Center. PCOS was diagnosed according to Rotterdam criteria. We estimated long-term (previous year) and short-term (previous month) artificial light at night values for residential addresses using 500 m resolution satellite imagery. We fitted multivariable models, using both linear and logistic regression, to estimate the association of artificial light at night with sex hormones, glucose homeostasis markers, and PCOS prevalence. RESULTS: Both long-term and short-term exposure to outdoor artificial light at night were negatively associated with follicle-stimulating hormone and luteinizing hormone levels, while positively associated with testosterone, fasting insulin, homeostasis model assessment-insulin resistance, and homeostasis model assessment-insulin resistance-ß levels. The second-highest quintile of artificial light at night was associated with increased PCOS prevalence (odds ratio [OR long-term ] = 1.4; 95% confidence interval [CI] = 1.2, 1.6 and OR short-term = 1.3; 95% CI = 1.1, 1.5) compared with the lowest quintile. In addition, prevalence of PCOS was linearly associated with long-term exposure to artificial light at night, but nonlinearly associated with short-term exposure. This association was more evident in younger, obese or overweight, moderately educated, rural women, and for the summer and fall seasons. CONCLUSION: Outdoor artificial light at night may be a novel risk factor for PCOS.

Associations of perchlorate, nitrate, and thiocyanate exposure with arthritis and inflammation indicators in young and middle-aged adults, NHANES 2005-2016.

Background: Perchlorates, nitrates, and thiocyanates are prevalent environmental chemicals. Their potential association with arthritis remains unexplored. This study aimed to investigate the link between perchlorate, nitrate, and thiocyanate exposure and arthritis, as well as the potential role of inflammation in this context. Methods: Utilizing the National Health and Nutrition Examination Survey (NHANES) data spanning from 2005 to 2016, the study enrolled 6597 participants aged 20-59 (young and middle-aged), of which 1045 had arthritis. Employing multivariate logistic regression modeling, multiple linear regression models, restricted cubic spline analysis, Bayesian kernel machine regression (BKMR) modeling, and mediation analysis, we assessed these relationships. Results: There was a significant positive association between elevated urinary thiocyanate levels and arthritis risk [1.19 (1.11, 1.28)]. This association held true across subgroups of osteoarthritis (OA) [1.24 (1.10, 1.40)] and rheumatoid arthritis (RA) [1.33 (1.15, 1.55)]. Thiocyanate levels displayed a dose-dependent relationship with arthritis risk, showing a linear trend (nonlinear P > 0.05). Conversely, perchlorate and nitrate did not exhibit associations with arthritis risk. BKMR outcomes highlighted a positive correlation between a mixture of perchlorate, nitrate, and thiocyanate and arthritis risk, with thiocyanate being the predominant predictors. Moreover, BKMR and generalized linear model analyses unveiled no significant synergistic effect of urinary perchlorate, nitrate, and thiocyanate on arthritis risk. Furthermore, thiocyanate exposure has been linked to elevated levels of inflammatory indicators (white blood cell, neutrophils, lymphocytes, and systemic immune-inflammatory index (SII)). Conclusion: Heightened thiocyanate exposure may be linked to elevated arthritis risk, either single or in combined effects. Additionally, thiocyanate exposure is associated with heightened inflammation levels.

Effect of Intravenous Zoledronic Acid on Total Knee Replacement in Patients With Symptomatic Knee Osteoarthritis and Without Severe Joint Space Narrowing: A Prespecified Secondary Analysis of a Two-Year, Multicenter, Double-Blind, Placebo-Controlled Clinical Trial.

OBJECTIVE: To determine the effect of zoledronic acid (ZA) on the risk of total knee replacement (TKR) in patients with symptomatic knee osteoarthritis and without severe joint space narrowing (JSN). METHODS: We included 222 participants (mean age 62 years, 52% female) from the two-year Zoledronic Acid for Osteoarthritis Knee Pain trial (113 received 5 mg of ZA annually and 109 received placebo) conducted between November 2013 and October 2017. Primary TKR were identified until February 22, 2022. The effect of ZA on TKR risk was evaluated using Cox proportional hazard regression models. Because the treatment effect failed the proportional hazards assumption, a time-varying coefficients analysis for treatment was conducted by splitting the study into two periods (ie, within and after two years of randomization). RESULTS: Over a mean follow-up of seven years, 39% and 30% of participants had any TKR in the ZA and placebo groups, and 28% and 18% had TKR in the study knee, respectively. Use of ZA was associated with a higher risk of TKR in any knee (hazard ratio [HR] 4.2, 95% confidence interval [CI] 1.2-14.7) and showed a trend in the study knee (HR 6.8, 95%CI 0.9-53.9) during the trial. In the posttrial period, the risk of TKR was similar in the ZA and the placebo groups for any knee (HR 1.2, 95%CI 0.5-1.8) and the study knee (HR 1.4, 95%CI 0.5-2.2). CONCLUSION: These results suggest that ZA is not protective against TKR in patients with symptomatic knee osteoarthritis and without severe JSN.

Factors associated with trajectories of bone marrow lesions over 4 years: data from the Osteoarthritis Initiative.

OBJECTIVE: To identify bone marrow lesion (BML) trajectories over 4 years and their demographic and structural predictors in middle-aged and older adults with or at increased risk of knee osteoarthritis (OA). METHODS: A total of 614 participants (mean age 61 years, 62% female) from the Osteoarthritis Initiative cohort (OAI) were included. BMLs in 15 anatomical locations of the knee were measured annually from baseline to 4 years using the Magnetic Resonance Imaging Osteoarthritis Knee Score (MOAKS) method. BML trajectories were determined using latent class mixed models (LCMMs). Multinomial logistic regression was used to examine baseline characteristics that predicted BML trajectories. RESULTS: Three distinct BML trajectories were identified: "Mild-stable BMLs" (25.9%), "Moderate-stable BMLs" (66.4%), and "Rapid-rise BMLs" (7.7%). Compared to the "Mild-stable BMLs" trajectory, current smokers were more likely to be in the "Moderate-stable BMLs" (odds ratio [OR] 2.089, P < 0.001) and "Rapid-rise" (OR 2.462, P < 0.001) trajectories. Moreover, female sex and meniscal tears were associated with an increased risk of being in the "Rapid-rise BMLs" trajectory (OR 2.023 to 2.504, P < 0.05). Participants who had higher education levels and drank more alcohol were more likely to be in the "Rapid-rise BMLs" trajectory (OR 1.624 to 3.178, P < 0.05) and less likely to be in the "Moderate-stable BMLs" trajectory (OR 0.668 to 0.674, P < 0.05). CONCLUSIONS: During the 4-year follow-up, most participants had relatively stable BMLs, few had enlarged BMLs, and no trajectory of decreased BMLs was identified. Sociodemographic factors, lifestyle, and knee structural pathology play roles in predicting distinct BML trajectories.

Association between diurnal temperature range and sperm quality: Evidence from a prospective cohort in Central China.

Inter-day temperature variability has been reported to be associated with sperm quality in a city-level exposure assessment study. However, studies exploring the impact of temperature variability within a single day on sperm quality at individual level are still lacking. The present study aims to bridge this research gap by analyzing the linear and non-linear associations between diurnal temperature range (DTR) exposure and sperm quality, utilizing data from the Anhui Prospective Assisted Reproduction Cohort. The study included 15,112 males (totaling 28,267 tests) and assessed individual exposure to various environmental factors (residential greenness, ambient particulate matter, sulfur dioxide, relative humidity, ambient temperature, and DTR) during the 0-90 day period before semen analysis. A combination of a linear mixed model, natural cubic splines, and subgroup analysis was employed. Significant "U"-shaped non-linear associations were observed between DTR exposure and total motility, sperm concentration, sperm count, total motile sperm count, and progressive motile sperm count. Lower DTR levels negatively impacted these parameters, whereas higher DTR levels showed a positive effect. Notably, these associations were more pronounced at ambient temperatures below 16.5 °C, while absent in warmer conditions. Sperm quality demonstrates increased sensitivity to DTR exposure in cooler environments. Therefore, implementing effective individual temperature management strategies is crucial for mitigating decreased sperm quality associated with DTR exposure, highlighting the potential benefits of government policies aimed at achieving carbon neutrality to enhance overall sperm quality in the general population.

Association of prediabetes progression and regression with cognitive decline: Findings from the CHARLS.

AIM: The aim of the study was to describe the association of prediabetes progression and regression with change in cognitive function. METHODS: Data from three waves (2011, 2015 and 2018) of the China Health and Retirement Longitudinal Study (CHARLS) were analysed. Diabetic statuses in 2011 and 2015 were ascertained using the American Diabetes Association criteria. Cognitive function was assessed and standardized at all three waves, where a total score and its two components (episodic memory and metal status) were calculated. We evaluated the association of prediabetes progression and regression (from 2011 to 2015) with changes in cognitive function from 2011 to 2015 and from 2015 to 2018. RESULTS: Of 2590 participants (56% women, mean age 58.6 ± 8.4 years) with prediabetes, 12% progressed to diabetes and 41% regressed to normoglycaemia. Compared with participants who remained as prediabetes, those who progressed to diabetes showed a trend to have accelerated decline in episodic memory (ß = -0.11, 95% confidence interval -0.22 to 0.003, p = 0.057). However, participants who regressed to normoglycaemia did not have less cognitive decline. Neither prediabetes progression nor regression predicted change in cognitive function from 2015 to 2018. In a separate group of participants who remained as normoglycaemia (n = 858), changes in cognitive function from 2011 to 2015 and from 2015 to 2018 were similar to those who remained as prediabetes. CONCLUSION: In people with prediabetes, progression to diabetes may be associated with accelerated cognitive decline but regression to normoglycaemia does not retard cognitive decline. Prediabetes progression and regression may not be predictive of change in cognitive function.

Cross-Sectional and Longitudinal Associations of Comorbidities with Knee Symptoms and Radiographic Abnormalities of Osteoarthritis.

INTRODUCTION: This study aimed to investigate the associations of comorbidities with knee symptoms and radiographic abnormalities of osteoarthritis (OA). METHODS: Participants were from the Osteoarthritis Initiative. Comorbidities were identified at baseline using the modified Charlson Comorbidity Index. For both knees, symptoms were assessed annually from baseline to 48 months using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores (rescaled range 0-100), and radiographic abnormalities using the Kellgren-Lawrence (KL, 0-4) grades. The presence of significant pain and functional disability was defined as a WOMAC score of ≥ 25 and ≥ 22, respectively, and radiographic OA (ROA) as KL ≥ 2. An increase of ≥ 9 in WOMAC scores and ≥ 1 in KL grades were defined as symptomatic and radiographic progression, respectively. RESULTS: Of 3337 participants, 28% and 9% had one and ≥ 2 comorbidities, respectively. The number of comorbidities was associated with the presence of significant functional disability (odds ratios [ORs] 1.15; 1.46) and predicted the progression of both knee pain and functional disability (ORs 1.11; 1.51). For the type of comorbidities, non-OA musculoskeletal diseases were associated with the presence of ROA and significant functional disability (ORs 1.63; 1.82) and showed a trend to predict incident ROA (OR 1.84, 95% confidence interval 1.00-3.38 p = 0.051). Diabetes and kidney diseases were associated with symptomatic progression of OA (ORs 1.38; 2.72). CONCLUSIONS: Having more comorbidities, especially diabetes and kidney diseases, is associated with symptomatic progression of knee OA. Moreover, non-OA musculoskeletal diseases may be associated with the presence and onset of ROA.

Associations of exposure to ambient fine particulate matter constituents from different pollution sources with semen quality: Evidence from a prospective cohort.

The association between ambient fine particulate matter (PM2.5) exposure and semen quality remains inconclusive, possibly due to variations in pollution sources and PM2.5 compositions. Studies investigating the constituents of PM2.5 have been hindered by small sample sizes, and research exploring the relationships between PM2.5 pollution sources and semen quality is lacking. To address this gap, we conducted a comprehensive study based on the Anhui prospective assisted reproduction cohort to evaluate the associations between semen quality and the constituents and pollution sources of PM2.5. This study included 9013 semen samples from 4417 males in the urban districts of Hefei. The median concentrations of PM2.5 constituents, including eight metals and four water-soluble ions (WSIs), were measured for seven days per month at two monitoring stations during the 0-90-day exposure window. A linear mixed-effects model, weighted quantile sum regression, and positive matrix factorisation were used to evaluate the associations of the constituents and pollution sources of PM2.5 with semen quality. The results showed that exposure to PM2.5-bound metals (antimony, arsenic, cadmium, lead, and thallium) and WSIs (sulphate and chloride) were negatively associated with semen quality parameters. Moreover, mixtures of PM2.5-bound metals and WSIs were negatively associated with semen quality. Additionally, PM2.5 derived from traffic emissions was negatively associated with semen quality. In summary, our study revealed that ambient PM2.5 and its constituents, especially metals, were negatively associated with semen quality. Antimony, lead, and thallium emerged as the primary contributors to toxicity, and PM2.5 from traffic emissions was associated with decreased semen quality. These findings have important public health implications for the management of PM2.5 pollution in the context of male reproductive health.

METTL14-m6A-FOXO3a axis regulates autophagy and inflammation in ankylosing spondylitis.

The role of m6A in ankylosing spondylitis (AS) remains largely obscure. In this study, we found that m6A modification was decreased in T cells of AS, and the abnormal m6A modification was attributed to the downregulation of methyltransferase-like 14 (METTL14). METTL14 exerted a critical role in regulating autophagy activity and inflammation via targeting Forkhead box O3a (FOXO3a). Mechanistically, the loss of METTL14 decreased the expression of FOXO3a, leading to the damage of autophagic flux and the aggravation of inflammation. Inversely, the forced expression of METTL14 upregulated the expression of FOXO3a, thereby activating autophagy and alleviating inflammation. Furthermore, our results revealed that METTL14 targeted FOXO3a mRNA and regulated its expression and stability in a m6A-dependent manner. These findings uncovered the functional importance of m6A methylation mechanisms in the regulation of autophagy and inflammation, which expanded our understanding of this interaction and was critical for the development of therapeutic strategies for AS.

Comparative analysis of clinicopathologic characteristics and prognosis between nasal and nonnasal extranodal NK/T-cell lymphoma.

BACKGROUND: The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy. METHODS: In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi-squared test and Kruskal-Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors. RESULTS: Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56-negative status (p < 0.05). The 5-year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L-asparaginase-based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL. CONCLUSIONS: The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.

Differences of RUNX2 gene promoter methylation and transcription level in ankylosing spondylitis.

BACKGROUND AND OBJECTIVE: Ankylosing spondylitis is a refractory immune disease that seriously affects the life and work of patients. Epigenetic modifications, especially DNA methylation, have become a research hotspot in complex diseases. We aim to explore the changes in runt-related transcription factor 2 (RUNX2) gene promoter methylation and transcription level in AS. METHOD: We detected the RUNX2 gene promoter methylation in 83 AS patients and 83 healthy controls (HCs), then inspected the mRNA difference of RUNX2 between 30 AS patients and 30 HCs by the quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The RUNX2 gene promoter was hypomethylated in AS patients compared to HCs (p < .001). The research involved 4 CpG regions and 74 CpG sites of RUNX2, of which CpG-2, CpG-4 regions, and 18 CpG sites have been differentially methylated. The CpG-4 island methylation was negatively correlated with C-reactive protein (p < .05) in AS patients. In the qRT-PCR validation phase, the mRNA level of RUNX2 in AS patients was significantly higher than HCs (p < .05), and in AS patients who were treated with biologics, the methylation level of CpG-2 island showed a negative correlation to mRNA (p < .05). ROC results indicated that RUNX2 methylation and its transcription level have good potential to distinguish AS patients from HCs. CONCLUSION: The RUNX2 gene promoter was hypomethylated in AS patients. Meanwhile, the qRT-PCR verified the up-regulated expression on the transcription level, suggesting the abnormal methylation of RUNX2 contributes to the pathogenesis of AS.

Association between exposure to mixture of heavy metals and hyperlipidemia risk among U.S. adults: A cross-sectional study.

Previous studies have suggested that exposure to heavy metals might increase the risk of hyperlipidemia. However, limited research has investigated the association between exposure to mixture of heavy metals and hyperlipidemia risk. To explore the independent and combined effects of heavy metal exposure on hyperlipidemia risk, this study involved 3293 participants from the National Health and Nutrition Examination Survey (NHANES), including 2327 with hyperlipidemia and the remaining without. In the individual metal analysis, the logistic regression model confirmed the positive effects of barium (Ba), cadmium (Cd), mercury (Hg), Lead (Pb), and uranium (U) on hyperlipidemia risk, Ba, Cd, Hg and Pb were further validated in restricted cubic splines (RCS) regression model and identified as positive linear relationships. In the metal mixture analysis, weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile-based g computation (qgcomp) models consistently revealed a positive correlation between exposure to metal mixture and hyperlipidemia risk, with Ba, Cd, Hg, Pb, and U having significant positive driving roles in the overall effects. These associations were more prominent in young/middle-aged individuals. Moreover, the BKMR model uncovered some interactions between specific heavy metals. In conclusion, this study offers new evidence supporting the link between combined exposure to multiple heavy metals and hyperlipidemia risk, but considering the limitations of this study, further prospective research is required.

Association of Exposure to Heavy Metal Mixtures with Systemic Immune-Inflammation Index Among US Adults in NHANES 2011-2016.

In reality, people are often co-exposed to multiple heavy metals; however, current research has focused on the association between individual heavy metals and inflammation. Therefore, it is more relevant to explore the combined effects of multiple heavy metal exposure on inflammation. The study included data from the National Health and Nutrition Examination Survey (NHANES), 2011-2016. The systemic immune-inflammation index (SII) was used to reflect systemic immune-inflammation status. In this study, single variable models were used to assess the linear and non-linear relationships between single heavy metal exposures and SII. To analyze the combined effect of mixed heavy metals exposure on SII, we constructed three statistical models, including weighted quantile sum (WQS) regression, quantile-based g computation (qgcomp), and Bayesian kernel machine regression (BKMR). The single-exposure analysis found positive associations between multiple heavy metals and SII, while mercury in blood was negatively associated with SII, and U-shaped correlations were observed between blood lead, urine barium and strontium, and SII. In the WQS model, SII increased significantly with increasing concentrations of mixed heavy metals, while consistent results in the qgcomp model, but not statistically significant. In the BKMR model, exposure to heavy metal mixtures was positively associated with SII, with mercury, cadmium, and cobalt in urine contributing the most to the mixed exposure. In addition, synergistic and antagonistic effects between heavy metals on increasing SII were found in our study. In summary, our results reveal that combined exposure to multiple heavy metals is positively associated with SII in the US adults.

Association of smoking with cartilage loss of knee osteoarthritis: data from two longitudinal cohorts.

BACKGROUND: Previous studies have been inconsistent concerning the association between smoking and risk of osteoarthritis (OA). This study aimed to explore the associations of smoking status and change in cartilage volume of OA in two longitudinal cohorts. METHODS: Subjects from the Osteoarthritis Initiative cohort (OAI, n = 593) and the Tasmanian Older Adult Cohort (TASOAC, n = 394) were included in this study. For both cohorts, participants were classified into three groups based on their smoking status, namely 'never', 'former', and 'current' smokers. The outcome measures were the annual rate of change of tibiofemoral cartilage volume over 2 years in OAI and of tibial cartilage volume over 2.6 years in TASOAC. Potential confounders were balanced using the inverse probability of treatment weighting (IPTW) method. RESULTS: Overall, 42.3% and 37.4% of participants were former smokers, and 5.7% and 9.3% were current smokers in the OAI and TASOAC cohorts, respectively. Compared to never smokers, neither former nor current smoking was associated with risk of the annual rate of change of tibiofemoral cartilage volume in OAI (former smoker: ß=-0.068%/year, 95% confidence interval [CI] -0.824 to 0.688, p = 0.860; current smoker: ß=-0.222%/year, 95% CI -0.565 to 0.120, p = 0.204) and tibial cartilage volume in TASOAC (former smoker: ß = 0.001%/year, 95% CI -0.986 to 0.989, p = 0.998; current smoker: ß=-0.839%/year, 95% CI -2.520 to 0.844, p = 0.329). CONCLUSIONS: Our findings from two independent cohorts consistently showed that smoking was not associated with knee cartilage loss in older adults.

Associations of long-term exposure to air pollution and green space with reproductive hormones among women undergoing assisted reproductive technology: A longitudinal study.

Studies investigating the association between long-term exposure to air pollution (AP)/green space and female reproductive hormones are still limited. Furthermore, their interactive effects remain unclear. Our study sought to explore the separate and interactive impacts of AP/green space on reproductive hormones among women undergoing assisted reproductive technology. We measured estradiol (E2), progesterone (P), testosterone (T), and follicle-stimulating hormone (FSH) from the longitudinal assisted reproduction cohort in Anhui, China. The annual mean concentrations of air pollutants were calculated at the residential level. Normalized Difference Vegetation Index (NDVI) within 500-m represented green space exposure. To assess the effect of AP/green space on hormones, we employed multivariable linear mixed-effect models. Our results showed that each one-interquartile range (IQR) increment in particulate matter (PM2.5 and PM10) and sulfur dioxide (SO2) was associated with -0.03[-0.05, -0.01], -0.03[-0.05, -0.02], and -0.03[-0.05, -0.01] decrease in P. An IQR increase in PM2.5, PM10, SO2, and carbon monoxide (CO) was associated with a -0.16[-0.17, -0.15], -0.15[-0.16, -0.14], -0.15[-0.16, -0.14], and -0.12[-0.13, -0.11] decrease in T and a -0.31[-0.35, -0.27], -0.30[-0.34, -0.26], -0.26[-0.30, -0.22], and -0.21[-0.25, -0.17] decrease in FSH. Conversely, NDVI500-m was associated with higher levels of P, T, and FSH, with ß of 0.05[0.02, 0.08], 0.06[0.04, 0.08], and 0.07[0.00, 0.14]. Moreover, we observed the "U" or "J" exposure-response curves between PM2.5, PM10, and SO2 concentrations and E2 and P levels, as well as "inverted-J" curves between NDVI500-m and T and FSH levels. Furthermore, we found statistically significant interactions of SO2 and NDVI500-m on E2 and P as well as CO and NDVI500-m on E2. These findings indicated that green space might mitigate the negative effects of SO2 on E2 and P, as well as the effect of CO on E2. Future research is needed to determine these findings and underlying mechanisms.

Vitamin D supplementation for improving bone density in vitamin D-deficient children and adolescents: systematic review and individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Vitamin D supplements are widely used for improving bone health in children and adolescents, but their effects in vitamin D-deficient children are unclear. OBJECTIVES: This study aimed to examine whether the effect of vitamin D supplementation on bone mineral density (BMD) in children and adolescents differs by baseline vitamin D status and estimate the effect in vitamin D-deficient individuals. METHODS: This is a systematic review and individual participant data (IPD) meta-analysis. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, MBASE, CINAHL, AMED, and ISI Web of Science (until May 27, 2020) for randomized controlled trials (RCTs) of vitamin D supplementation reporting bone density outcomes after ≥6 mo in healthy individuals aged 1-19 y. We used two-stage IPD meta-analysis to determine treatment effects on total body bone mineral content and BMD at the hip, femoral neck, lumbar spine, and proximal and distal forearm after 1 y; examine whether effects varied by baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, and estimate treatment effects for each 25(OH)D subgroup. RESULTS: Eleven RCTs were included. Nine comprising 1439 participants provided IPD (86% females, mean baseline 25(OH)D = 36.3 nmol/L). Vitamin D supplementation had a small overall effect on total hip areal BMD (weighted mean difference = 6.8; 95% confidence interval: 0.7, 12.9 mg/cm2; I2 = 7.2%), but no effects on other outcomes. There was no clear evidence of linear or nonlinear interactions between baseline 25(OH)D and treatment; effects were similar in baseline 25(OH)D subgroups (cutoff of 35 or 50 nmol/L). The evidence was of high certainty. CONCLUSIONS: Clinically important benefits for bone density from 1-y vitamin D supplementation in healthy children and adolescents, regardless of baseline vitamin D status, are unlikely. However, our findings are mostly generalizable to White postpubertal girls and do not apply to those with baseline 25(OH)D outside the studied range or with symptomatic vitamin D deficiency (e.g., rickets). This study was preregistered at PROSPERO as CRD42017068772. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017068772.