BMC Medicine最新文献

Background: The relationship between ozone (O₃) exposure and blood pressure (BP) remains inconclusive. Given the scarcity of Chinese epidemiological data, more research on this association is of paramount importance, particularly among middle-aged and older Chinese populations.

Methods: This study involved 10,875 participants (median age: 60.0 years) in Xiamen, China, from 2013 to 2019, with 34,939 repeated BP measurements. Air pollutant exposure data, including O₃, particulate matter, nitrogen dioxide, sulfur dioxide, and carbon monoxide were derived from China High Air Pollutants and High-resolution Air Quality Reanalysis datasets using a k-nearest neighbor algorithm. The relationship between mixed air pollutant exposure and BP was evaluated using Bayesian kernel machine regression model. The effects of daily-specific O₃ exposure on BP were assessed by distributed lag models integrated into a linear mixed-effects framework. The mediating role of total cholesterol (TC), serum total bilirubin (STB), triglyceride (TG), and low-density lipoprotein (LDL) were examined using multilevel mediation analysis with a fully adjusted model.

Results: Mixed air pollutant exposure was positively correlated with BP, with O₃ being a predominant contributor exhibiting an inverse effect. O₃ exposure had immediate effects on pulse pressure (PP), while systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) showed delayed responses, with 3-, 14-, and 8-day lags, respectively. During the study period of up to 30 days, each 10 μg/m³ increase in maximum daily 8-h average O₃ concentration was associated with reductions in SBP (β =  - 1.176 mm Hg), DBP (- 0.237 mm Hg), PP (β =  - 0.973 mm Hg), and MAP (β =  - 0.544 mm Hg). Stronger correlations were observed in the older participants (aged ≥ 65 years), overweight/obese individuals, smokers and alcohol consumers, and those with hypertension or type 2 diabetes mellitus. STB and LDL mediated these effects, while TC and TG played mitigating roles.

Conclusions: Short-term O₃ exposure is negatively associated with BP in middle-aged and older Chinese individuals. The findings provide preliminary evidence for the impact of O₃ exposure on BP regulation and underscore the urgent need to reassess public health policies in response to O₃ pollution.

Background: The potential impact of specific food additives, common in Western diets, on the risk of developing type 2 diabetes is not well understood. This study focuses on carrageenan, a widely used food additive known to induce insulin resistance and gut inflammation in animal models, and its effects on human health.

Methods: In a randomised, double-blind, placebo-controlled, cross-over trial conducted at a university hospital metabolic study centre, 20 males (age 27.4 ± 4.3 years, BMI 24.5 ± 2.5 kg/m²) participated. The intervention involved oral intake of carrageenan (250 mg) or placebo in the morning and in the evening and each intervention lasted 2 weeks. The primary outcome measured was insulin sensitivity (using oral glucose tolerance test [OGTT] and hyperinsulinaemic-euglycaemic clamp). Additional end-points included whole body and hepatic insulin sensitivity, MRI-measured brain inflammation and insulin resistance, intestinal permeability (via lactulose-mannitol test and plasma zonulin levels), and gut microbiome composition. Immune-cell activation and pro-inflammatory cytokine release from peripheral blood mononuclear cells were measured.

Results: Overall insulin sensitivity did not show significant differences between the treatments. However, interactions between BMI and treatment were observed (OGTT-based insulin sensitivity index: p=0.04, fasting insulin resistance: p=0.01, hepatic insulin sensitivity index: p=0.04). In overweight participants, carrageenan exposure resulted in lower whole body and hepatic insulin sensitivity, a trend towards increased brain inflammation, and elevated C-reactive protein (CRP) and IL-6 levels compared to placebo. Additionally, carrageenan was associated with increased intestinal permeability. In vitro natural killer (NK-)cell activation and increased pro-inflammatory cytokine release were found after carrageenan exposure in the participant's peripheral blood mononuclear cells.

Conclusions: These findings suggest that carrageenan, a common food additive, may contribute to insulin resistance and subclinical inflammation in overweight individuals through pro-inflammatory mechanisms in the gut. Further investigation into the long-term health impacts of carrageenan and other food additives is warranted.

Trial registration: NCT02629705.

Background: Paracetamol is the most consumed medicine globally. Its accessibility contributes to common overdose. Paracetamol overdose is responsible for > 50% of acute liver failure cases, making it the second most common reason for a liver transplant. Rapid quantitation of paracetamol is crucial to guide treatment of paracetamol overdose. Current tests require invasive sampling and relatively long turnaround times. Paper arrow-mass spectrometry (PA-MS) combines sample collection, extraction, separation, enrichment and ionisation onto a single paper strip, achieving rapid, accurate, cost-effective and eco-friendly analysis direct from raw human saliva.

Methods: To validate PA-MS against an established test, 17 healthy adults were recruited. Samples were collected before and at 15, 30, 60, 120 and 240 min after ingesting 1 g of paracetamol. Plasma measured with an established clinical test served as the reference standard to validate PA-MS with three biofluids-plasma, resting saliva (RS) and stimulated saliva (SS). Participants' views of blood, RS and SS sampling procedures were assessed qualitatively. Cross-validation was assessed using Lin's concordance correlation coefficients (CCC), Bland-Altman difference plots, and ratios of PA-MS to the reference standard test.

Results: PA-MS using stimulated saliva offers a reliable alternative to intravenous blood sampling. The CCC is 0.93, the mean difference with the reference test is - 0.14 mg/L, and the ratios compared to the reference test are 0.84-1.27 from correlated samples collected at 5 intervals over 4 h for each participant.

Conclusions: Paracetamol detection from SS with PA-MS provides a reliable result that can aid timely treatment decisions. Differences between paracetamol concentration in resting and stimulated saliva were also identified for the first time, highlighting the importance of standardising saliva collection methods in general. This study marks a major milestone towards rapid and convenient saliva analysis.

Background: The spatial layout of large-scale functional brain networks exhibits considerable inter-individual variability, especially in the association cortex. Research has demonstrated a link between early socioeconomic status (SES) and variations in both brain structure and function, which are further associated with cognitive and mental health outcomes. However, the extent to which SES is associated with individual differences in personalized functional network topography during childhood remains largely unexplored.

Methods: We used a machine learning approach-spatially regularized non-negative matrix factorization (NMF)-to delineate 17 personalized functional networks in children aged 9-10 years, utilizing high-quality functional MRI data from 6001 participants in the Adolescent Brain Cognitive Development study. Partial least square regression approach with repeated random twofold cross-validation was used to evaluate the association between the multivariate pattern of functional network topography and three SES factors, including family income-to-needs ratio, parental education, and neighborhood disadvantage.

Results: We found that individual variations in personalized functional network topography aligned with the hierarchical sensorimotor-association axis across the cortex. Furthermore, we observed that functional network topography significantly predicted the three SES factors from unseen individuals. The associations between functional topography and SES factors were also hierarchically organized along the sensorimotor-association cortical axis, exhibiting stronger positive associations in the higher-order association cortex. Additionally, we have made the personalized functional networks publicly accessible.

Conclusions: These results offer insights into how SES influences neurodevelopment through personalized functional neuroanatomy in childhood, highlighting the cortex-wide, hierarchically organized plasticity of the functional networks in response to diverse SES backgrounds.

Background: Few studies have examined associations between maternal epigenetic age acceleration and adverse birth outcomes, and none have investigated paternal epigenetic age acceleration. Our objective was to assess the associations of parental (both maternal and paternal) epigenetic age acceleration in relation to birth outcomes.

Methods: Parental epigenetic age was estimated using seven established epigenetic clocks in 2198 mothers and 2193 fathers from the Norwegian Mother, Father, and Child Cohort Study (MoBa). Individual epigenetic age acceleration was then calculated as residuals from linear regressions of estimates from the epigenetic clocks on chronological age. Further, linear regression was used to analyze differences in continuous outcomes (gestational length and standardized birthweight), while logistic regression was used for binary outcomes (preterm birth, post-term birth, small-for-gestational age [SGA], large-for-gestational age [LGA], and pre-eclampsia), adjusting for chronological age, parity, educational level, smoking, and BMI.

Results: Increasing maternal, but not paternal, epigenetic age acceleration was associated with decreased gestational length for five out of six clocks, with adjusted estimates ranging from a mean 0.51-day decrease (95% CI - 1.00, - 0.02; p-value 0.043) for the Horvath clock to a 0.80-day decrease (95% CI - 1.29, - 0.31; p-value 0.002) for the Levine clock. An association with increasing maternal epigenetic age acceleration according to the DunedinPACE clock was also seen with greater standardized birthweight [mean difference 0.08 (95% CI 0.04, 0.12; p-value < 0.001]. These results were also reflected in an increased risk of spontaneous preterm birth and LGA. No associations were observed with post-term birth, SGA, or pre-eclampsia.

Conclusions: Maternal, but not paternal, epigenetic age acceleration is associated with shorter pregnancies and an increased risk of spontaneous preterm birth. This may suggest that women's biological age acceleration, including factors such as metabolic and physiologic state, is an additional risk factor for preterm delivery, beyond chronological age.

Background: Failure of systemic corticosteroid therapy is common in patients with newly diagnosed acute graft-versus-host disease (aGVHD) above grade II. Mesenchymal stem cells (MSCs) have been used as a tolerable and potentially effective second-line therapy for steroid-refractory aGVHD (SR-aGVHD); however, well-designed, prospective, controlled studies are lacking.

Methods: This multicentre, randomized, double-blind, placebo-controlled, exploratory phase 2 study enrolled patients with SR-aGVHD above grade II from 7 centres. Patients were randomized 1:1 to receive umbilical cord-derived MSCs or placebo added to one centre's choice of second-line agents (except for ruxolitinib). The agents were infused twice weekly. Patients with complete response (CR), no response (NR), or progression of disease (PD) at d28 received 8 infusions, and those with partial response (PR) received the above infusions for another 4 weeks. The per-protocol population consisted of patients who received ≥ 8 infusions. The primary endpoint was the overall response rate (ORR, CR + PR) at d28, analyzed in the per-protocol and intention-to-treat populations.

Results: Seventy-eight patients (median age 38, range 13-62) were enrolled: 40 in the MSC group and 38 in the control. Patients in the MSC group received a median of 8 doses, with a median response time of 14 days. In intention-to-treat analysis, ORR at d28 was 60% for MSC group and 50% for control group (p = 0.375). The 2-year cumulative incidence of moderate to severe cGVHD was marginally lower in the MSC group than in the control (13.8% vs. 39.8%, p = 0.067). The 2-year failure-free survival was similar between the MSC and control groups (52.5% vs. 44.4%, p = 0.43). In per-protocol analysis (n = 62), ORR at d28 was significantly greater in the MSC group than in the control group (71.9% vs. 46.7%, p = 0.043). Among patients with gut involvement, ORR at d28 was significantly greater in the MSC group than in the control (66.7% vs. 33.3%, p = 0.031). The adverse events incidences were similar between groups.

Conclusions: In this exploratory study, there was no superior ORR at d28 demonstrated in the MSC group compared with the control. However, MSCs showed a gradual treatment effect at a median of 2 weeks. Patients who completed 8 infusions may benefit from adding MSCs to one conventional second-line agent, especially those with gut involvement. MSCs was well tolerated in patients with SR-aGVHD.

Trial registration: chictr.org.cn ChiCTR2000035740.

Background: Chronological age (CA) does not reflect individual variation in the aging process. However, existing biological age predictors are mostly based on European populations and overlook the widespread nonlinear effects of clinical biomarkers.

Methods: Using data from the prospective Dongfeng-Tongji (DFTJ) cohort of elderly Chinese, we propose a physiological aging index (PAI) based on 36 routine clinical biomarkers to measure aging progress. We first determined the optimal level of each biomarker by restricted cubic spline Cox models. For biomarkers with a U-shaped relationship with mortality, we derived new variables to model their distinct effects below and above the optimal levels. We defined PAI as a weighted sum of variables predictive of mortality selected by a LASSO Cox model. To measure aging acceleration, we defined ΔPAI as the residual of PAI after regressing on CA. We evaluated the predictive value of ΔPAI on cardiovascular diseases (CVD) in the DFTJ cohort, as well as nine major chronic diseases in the UK Biobank (UKB).

Results: In the DFTJ training set (n = 12,769, median follow-up: 10.38 years), we identified 25 biomarkers with significant nonlinear associations with mortality, of which 11 showed insignificant linear associations. By incorporating nonlinear effects, we selected CA and 17 clinical biomarkers to calculate PAI. In the DFTJ testing set (n = 15,904, 5.87 years), PAI predict mortality with a concordance index (C-index) of 0.816 (95% confidence interval, [0.796, 0.837]), better than CA (C-index = 0.771 [0.755, 0.788]) and PhenoAge (0.799 [0.784, 0.814]). ΔPAI was predictive of incident CVD and its subtypes, independent of traditional risk factors. In the external validation set of UKB (n = 296,931, 12.80 years), PAI achieved a C-index of 0.749 (0.746, 0.752) to predict mortality, remaining better than CA (0.706 [0.702, 0.709]) and PhenoAge (0.743 [0.739, 0.746]). In both DFTJ and UKB, PAI calibrated better than PhenoAge when comparing the predicted and observed survival probabilities. Furthermore, ΔPAI outperformed any single biomarker to predict incident risks of eight age-related chronic diseases.

Conclusions: Our results highlight the potential of PAI and ΔPAI as integrative biomarkers to evaluate aging acceleration and facilitate the development of targeted intervention strategies for healthy aging.

Background: Geriatric rehabilitation is a multidisciplinary intervention that promotes functional recovery in older adults. Our objective was to assess the efficacy of geriatric rehabilitation in inpatient and geriatric day hospital settings.

Methods: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, PEDro and AgeLine from inception to September 30, 2022 for randomized controlled trials (RCTs) including older adults (age ≥ 65 years) undergoing geriatric rehabilitation (inpatient or day hospital) with a usual care comparator group. Primary outcome measures included mortality, long-term care home (LTCH) admission, and functional status. Secondary outcomes included discharge/remaining at home, functional improvement, length of stay, cognition, mood, and quality of life. Records were screened, abstracted and assessed for risk of bias (Cochrane Risk of Bias [RoB] 2) by two reviewers independently. We conducted a random effects meta-analysis to summarize risk ratios (RR, dichotomous outcomes) and standardized mean differences (SMD, continuous outcomes).

Results: Of the 5304 records screened, 29 studies (7999 patients) met eligibility criteria. There were 23 RCTs of inpatient geriatric rehabilitation (6428 patients) and six of geriatric day hospital (1571 patients) reporting outcomes of mortality (26 studies), LTCH admission (22 studies), functional status (19 studies), length of stay (18 studies), cognition (5 studies), mood (5 studies) and quality of life (6 studies). The primary outcome of mortality at longest follow up was lower in the rehabilitation group (RR 0.84, 95% confidence interval [CI] 0.76 to 0.93, I² = 0%). LTCH admission was lower in the rehabilitation group at longest follow up (RR 0.86, 95% CI 0.75 to 0.98, I² = 8%). Functional status was better in the rehabilitation group at longest follow up (SMD 0.09, 95% CI 0.02 to 0.16, I² = 24%). Cognition was improved in the rehabilitation group (mean difference of mini-mental status exam score 0.97, 95% CI 0.35 to 1.60, I² = 0%). No difference was found for patient length of stay, mood, or quality of life.

Conclusions: Geriatric rehabilitation in inpatient and day hospital settings reduced mortality, LTCH admission, and functional impairment. Future studies should explore implementation of this intervention for older adults.

Review registration: PROSPERO: CRD42022345078.

Background: Estimating the economic burden of modifiable risk factors is crucial for allocating scarce healthcare resources to improve population health. We quantified the economic burden attributable to modifiable risk factors in an urban area of China.

Methods: Our Shanghai Municipal Health Commission dataset covered 2.2 million inpatient admissions for adults (age ≥ 20) in public and private hospitals in 2015 (1,327,187 admissions) and 2020 (837,482 admissions). We used a prevalence-based cost-of-illness approach by applying population attributable fraction (PAF) estimates for each modifiable risk factor from the Global Burden of Diseases Study (GBD) to estimate attributable costs. We adopted a societal perspective for cost estimates, comprising direct healthcare costs and productivity losses from absenteeism and premature mortality. Future costs were discounted at 3% and adjusted to 2020 prices.

Results: In 2020, the total societal cost attributable to modifiable risk factors in Shanghai was US$7.9 billion (95% uncertainty interval [UI]: 4.6-12.4b), mostly from productivity losses (67.9%). Two health conditions constituted most of the attributable societal cost: cancer (51.6% [30.2-60.2]) and cardiovascular disease (31.2% [24.6-50.7]). Three modifiable risk factors accounted for half of the total attributable societal cost: tobacco (23.7% [16.4-30.5]), alcohol (13.3% [8.2-19.7]), and dietary risks (12.2% [7.5-17.7]). The economic burden varied by age and sex; most of the societal costs were from males (77.7%), primarily driven by their tobacco and alcohol use. The largest contributor to societal costs was alcohol for age 20-44, and tobacco for age 45 + . Despite the COVID-19 pandemic, the pattern of major modifiable risk factors remained stable from 2015 to 2020 albeit with notable increases in attributable healthcare costs from cancers and productivity losses from cardiovascular diseases.

Conclusions: The substantial economic burden of diseases attributable to modifiable risk factors necessitates targeted policy interventions. Priority areas are reducing tobacco and alcohol consumption and improving dietary habits that together constitute half of the total attributable costs. Tailored interventions targeting specific age and sex groups are crucial; namely tobacco in middle-aged/older males and alcohol in younger males.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a prevalent hepatic condition linked to metabolic alterations. It gradually causes liver damage and potentially progresses to cirrhosis. Despite its significance, research, especially in the pediatric population, is limited, leading to contradictory findings in diagnosis and treatment. This meta-analysis aims to synthesize existing literature on therapeutic interventions for MASLD in children and adolescents.

Methods: A comprehensive search of randomized controlled clinical trials yielded 634 entries from PubMed, Scopus, and Web of Science up to 2023. Interventions included medications, behavioral modifications, dietary changes, probiotics, supplements, surgical procedures, or combinations. The analysis focused on studies with treatment duration of at least 3 months, employing a random-effects REML meta-analysis model. Treatment effects on anthropometric measurements and biochemical components were examined and adjusted for heterogeneity factors analysis. A bibliometric analysis for insights into research contributors was performed.

Results: The systematic review incorporated 31 clinical trials, with 24 meeting criteria for meta-analysis. These comprised 3 medication studies, 20 with supplements, 4 focusing on lifestyle, and 4 centered on diets. Significant overall treatment effects were observed for ALT, AST, BMI, and HOMA-IR mainly by supplements and lifestyle. Meta-regression identified age, BMI changes, and treatment duration as factors modifying ALT concentrations. Bibliometric analysis involving 31 linked studies highlighted contributions from 13 countries, with the USA, Spain, and Chile being the most influential.

Conclusions: We conclude that supplementation and lifestyle changes can effectively impact ALT and AST levels, which can help address liver issues in obese children. However, the evaluation of risk bias, the high heterogeneity, and the bibliometric analysis emphasize the need for more high-quality studies and broader inclusion of diverse child populations to provide better therapeutic recommendations.

Trial registration: PROSPERO, CRD42023393952. Registered on January 25, 2023.