BMC Medicine[JOURNAL]
Sun
200 papers
Lipid levels and risk-stratified management gaps of dyslipidemia in China.
Zhang L, Liu X, Fan F … +25 more , Zhang M, Liu Z, Zhou Z, Liu Y, Yi T, Li Y, Liu S, Weng H, Zhao Y, Wang L, Sun Y, Zhai C, Bian J, Jin J, Zheng R, Jia J, Chen Y, Wang L, Qin Y, Ding H, Fu Z, Zhou M, Zhou S, Zhang Y, Li J
BMC Med · 2026 May · PMID 42069594 · Full text
BACKGROUND: Dyslipidemia remains a major modifiable contributor to China's cardiovascular disease (CVD) burden, yet large-scale evidence on risk-stratified management gaps is lacking. METHODS: In this nationwide study ac...
BACKGROUND: Dyslipidemia remains a major modifiable contributor to China's cardiovascular disease (CVD) burden, yet large-scale evidence on risk-stratified management gaps is lacking. METHODS: In this nationwide study across 1,785 hospitals in 28 Chinese provinces, 604,250 outpatients with dyslipidemia were enrolled. We analyzed lipid levels, quantified control rate among treated population and rates of requiring lipid-lowering therapy (LLT) among untreated population across regions, socioeconomic status, and demographic groups. RESULTS: Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were higher among females, middle-aged individuals, and individuals with obesity. LDL-C levels were also higher among urban residents, while TC showed no significant urban-rural difference. Triglyceride (TG) levels were higher in males, middle-aged individuals, individuals with obesity, and rural residents. Among treated population, LDL-C/non-HDL-C control rates reached 95% in low-risk, 70-90% in moderate-risk, 40-50% in high-risk, and 5-15% in very-high-risk groups. Among untreated population, rates of requiring LLT reached about 20% in the low-risk group and over 70% in moderate- and high-risk groups. After adjusting for covariates, males, older individuals, smokers, patients with hypertension or type 2 diabetes mellitus, as well as those in rural and low-gross-domestic-product areas were associated with lower lipid control rates and higher treatment needs. CONCLUSIONS: Our findings highlight the urgent need for risk-stratified lipid management in primary care, improved access to LLT, and policies addressing regional and socioeconomic disparities to enhance lipid control and reduce CVD burden in China. Lessons from China can inform global strategies to improve lipid management and reduce the CVD burden.
The neuroimmune axis in breast cancer: from mechanistic insights to clinical applications.
Wu Y, Zhang K, Xia X … +10 more , Zhang T, Jiang N, Zhang Y, Zheng F, Jiang Y, Xiang X, Miao H, Tang H, Ren S, Li MY
BMC Med · 2026 Apr · PMID 42063127 · Full text
BACKGROUND: Breast cancer is the most commonly diagnosed malignancy in women worldwide, and its marked heterogeneity together with the complexity of the tumor microenvironment contributes to substantial variability in th...
BACKGROUND: Breast cancer is the most commonly diagnosed malignancy in women worldwide, and its marked heterogeneity together with the complexity of the tumor microenvironment contributes to substantial variability in therapeutic responses. Although conventional studies have mainly focused on tumor cell-intrinsic alterations, increasing evidence has identified the neuroimmune axis as a critical regulator of breast cancer progression and treatment resistance. MAIN BODY: The neuroimmune axis involves bidirectional crosstalk between the nervous system and the immune system, mediated by neurotransmitters, neuropeptides, and neurotrophins. These mediators modulate immune cell activity and reshape tumor behaviors, including proliferation, epithelial-mesenchymal transition, angiogenesis, and metastasis, while immune-derived cytokines can in turn remodel neural circuits and sustain a pro-tumor microenvironment. In this review, we summarize the major mechanisms underlying neuroimmune regulation in breast cancer and discuss emerging therapeutic strategies, including repurposing of neuroactive agents, breast-targeted drug delivery systems, neural stimulation combined with immune checkpoint blockade, and microbiota-neuroimmune interventions. We also outline key challenges to clinical translation, such as the spatiotemporal heterogeneity of neuroimmune regulation, the narrow therapeutic window of neuropharmacological agents, and the lack of standardized biomarkers. CONCLUSION: A deeper understanding of the neuroimmune axis may provide a theoretical basis for precision therapeutic strategies and help improve outcomes, particularly in therapy-resistant subtypes such as triple-negative breast cancer.
Rational use of expensive medicines in the Netherlands: strategies to improve effectiveness and reduce burden on patients and society - a narrative review.
Penninx BMF, Tas SW, Timmers L … +5 more , van de Kar NCAJ, Huisman A, van den Berg D, van Kempen ZLE, Hollak CEM
BMC Med · 2026 Apr · PMID 42062879 · Full text
BACKGROUND: While new expensive medicines often offer substantial benefits to patients, they can carry inherent drawbacks such as uncertainty regarding efficacy translating into effectiveness, safety and rational use, as...
BACKGROUND: While new expensive medicines often offer substantial benefits to patients, they can carry inherent drawbacks such as uncertainty regarding efficacy translating into effectiveness, safety and rational use, as well as a substantial financial burden on society and/or patients. Rational use of medicines aims to maximize effectiveness whilst minimizing side effects, patient burden, and societal costs. In the Netherlands, initiatives aiming to improve the rational use of expensive medicines are being carried out with increasing frequency and in a programmatic manner. This review identified the strategies used, and includes a structured approach for their application during the medicine's use in clinical practice. MAIN BODY: Rational use initiatives, driven by clinicians and pharmacists, and funded by the Dutch Ministry of Health and the Dutch health insurers were evaluated for strategies that aim to improve the rational use of expensive medicines. In addition, a non-systematic narrative review was carried out through searches in Google, Google Scholar, Pubmed, the Artificial Intelligence (AI)- tools Global Campus and Evidence Hunt to identify additional strategies. Identified strategies were categorized by assessing whether they aimed to address the efficacy-effectiveness gap or to reduce the side effects and societal burden of expensive medicines. Thirteen strategies to improve rational use were identified. Two strategies were identified that aim to address the efficacy-effectiveness gap: optimize patient selection and generating evidence on clinical endpoints. 11 additional strategies that aim to reduce side effects or societal burden were identified: dose reduction, personalized dose optimization, interval lengthening, shortening of the treatment duration, biosimilar/generic drug use, non-medical drug switching, reduction of additional non-medication costs, reduction of drug wastage, switching the route of administration, boosting (improve drug exposure and/or reduce the dose by influencing pharmacokinetic parameters through co-interventions), and optimization of medication adherence. CONCLUSIONS: Rational use of expensive medications is essential as part of a drug's life cycle and can benefit patients as well as society. The framework and strategies described in this overview provide guidance for the future rational use of expensive medicines, both for those already in use and for those newly introduced.
Efficacy and safety of cyclosporine plus luspatercept versus cyclosporine in newly diagnosed non-transfusion-dependent non-severe aplastic anemia: A prospective randomized trial.
Zhang Z, Hu Q, Wang L … +3 more , Yang C, Chen M, Han B
BMC Med · 2026 Apr · PMID 42057135 · Full text
BACKGROUND: The clinical need for treating anemia in aplastic anemia (AA) patients remains unmet. Luspatercept has been shown to be effective in myelodysplastic neoplasms (MDS). METHODS: Patients who were newly diagnosed...
BACKGROUND: The clinical need for treating anemia in aplastic anemia (AA) patients remains unmet. Luspatercept has been shown to be effective in myelodysplastic neoplasms (MDS). METHODS: Patients who were newly diagnosed with non-transfusion-dependent non-severe AA (NTD-NSAA) were randomly assigned to receive either cyclosporine (CsA) combined with luspatercept or CsA monotherapy at a 1:1 ratio. This study (ClinicalTrials.gov NCT05399732) aimed to compare their treatment responses, safety, disease progression, and outcomes. RESULTS: In total, 58 patients participated in the final analysis, with 29 receiving CsA+luspatercept and 29 receiving CsA monotherapy. With a median follow-up of 12 months (range: 6-25) and 12 months (range: 7-25), respectively, the overall response rates (ORRs) were 69.0% vs. 37.9% (p = 0.018) at the 3rd month, 79.3% vs. 51.7% (p = 0.027) at the 6th month, and 72.4% vs. 51.7% (p = 0.104) at the end of follow-up. Patients receiving CsA+luspatercept had a shorter time to achieve a positive response than those receiving CsA alone (p = 0.004). A post hoc subgroup analysis based on age (< 60 vs. ≥60 years) showed no significant difference in ORRs for those < 60 years old. However, for patients ≥ 60 years old receiving CsA+luspatercept, a significantly greater ORR was demonstrated at both the 3rd month (p = 0.032) and 6th month (p = 0.046) compared with CsA monotherapy. CONCLUSIONS: Compared with CsA monotherapy, the combination of CsA and luspatercept resulted in a higher response rate and a shorter time to response for patients with NTD-NSAA, with an acceptable safety profile. The benefit of CsA+luspatercept was most pronounced in older patients.
Adherence to the EAT-Lancet Diet, plasma proteomics, and risk of venous thromboembolism: a large-scale prospective cohort study.
He Q, Sun M, Wang Y … +2 more , Yao J, Shen Y
BMC Med · 2026 Apr · PMID 42056985 · Full text
BACKGROUND: The EAT Lancet diet is increasingly recognized for its simultaneous benefits to human and planetary health. Its key components are known to exert anti-inflammatory and antiplatelet effects; however, the poten...
BACKGROUND: The EAT Lancet diet is increasingly recognized for its simultaneous benefits to human and planetary health. Its key components are known to exert anti-inflammatory and antiplatelet effects; however, the potential association between adherence to the EAT‑Lancet diet and incident venous thromboembolism (VTE), as well as the underlying biological mechanisms, remains unclear. METHODS: This prospective study involved 201,695 UK Biobank participants who were free of VTE at baseline, and integrated large-scale Olink plasma proteomics to identify diet-related molecular signatures. Adherence to the EAT-Lancet diet was quantified using two validated indices. Cox models were employed to evaluate associations between EAT-Lancet diet, plasma proteins, and incident VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]). Mediation analyses quantified the role of plasma proteins. RESULTS: During a median follow-up of 13.77 years, participants in the highest adherence group of the Stubbendorff index showed lower risks of VTE (HR = 0.809, 95% CI: 0.750-0.874), DVT (HR = 0.856, 95% CI: 0.781-0.938), and PE (HR = 0.754, 95% CI: 0.678-0.838). Consistent protective associations were observed with the Knuppel index. Mediation analyses identified 94 shared plasma protein mediators, with mediation proportions ranging from - 4.77% to 8.45% of the association, among which FABP4, LEP, and ENPP6 were the top-ranked mediators. The overall proteomic signature mediated 59.19% (95% CI: 27.02%-92.15%) and 40.10% (95% CI: 14.53%-65.96%) of the associations between the Stubbendorff and Knuppel index and incident VTE, respectively. CONCLUSIONS: Higher adherence to the EAT-Lancet diet is significantly associated with a reduced risk of incident VTE, DVT, and PE, with plasma proteins potentially mediating this effect.
Smoking history, eligibility for lung cancer screening and risk of death by lung cancer or other causes -- a longitudinal, time-variable analysis of the EPIC-Heidelberg cohort.
Chen Y, Dutta S, Bajracharya R … +4 more , Cortès-Ibañez F, Fortner RT, Katzke V, Kaaks R
BMC Med · 2026 Apr · PMID 42050626 · Full text
BACKGROUND: Eligibility criteria for lung cancer (LC) screening aim to identify long-term smokers who have exceeded a minimum-risk threshold of having LC, while still having sufficiently long remaining life expectancy. F...
BACKGROUND: Eligibility criteria for lung cancer (LC) screening aim to identify long-term smokers who have exceeded a minimum-risk threshold of having LC, while still having sufficiently long remaining life expectancy. For individuals who have once met eligibility criteria (i.e., reached sufficiently high LC risk), a question is whether longer-term smoking cessation and corresponding improvement in other-cause mortality risk could justify a higher maximum screening age for former smokers than for continuing smokers. METHODS: We performed time-varying Cox models in the EPIC-Heidelberg cohort (N = 24,715), using 3-yearly questionnaire data collected between 1994 and 2014 to estimate hazard ratios (HRs) and incidence rates for death by LC or other causes, in relation to age-specific smoking status and eligibility by German LC screening criteria (LCSC). RESULTS: Depending on age, models showed up to 3-fold higher risk of other-cause mortality for recent and LCSC-eligible smokers, relative to never smokers. Among former smokers, those who quit before age 30 or 40 showed no significant difference in other-cause mortality compared with never-smokers, in men and women, respectively. However, at higher quitting ages HRs increased up to about 1.9 for men who stopped at age ≥60, or 1.5 in women who stopped at age 50-<60. Also, depending on age, former smokers who had once met the LCSC, but then quit for >10 years (thereby losing formal screening eligibility), showed HRs of about 1.5–3.0 for other-cause mortality in men and 1.3–1.9 in women. In both sexes, the absolute incidence rate for other-cause mortality amongst past-eligible smokers age 75-<80 was similar to that for current-eligible smokers of the younger, 70-<75-year age group. For LC, both current and former smoking were associated with persistently increased HRs, even after long-term cessation. CONCLUSIONS: For smokers who once met LCSC, but then quit for >10 years the risk of other-causes mortality remains elevated, but less so than for continuing smokers, which may argue for a moderate extension of the maximum age limit for LC screening. Larger studies will be needed to obtain more precise risk estimates.
Familial healthy aging and longevity: the role of spouses.
Netra S, Galvin A, Keys M … +7 more , Lawaetz Kristensen K, Krabbe Pedersen J, Thyagarajan B, Ukraintseva S, Wojczynski MK, Boomsma DI, Christensen K
BMC Med · 2026 Apr · PMID 42050620 · Full text
BACKGROUND: Families with exceptional longevity often experience delayed onset of age-related diseases and reduced mortality across generations-a pattern influenced by shared genetic and behavioral factors. While several...
BACKGROUND: Families with exceptional longevity often experience delayed onset of age-related diseases and reduced mortality across generations-a pattern influenced by shared genetic and behavioral factors. While several studies have focused on the members of longevity-enriched families (LEF), little is known about the health trajectories of the spouses marrying into these families. Given prior evidence of substantially reduced mortality among spouses of LEF members, determining whether this advantage reflects selection, shared environments, or behavioral convergence is essential for understanding the mechanisms that underlie intergenerational health transmission. METHODS: We conducted a multigenerational, retrospective matched cohort study using nationwide Danish civil and health registers. We identified 4378 spouses of LEF offspring and 5378 spouses of LEF grandchildren and matched each of these to ten married population controls by sex, birth year, and year of first marriage. Health outcomes were assessed before and throughout marriage, and after divorce, including hospitalizations by major disease categories, cancer incidence, alcohol-related disorders, as well as cause-specific and all-cause mortality. Educational attainment and familial predisposition for longevity were evaluated as potential explanatory factors. Stratified Cox regression and negative binomial models were used. RESULTS: Spouses of LEF offspring and grandchildren demonstrated broadly better health than in matched controls. Throughout marriage, they experienced up to a 25% reduction in all-cause mortality and lower risks of hospitalization, lifestyle-related cancers, alcohol-related disorders, and mental and behavioral disorders. Mortality advantages persisted after divorce. Before marriage, spouses of grandchildren redeemed fewer prescription medications, suggesting better baseline health. These advantages were not explained by higher educational attainment or familial predisposition for longevity. Effect estimates were consistent across outcomes and generations, although they attenuated in the younger grandchildren-spouse cohort, likely due to shorter follow-up. CONCLUSIONS: Spouses marrying into longevity-enriched families exhibit a substantial and broad health advantage that is not attributable to shared genetic predisposition to longevity or socioeconomic differences. These results are consistent with phenotypic assortative mating, convergence of health behaviors within couples, or a combination of both. Our findings suggest that intergenerational clustering of exceptional health extends beyond genetic inheritance and highlight spouses as an important, previously understudied, component of research on longevity-enriched families.
Dietary intake and epigenetic aging in an African population: food groups, dietary patterns, and plant-based diets in the RODAM study.
Auwerda NCS, Mungamba MM, Van der Linden E … +9 more , Beune E, Meeks KAC, Henneman P, Agyemang C, Nicolaou M, Danquah I, Janssens GE, Salomons GS, Chilunga FP
BMC Med · 2026 Apr · PMID 42050526 · Full text
BACKGROUND: Epigenetic age acceleration (EAA) is a biological marker of healthy longevity. While diet–EAA associations are documented in high-income countries, data from low- and middle-income populations—where diets can...
BACKGROUND: Epigenetic age acceleration (EAA) is a biological marker of healthy longevity. While diet–EAA associations are documented in high-income countries, data from low- and middle-income populations—where diets can differ substantially—are unavailable. We examined associations between three complementary dietary components (specific food groups, dietary patterns, and plant-based food proportions) and EAA among Ghanaians across the nutrition transition (rural Ghana, urban Ghana, the Netherlands). METHODS: We analyzed cross-sectional data from 705 adults in the RODAM study (2019–2021). Dietary intake was assessed via a Ghana-adapted Food Frequency Questionnaire (30 food groups; PCA-derived dietary patterns; Satija plant-based diet approach). EAA was estimated using DNA methylation clocks (Horvath, Hannum, PhenoAge, GrimAge) from Illumina EPIC array data. Linear regression models were used adjusted for demographic, lifestyle, health factors, and immune cell composition. Mediation analyses assessed potential biological pathways. RESULTS: In rural Ghana, fish intake was associated with lower Horvath EAA (β= -0.028) and PhenoAge EAA (β= -0.026). In urban Ghana, fermented maize intake was inversely associated with Hannum EAA (β= -0.002) and PhenoAge EAA (β= -0.006). In Amsterdam, condiment intake was positively associated with Hannum EAA (β = 0.010) and PhenoAge EAA (β = 0.012). Dietary patterns and plant-based proportions were not associated with EAA. Dietary vitamins D, B9 and B12 partially mediated associations (11 to 49%). CONCLUSIONS: Among Ghanaians, intake of specific food groups (fish, fermented maize, condiments) were associated with EAA in specific contexts. Dietary patterns and plant-based food proportions did not show associations with EAA. Given the cross-sectional design, causal inference is not possible; longitudinal studies in these settings are warranted.
Mitoxantrone hydrochloride liposome (Lipo-MIT) combined with capecitabine in HER2-negative advanced breast cancer: a dose-escalation, phase I study.
Liu J, Jiang M, Zhang M … +10 more , Zhou S, Li M, Shi X, Li L, Yang X, Li P, Tian M, Ma F, Xu B, Li Q
BMC Med · 2026 Apr · PMID 42050512 · Full text
BACKGROUND: Patients with HER2-negative advanced breast cancer (ABC) have limited chemotherapy options after progression on anthracyclines and taxanes. Mitoxantrone Hydrochloride Liposome (Lipo-MIT), a nanoparticle formu...
BACKGROUND: Patients with HER2-negative advanced breast cancer (ABC) have limited chemotherapy options after progression on anthracyclines and taxanes. Mitoxantrone Hydrochloride Liposome (Lipo-MIT), a nanoparticle formulation with a 60-nm particle size, is designed to reduce toxicity and enhance tumor targeting. We investigated the safety and efficacy of Lipo-MIT combined with capecitabine in pretreated HER2-negative ABC. METHODS: In this phase I dose-escalation study, eligible patients were sequentially enrolled to receive escalating doses of Lipo-MIT (ranging from 16 to 24 mg/m2) administered either every 3 weeks (Q3W) or every 4 weeks (Q4W), combined with standard capecitabine. Primary endpoints included dose-limiting toxicities (DLTs) and determination of the recommended phase 2 dose (RP2D). Secondary endpoints assessed safety and preliminary efficacy. RESULTS: Twenty-six patients were enrolled. Lipo-MIT 22 mg/m2 administered Q4W was identified as the RP2D. The combination demonstrated a manageable safety profile, with no reports of severe cardiac toxicity or hand-foot syndrome. Interstitial lung disease was observed in 19.2% of patients, all of which were manageable and low-grade (Grade 1–2). In a post hoc, exploratory analysis, the objective response rate (ORR) was 36.4% in the Q4W cohort and 13.3% in the Q3W cohort. The Q4W regimen yielded a median progression-free survival (mPFS) of 12.7 months (95% CI, 9.3–NR), which was numerically longer than the mPFS of 5.4 months observed in the Q3W cohort, albeit in the context of a sequential design and baseline imbalances. CONCLUSIONS: The combination of Lipo-MIT and capecitabine showed preliminary antitumor activity and manageable tolerability in heavily pretreated HER2-negative ABC. While the Q4W dosing schedule (22 mg/m²) yielded numerically longer PFS, this comparison is based on a non-randomized, sequential cohort design; thus, all inter-cohort efficacy findings are strictly exploratory and hypothesis-generating. Further evaluation in phase II/III trials as a potential later-line strategy. CLINICAL TRIAL REGISTRATION: NCT06156761.
Adverse events in both childhood and adulthood are associated with molecular, clinical and functional markers of ageing.
Aas M, Hoppen TH, Morina N … +4 more , Zhang S, Li B, Mlakar V, Mutz J
BMC Med · 2026 Apr · PMID 42046058 · Full text
BACKGROUND: Adverse events across the lifespan have been linked to poorer health outcomes, but the biological mechanisms remain unclear. The aim of this study was to quantify the independent and joint associations of adv...
BACKGROUND: Adverse events across the lifespan have been linked to poorer health outcomes, but the biological mechanisms remain unclear. The aim of this study was to quantify the independent and joint associations of adversity experienced in childhood and/or adulthood with molecular, clinical and functional markers of biological ageing. METHODS: We analysed data from up to 153,557 middle-aged and older adults in the UK Biobank. Adversity was assessed through questionnaires capturing five types of childhood and adulthood adverse events. Biological ageing markers included metabolomic age (MileAge) delta, a metabolomic mortality profile, the frailty index, telomere length and grip strength. Regression models were adjusted for age, sex, education, income, ethnicity and neighbourhood deprivation. RESULTS: Across childhood and adulthood exposures, adversity and its severity were most consistently associated with higher frailty index values. The strongest associations were observed in individuals exposed to multiple types of adverse events. Individuals who experienced adversity in both childhood and adulthood also had a metabolite-predicted age exceeding their chronological age and lower grip strength. Abuse was more consistently associated with biological ageing markers than neglect. CONCLUSIONS: Cumulative exposure to adversity across childhood and adulthood is associated with older biological ageing profiles across multiple domains. These findings highlight biological ageing as a potential pathway linking adversity to poor health outcomes and premature mortality.
Prenatal computed tomography (CT) and risk of congenital heart disease and cerebral palsy: A nationwide mother-child paired cohort study.
Kang TW, Heo J, Park T … +9 more , Cho J, Oh SY, Shin JS, Hwang JA, Song KD, Lee MW, Yang WJ, Kim I, Kang D
BMC Med · 2026 Apr · PMID 42045952 · Full text
BACKGROUND: Although the use of computed tomography (CT) imaging during pregnancy is increasing, the decision to use CT imaging remains challenging due to the conflicting considerations of the potential risks of fetal ra...
BACKGROUND: Although the use of computed tomography (CT) imaging during pregnancy is increasing, the decision to use CT imaging remains challenging due to the conflicting considerations of the potential risks of fetal radiation and the medical benefits to the mother, with inconsistent evidence on offspring outcomes. METHODS: Nationwide retrospective cohort study based on the Korean National Health Insurance Service database, including 5,457,153 live births between 2005 and 2019. After 1:4 propensity score matching by maternal characteristics and diagnosis at the same gestational age, 13,307 CT-exposed and 42,946 unexposed pregnancies were included. CT exposure during pregnancy was identified using claims data from the last menstrual period to delivery. Estimated fetal radiation exposure was approximated based on anatomical scan location and categorized into lower and higher exposure groups, corresponding to non-abdominopelvic and abdominopelvic CT, respectively. Outcomes included major congenital malformations, congenital heart disease, and cerebral palsy identified using ICD-10 codes. Cox and logistic regression models were used, accounting for clustering by mother. RESULTS: Among CT-exposed pregnancies, 37.0% occurred within 14 days post-last menstrual period (LMP), and no increased risk of malformations or cerebral palsy was observed in this group. However, CT exposure during the first trimester was associated with a higher risk of major congenital malformations (Odds ratio (OR) 1.14, 95% confidence interval (CI) 1.02–1.30) and cerebral palsy (Hazard ratio (HR) 2.10, 95% CI 1.48–2.97). In a sensitivity analysis, non-abdominopelvic CT was associated with congenital heart disease (OR 1.23, 95% CI 1.03–1.47), but not with cerebral palsy, while abdominopelvic CT was associated with both congenital heart disease (OR 1.47, 95% CI 1.12–1.92) and cerebral palsy (HR 2.04, 95% CI 1.08–3.84). CONCLUSIONS: Even diagnostic-level CT radiation exposure during pregnancy may be associated with increased risks of congenital and neurodevelopmental disorders. Current radiation safety thresholds based solely on carcinogenic risk may underestimate fetal developmental vulnerability. However, this study has limitations, particularly the potential for residual confounding related to clinical acuity at presentation, which may not be fully addressed despite restriction to similar diagnostic indications and extensive propensity score matching.
Peripheral blood biomarkers RCAN1, Clusterin, RAGE, and malondialdehyde for early diagnosis and progression of Alzheimer's disease.
Román-Domínguez A, Mas-Bargues C, Pérez V … +4 more , Medina M, Ávila J, Borrás C, Viña J
BMC Med · 2026 Apr · PMID 42045900 · Full text
BACKGROUND: Alzheimer’s disease (AD) diagnosis often relies on invasive or costly techniques such as cerebrospinal fluid sampling and PET imaging. Peripheral blood biomarkers could offer a minimally invasive and accessib...
BACKGROUND: Alzheimer’s disease (AD) diagnosis often relies on invasive or costly techniques such as cerebrospinal fluid sampling and PET imaging. Peripheral blood biomarkers could offer a minimally invasive and accessible alternative. We aimed to evaluate the diagnostic and prognostic value of four candidate biomarkers—Clusterin, RCAN1, RAGE, and MDA—in the context of cognitive decline, and to generate a predictive model for AD diagnosis. METHODS: We conducted longitudinal and cross-sectional analyses among participants in the Vallecas Project (Spain). For longitudinal analyses, 52 subjects with paired baseline and 5-year follow-up samples were classified as stable cognitively healthy controls, MCI converters, or AD progression. Cross-sectional analyses were conducted using a single observation per subject (n = 83) selected to reduce age differences between the three groups, although AD patients were significantly older. Biomarker levels were measured in plasma or serum by ELISA (Clusterin, RCAN1, RAGE) or UPLC (MDA). A predictive model for AD diagnosis was developed using penalized logistic regression based on baseline data from 76 subjects, incorporating biomarkers, age, sex, and APOE ε4 genotype. RESULTS: In the longitudinal analysis, RCAN1 levels decreased significantly over time in cognitively stable controls, whereas Clusterin levels decreased in the AD progression group. No significant longitudinal changes were observed in MCI converters. In the cross-sectional analysis, RCAN1 and MDA levels were significantly lower in AD patients than in cognitively healthy controls and MCI patients. RAGE levels showed a trend toward reduction in MCI but did not remain significant. At baseline, cognitively healthy individuals who later converted to MCI exhibited higher MDA levels and lower RAGE levels than stable controls. The predictive model achieved a mean cross-validated accuracy of approximately 92% and an area under the ROC curve (AUC) of 0.95 (95% CI: 0.94–0.96), with good calibration. CONCLUSIONS: RCAN1, Clusterin, RAGE, and MDA show potential as peripheral biomarkers for monitoring and early detection of Alzheimer’s disease. Longitudinal and cross-sectional alterations in these markers suggest that biochemical changes may precede clinical symptoms. A multivariable predictive model combining biomarkers with demographic and genetic factors demonstrated robust discriminative performance, supporting the potential utility of minimally invasive blood-based screening tools for AD.
Dystrophin-gene mutation location influences severity of electroretinogram defects in mouse models of Duchenne muscular dystrophy.
Liber AMP, Barboni M, Aoki Y … +2 more , Kremers J, Vaillend C
BMC Med · 2026 Apr · PMID 42035144 · Full text
BACKGROUND: Duchenne muscular dystrophy (DMD) results from mutations in the DMD gene, which differentially affect dystrophin isoforms (Dp427, Dp260, Dp140, Dp71) expressed in distinct brain and retinal cell types. The se...
BACKGROUND: Duchenne muscular dystrophy (DMD) results from mutations in the DMD gene, which differentially affect dystrophin isoforms (Dp427, Dp260, Dp140, Dp71) expressed in distinct brain and retinal cell types. The selective loss of one or more isoforms contributes to heterogeneous cognitive and neuropsychiatric comorbidities. Here, we investigated whether specific mutations differentially affect retinal function by comparing genotype-dependent electroretinographic (ERG) responses in mouse models lacking different dystrophins. METHODS: We analyzed in vivo dark-adapted (DA) and light-adapted (LA) flash electroretinograms (ERG) in four adult DMD mouse models: Mdx and mdx5cv mice lacking Dp427; mdx mice lacking Dp427 and Dp260; and dmd-null mouse lacking all dystrophins, compared to their respective WT littermate male mice and to ERGs previously recorded in mdx52 mice (lacking Dp427, Dp260 and Dp140). RESULTS: Mutations affecting the expression of the Dp140 and Dp71 isoforms produced more severe ERG abnormalities, consistent with findings in patients and aligned with intellectual disability severity. ERG parameter analysis revealed unique roles for Dp427 and Dp260 in rod ribbon-synapse transmission, additional Dp260 function in inner retina, and involvement of Dp140/Dp71 in cone photoreceptor pathways. CONCLUSIONS: These findings highlight the relevance of ERG as a potential biomarker for central dysfunction in DMD, and support its translational application for patient stratification and targeted therapeutic approaches.
Personalizing the treatment of head and neck cancer in vitro: The 3D-OTC model.
Stögbauer F, Weiser T, Dezfouli AB … +11 more , Wirth J, Engelmann L, Budczies J, Ourailidis I, Boxberg M, Pigorsch K, Schmidl B, Strittmatter N, Steiger K, Mogler C, Wollenberg B
BMC Med · 2026 Apr · PMID 42035072 · Full text
BACKGROUND: Treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging and the survival rates of affected patients remain poor. A three-dimensional organotypic co-culture (3D-OTC) model where patient...
BACKGROUND: Treatment of head and neck squamous cell carcinoma (HNSCC) remains challenging and the survival rates of affected patients remain poor. A three-dimensional organotypic co-culture (3D-OTC) model where patient derived tumor tissue is cultured on human-derived fibroblasts (dermal equivalent, DE) was evaluated regarding its comparability to primary tumor tissue and its applicability in drug resistance testing. METHODS: 3D-OTC models were cultured from n = 10 HNSCC patients for up to 21 days. The growth pattern at the DE was compared to tumor budding of corresponding resection specimens. Furthermore, we immunohistochemically determined the immune cell infiltrate of primary tumor tissue and corresponding 3D-OTC models. Spatially resolved gene expression analysis (“Xenium in situ”) was performed for separate regions of interest within the 3D-OTC specimens and within primary tumor tissue. Up-regulated and down-regulated genes of the 3D-OTC samples were included in gene set enrichment analysis and up-regulated genes between invasive (invading the DE) and non-invasive tumor cells within the 3D-OTC samples were included in drug resistance testing using publicly available databases. RESULTS: The growth pattern observed at the DE was associated with tumor budding in primary tumor tissue. The density of CD3-/CD20-/CD56-positive cells was lower in 3D-OTC samples compared to primary tumor tissue. No such changes were observed for CD68-positive cells and no significant changes in the density of the immune cell infiltrate were detected during the cultivation period. The centroids and dispersion of the gene expression of the 3D-OTC samples did not differ from the corresponding primary tumor tissue. The regions of interest within the 3D-OTC samples showed distinct functional states in gene set enrichment analysis. The comparison of genes up-regulated in invasive tumor parts of the 3D-OTC samples could explain resistance of tumor subclones to certain chemotherapeutics. CONCLUSIONS: The 3D-OTC model morphologically and transcriptomically resembles primary tumor tissue and its biology while preserving the tumor microenvironment. Furthermore, the 3D-OTC model allows the standardized evaluation of tumor tissue by the definition of transcriptomically separate regions of interest and thus, could help to evaluate the impact of personalized therapeutic interventions on the tumor and its microenvironment in vitro.
Introducing the need for a consensus-based framework for protocol modifications to improve trial trustworthiness.
Burgwinkel C, Gicquel M, Boutron I … +5 more , Chevret S, Held L, Moher D, Naudet F, Locher C
BMC Med · 2026 Apr · PMID 42032663 · Full text
BACKGROUND: Transparency in randomized controlled trials (RCTs) has substantially improved in recent years, notably through trial registration and public availability of protocols and statistical analysis plans (SAPs). H...
BACKGROUND: Transparency in randomized controlled trials (RCTs) has substantially improved in recent years, notably through trial registration and public availability of protocols and statistical analysis plans (SAPs). However, the reporting of protocol and SAPs modifications remains insufficiently standardized. As a result, even when these documents are publicly available, it is often challenging and time-consuming to identify what changes were made, why they were implemented, and whether they may affect the trustworthiness of the trial results. ARGUMENTS: In this paper, we advocate for the development of a consensus-based framework for protocol modifications in RCTs. This need arises from the inherent tension between the necessity and the risks of protocol modifications. On the one hand, such modifications are often essential to address unforeseen operational, scientific, or ethical challenges. On the other hand, they may introduce bias and undermine confidence in trial findings, particularly when changes are data-driven or insufficiently justified. Although major transparency initiatives have strengthened trial reporting, important gaps persist. We review empirical evidence demonstrating the prevalence and nature of such modifications and discuss their potential implications for the validity, interpretation, and credibility of trial findings. Furthermore, readers, reviewers, and decision-makers face substantial challenges in identifying, understanding, and evaluating the potential impact of protocol changes. In the absence of standardized reporting, key information remains dispersed across multiple documents, placing an unreasonable burden on stakeholders to identify, interpret, and assess protocol modifications and their implications for the credibility of trial results. CONCLUSIONS: Standardized and transparent reporting of protocol modifications is essential to ensure that their nature, timing, and rationale can be clearly understood and critically evaluated. We therefore advocate for the development of a consensus-based reporting framework, informed by a Delphi process, to improve transparency, facilitate critical appraisal, and strengthen confidence in RCT findings.
Therapeutic TG2 inhibition reverses systemic multiomic dysregulation in celiac disease.
Dotsenko V, Le HH, Rajić S … +18 more , Moulder R, Kettunen J, Hirvonen MK, Dickens AM, Hyötyläinen T, Tewes B, Zimmermann T, Mohrbacher R, Suomi T, Lehtimäki T, Lahesmaa R, Orešič M, Elo LL, Raitoharju E, Schuppan D, Mäki M, Viiri K, CEC-3 Investigators
BMC Med · 2026 Apr · PMID 42032651 · Full text
BACKGROUND: Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD autoantigen and enzyme transglutaminase 2 (TG2) is c...
BACKGROUND: Celiac disease (CeD) is an autoimmune disease triggered by dietary gluten in genetically predisposed individuals. Deamidation of gluten peptides by the CeD autoantigen and enzyme transglutaminase 2 (TG2) is central to the pathogenesis of CeD. Inhibition of TG2 with the specific inhibitor ZED1227 effectively prevents gluten-induced histological damage in CeD patients. Here we aimed to explore the systemic plasma lipidomic, proteomic and DNA methylomic changes in ZED1227-treated CeD patients undergoing a gluten challenge. METHODS: Individuals with CeD on a long-term gluten-free diet (GFD) underwent a 6-week gluten challenge combined with daily 100 mg ZED1227 drug (PGCd, n = 28) or placebo (PGCp, n = 19). Samples were collected at baseline (GFD) and post-gluten challenge (PGC). Mass spectrometry-based lipidomic and proteomics profiling were applied to plasma samples matched with duodenal histology. Whole blood samples (drug, n = 20; placebo, n = 16) were subjected to DNA methylation analysis. Comparative analyses were performed between the groups, with adjustment for BMI, age, sex, and country of origin. RESULTS: Significantly different gluten-induced plasma lipidomic changes were detected between GFD vs. PGCp and between GFD vs. PGCd, with 46 lipids differentially expressed in the placebo group and 6 in the drug group suggesting that the ZED1227 normalized gluten-induced lipidomic changes in plasma. Changes in medium-chain fatty acylcarnitines (CARs), particularly CAR 10:1 and CAR 9:0, were correlated with transient, non–clinically significant changes in renal biomarkers, with kidney function remaining within the normal range in the PGCp group. Glomerular filtration rate and plasma creatinine were restored with ZED1227. Integrated multi-omics analysis revealed a coordinated immune–epigenetic–lipid module centered on Ficolin-2, PUFA-enriched triglycerides, and a tightly co-regulated CpG cluster in the PER3 circadian regulator gene, highlighting selective immunometabolic coupling independent of clinical stratification. Drug treatment revealed consistent patterns suggesting normalization of the proteome and DNA methylome indicating that ZED1227 attenuated the systemic responses to gluten challenge. CONCLUSIONS: These findings provide evidence that ZED1227 can significantly prevent the gluten-induced CeD-associated systemic changes in plasma/blood. CLINICAL TRIAL: EudraCT 2017-002241-30.
Adulthood stressful life events as predictors of incident cardiovascular disease: insights from two prospective cohorts.
Wu S, Lyu S, Wang Y … +9 more , Liang H, Xu W, Wang J, Shao X, Zhang H, Liu H, Huang B, Chen Y, Lip GYH
BMC Med · 2026 Apr · PMID 42026604 · Full text
BACKGROUND: Stressful life events (SLEs) in adulthood are potential risk factors for cardiovascular disease (CVD), yet evidence remains inconsistent. This study examined the association between adulthood SLEs and inciden...
BACKGROUND: Stressful life events (SLEs) in adulthood are potential risk factors for cardiovascular disease (CVD), yet evidence remains inconsistent. This study examined the association between adulthood SLEs and incident CVD and evaluated mediation by depression, physical inactivity, and smoking. METHODS: We analyzed harmonized data from two nationally representative aging cohorts: the US Health and Retirement Study and the English Longitudinal Study of Ageing. SLEs were assessed at baseline, and incident CVD was physician-diagnosed. We used Cox and restricted mean survival time (RMST) regression to estimate hazard ratios (HRs) and RMST differences, set at the time point when 90% of incident CVD events had accrued (7.8 years). Population attributable fractions (PAFs) based on RMST and mediation analyses via RMST pseudo-value regression quantified contributions of SLEs and behavioral pathways. RESULTS: Among 18,898 participants without baseline cardiovascular disease (mean age 64.5 years; 39.8% male), 2,782 incident CVD cases were documented (incidence rate: 2.51 per 100 person-years). RMST analysis showed that any SLE exposure was related to significant reductions in event-free survival, including a 2.22-month decrease for CVD (95% CI: -2.90 to -1.53), a 1.57-month decrease for heart disease (95% CI: -2.16 to -0.99), and a 0.79-month decrease for stroke (95% CI: -1.16 to -0.41), with a clear dose-response relationship. Corresponding Cox proportional hazards models showed adjusted HRs of 1.20 (95% CI: 1.11–1.30) for CVD, 1.16 (95% CI: 1.07–1.27) for heart disease, and 1.26 (95% CI: 1.09–1.46) for stroke. Each additional SLE increased CVD, heart disease, and stroke risks by 11%, 10%, and 11%. PAFs attributable to SLEs exposure were 2.6% for CVD, 1.7% for heart disease, and 0.8% for stroke. Mediation analyses revealed that depression, physical inactivity, and current smoking accounted for 7.2%, 4.5%, and 4.5% of the total effect of SLEs on CVD, respectively. CONCLUSIONS: Adulthood SLEs are independently associated with increased CVD risk, with depression, physical inactivity, and smoking explaining a modest proportion of this association.
Camrelizumab plus apatinib for immune checkpoint inhibitor-naive patients with metastatic clear cell renal cell carcinoma after first-line tyrosine kinase inhibitor treatment failure: a single-arm phase 2 trial.
Cai X, Zheng X, Wang D … +10 more , Huang T, Peng Y, Zhang Z, Guo S, Han H, He L, Xu W, Zhou F, Jiang L, Dong P
BMC Med · 2026 Apr · PMID 42026573 · Full text
BACKGROUND: In the immunotherapy era, tyrosine kinase inhibitor (TKI) monotherapy is still commonly used for patients with metastatic renal cell carcinoma (RCC) in clinical practice. Prospective evidence on immunotherapy...
BACKGROUND: In the immunotherapy era, tyrosine kinase inhibitor (TKI) monotherapy is still commonly used for patients with metastatic renal cell carcinoma (RCC) in clinical practice. Prospective evidence on immunotherapy plus tyrosine kinase inhibitor (TKI) after first-line TKI treatment failure is scarce. This study evaluated the efficacy and safety of camrelizumab plus apatinib in this setting. METHODS: In this single-arm, two-center phase 2 study, patients with metastatic clear cell RCC who had failed first-line TKI treatment were enrolled. Camrelizumab 200 mg once every 2 weeks and apatinib 250 mg once daily were continuously administered until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Between August 2020 and January 2024, 41 patients were enrolled and treated. Median age was 57.0 years (range, 36-81), and 34 (82.9%) patients were males. By the data cutoff date on December 31, 2024, the median follow-up duration was 19.0 months (range, 3.4-49.4). Median PFS was 11.6 months (95% confidence interval [CI], 6.2-18.5), and the median overall survival was not reached. The objective response rate was 41.5% (95% CI, 26.3%-57.9%). The most common grade 3-4 treatment-related adverse events were increased alanine aminotransferase (11 [26.8%]), increased aspartate aminotransferase (nine [22.0%]), and proteinuria (nine [22.0%]). No treatment-related deaths occurred. CONCLUSIONS: Our findings suggest the potential of camrelizumab plus apatinib in patients with immunotherapy-naïve metastatic RCC after first-line TKI treatment failure, warranting further investigation. TRIAL REGISTRATION: ChiCTR.org.cn, ChiCTR2000034384. Registered on July 4, 2020.
Multiparameter concept-based interpretable model for early breast cancer diagnosis and structured reporting: a multi-center, multi-reader, radiologist-in-the-loop study.
Qu J, Liu Y, Zhang M … +17 more , Xie H, Yang J, Xu M, Yang L, Qian W, Li Y, Jiang J, Zhou L, Zeng J, Tu D, Zhang J, Sun J, Huang J, Jing J, Shi H, Gu S, Lui S
BMC Med · 2026 Apr · PMID 42026532 · Full text
BACKGROUND: Accurately differentiating early-stage breast cancer from benign lesions on MRI is essential to reduce unnecessary biopsies. However, the limited interpretability of current deep learning models hinders their...
BACKGROUND: Accurately differentiating early-stage breast cancer from benign lesions on MRI is essential to reduce unnecessary biopsies. However, the limited interpretability of current deep learning models hinders their clinical trustworthiness and adoption. This study aimed to develop a clinically interpretable concept bottleneck model (CBM) that integrates radiologist-specific knowledge and automatically generates structured reports, thereby improving diagnostic accuracy and consistency in breast MRI interpretation. METHODS: Preoperative breast MR images and radiological reports were retrospectively collected from five institutions (January 2016–July 2025) and allocated to internal, external and multi-reader cohorts. Lesion-related descriptors from free-text MRI reports were standardized into BI-RADS-compliant concepts. These concepts, alongside multiparametric MR sequences, were input into the CBM for classification and structured reporting of the lesions annotated by radiologists using bounding boxes. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and compared against a black-box deep learning model. The accuracy of CBM-generated concepts was evaluated. A two-phase multi-reader study was further conducted to assess clinical utility. RESULTS: A total of 1,695 pathology-confirmed breast lesions (857 malignant and 838 benign) from 1,634 patients (median age 46 years, IQR 39–53) were included. The CBM achieved an AUC of 0.92 (95%CI 0.90–0.93) on the test set, comparable to the black-box model (AUC: 0.93, 95%CI 0.92–0.94). Concept accuracy ranged from 0.64 to 1.00. In the multi-reader study, the CBM matched the diagnostic accuracy of one radiologist and exceeded that of seven others (all P < 0.05). With CBM assistance, radiologists correctly downgraded 22.1% of lesions to benign. Diagnostic accuracy improved for three radiologists (from 0.71 to 0.72 to 0.82–0.91, all P < 0.05), and inter-reader agreement increased for both concept recognition and BI‑RADS category (Gwet’s AC1: 0.27-1.00 to 0.46-1.00). CONCLUSIONS: The CBM provides a versatile framework for classifying early breast cancer and benign lesions. By employing an image-concept alignment strategy, it enhances intrinsic interpretability and offers radiologists clinically relevant, intelligible decision support that serves both diagnostic and educational needs. Moreover, this retrospective study demonstrates its potential to reduce unnecessary biopsies for benign breast lesions and to improve reporting consistency in breast MRI.
Duration of anti-seizure medicines started for acute symptomatic seizures due to acute meningitis: a systematic review and meta-analysis.
Prasad M, Kumar A, Couban R … +6 more , Schiess N, Kothari K, Brohan E, Binello N, Venuti F, Dua T
BMC Med · 2026 Apr · PMID 42021346 · Full text
BACKGROUND: Acute symptomatic seizures (ASS), a frequent complication of meningitis, are potentially life-threatening and are a predictor of epilepsy if not managed appropriately. The optimal duration of anti-seizure med...
BACKGROUND: Acute symptomatic seizures (ASS), a frequent complication of meningitis, are potentially life-threatening and are a predictor of epilepsy if not managed appropriately. The optimal duration of anti-seizure medicines (ASM) in these patients remains unclear. This systematic review evaluates the evidence for earlier versus later cessation of ASM in patients with meningitis who experience ASS. METHODS: A comprehensive literature search was conducted across Medline via OVID, Embase via OVID, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov. Eligible studies included randomized controlled trials and cohort studies that compared ASM cessation within 3 months of initiation of treatment to cessation beyond 3 months. Pooled estimates for outcomes including epilepsy development, seizure recurrence, and adverse events were calculated using random-effects meta-analysis. The certainty of evidence was assessed using the GRADE methodology. RESULTS: Out of 4283 records screened for eligibility, none were found to provide direct evidence in people with meningitis. Two studies on people with encephalitis were included in the meta-analysis as indirect evidence. A randomized controlled trial (RCT) compared 4 weeks versus 12 weeks of ASM in children with acute encephalitis syndrome, while a cohort study investigated ASM duration in adults, including a subset with bacterial meningitis. Both studies found no significant difference in seizure recurrence between earlier and later cessation groups. The pooled risk ratio for seizure recurrence was 1.14 (95% CI, 0.26-5.01). The certainty of the evidence was very low due to indirectness and imprecision. Indirect evidence from other causes of ASS was inconclusive with regard to the duration of ASM. CONCLUSIONS: The available evidence is inconclusive with regard to the difference between early and late ASM cessation in reducing seizure recurrence. Due to very low certainty of evidence, individualized clinical judgment remains crucial. Further research, specifically targeting bacterial meningitis, is needed to clarify optimal ASM duration in this population.
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