Communications medicine最新文献

Background: Multimorbidity, the co-occurrence of multiple long-term conditions (LTCs), is an increasingly important clinical problem, but little is known about the underlying causes. We investigate the role of a critical multimorbidity risk factor, obesity, as measured by body mass index (BMI), in explaining shared genetics amongst 71 common LTCs.

Methods: In a population of northern Europeans, we estimated genetic correlation, between LTCs and partial genetic correlations after adjustment for the genetics of BMI. We used multiple causal inference methods to confirm that BMI causally affects individual LTCs, and their co-occurrence. Finally, we quantified the population-level impact of intervening and lowering BMI on the prevalence of 15 key common multimorbid LTC pairs.

Results: BMI partially explains some of the shared genetics for 740 LTC pairs (30% of all pairs considered). For a further 161 LTC pairs, the genetic similarity between the LTCs was entirely accounted for by BMI genetics. This list included diabetes and osteoarthritis and gout and osteoarthritis: Causal inference methods confirmed that higher BMI acts as a common risk factor for a subset of these pairs, and therefore BMI-lowering interventions would likely reduce their prevalence. For example, we estimated that a 1 standard deviation or 4.5 unit decrease in BMI would result in 17 fewer people with both chronic kidney disease and osteoarthritis per 1000 who currently have both LTCs.

Conclusions: Our genetics-centred approach quantifies the contribution of obesity to multi-morbidity. Our method for calculating full and partial genetic correlations is published as an R package {partialLDSC}.

Background: Early life nutrition is associated with child behaviour; however, the interplay with genetic vulnerability is understudied. We hypothesised that psychiatric genetic risk interacted with early nutrition to predict behavioural problems in childhood and adolescence.

Methods: The Raine Study participants with genetic information aged 2-17 were repeatedly evaluated with the child behaviour checklist total problems score (CBCL_TOT). Breastfeeding duration was recalled at age 1, 2 and 3 follow-up, and toddler diet derived by an age-1 24-h maternal recall (EAT1, scale 0-70, SD 10, higher scores proxying healthy diet). We derived polygenic scores (PGS) impacting general psychopathology: attention-deficit hyperactivity disorder (ADHD), depression, chronic multisite pain (CMSP), total behaviour problems and birthweight. In confounder-adjusted mixed-effects models of CBCL_TOT throughout follow-up we examined nutrition-by-PGS interactions.

Results: In 1393 participants, a borderline signal suggests that 1 month longer breastfeeding reduces CBCL_TOT by -0.108 (95% CI [-0.184, -0.0289]) exclusively in individuals with a higher CMSP PGS (Interaction p = 0.03). In 1310 participants, a strong signal suggests that 1 EAT1 point increase results in a reduced CBCL_TOT by 0.121 points (95% CI [-0.171, -0.0704]) exclusively in individuals with a lower ADHD PGS (Interaction p = 0.0005). Post hoc analysis suggests that plant-based food consumption drives the favourable EAT1-CBCL_TOT association.

Conclusions: Nutrition in early life and psychiatric genetic risk may interact to determine lasting child behaviour. Contrary to our hypothesis, we find dietary benefits in individuals with lower ADHD PGS, necessitating replication. We also highlight the possibility of including genetics in early nutrition intervention trials for causal inference.

Background: Many transfeminine people (assigned male at birth with feminine gender identities) undergo vaginoplasty, a surgical procedure constructing a neovagina, typically using penile and scrotal tissue. In cisgender females, gynecological symptoms (pain, discharge, malodor) are often attributed to bacterial vaginosis, which can be diagnosed using Nugent scoring of gram-stained vaginal smears. The Nugent score assesses the abundance of large gram-positive rods versus small or curved gram-variable rods, traditionally for the detection of Lactobacillus, Gardnerella vaginalis, and Mobiluncus, respectively. Although unvalidated, this method is frequently applied to neovaginal samples to diagnose gynecological symptoms and dysbiosis. This study assessed the Nugent score's utility for diagnosing neovaginal dysbiosis in transfeminine people.

Methods: As a part of the TransBiota study, n = 39 transfeminine participants self-collected neovaginal smears. Smears were Gram stained and Nugent scored, and scores were correlated with data on neovaginal bacterial composition (16S rRNA gene sequencing), neovaginal cytokines (Luminex multiplex immunoassay), and self-reported symptoms.

Results: We show more than 70% of neovaginal smears fell in the 7-10 Nugent score range, indicative of Bacterial Vaginosis in cisgender women. However, scores fail to correlate with the abundance of Nugent-targeted bacteria. Bacteria with similar morphotypes, but not belonging to Lactobacillus, Gardnerella, or Mobiluncus, are highly abundant and prevalent in the neovagina. Nugent score also fails to predict local inflammation or clinical symptoms.

Conclusions: The Nugent score is not an effective tool to identify neovaginal dysbiosis or indicators of health in transfeminine individuals. Clinicians need the development of accurate, evidence-based diagnostic tools for the neovagina.

Background: Traumatic joint dislocations of the hip, knee, and shoulder (DOH, DOK, and DOS) significantly impact global healthcare. This study assesses the global burden of joint dislocations using the Global Burden of Disease (GBD) 2021 database, focusing on their association with the socio-demographic index (SDI).

Methods: Data from the GBD 2021 are analyzed to determine the age-standardized rates (ASR) of incidence, prevalence, and years lived with disability (YLDs) for dislocations. We integrate the SDI with the concentration index, assessing disparities in the burden of these joint dislocations. Frontier analysis is performed to identify potential improvement areas and disparities among countries by development status. The age-period-cohort (APC) model projects the disease burden to 2045, with a focus on age and gender distributions and primary causes.

Results: From 1990 to 2021, the incidence, prevalence, and YLDs of DOH/DOK/DOS all increase, while ASRs decline, suggesting a deceleration in growth. YLDs of DOH, DOK, and DOS rise by 57.21%, 28.38%, and 15.48%, respectively. Men exhibit a higher burden, yet women show a steeper rise. Significant geographical variation exists, with lower SDI countries facing higher burdens. Falls and road injuries remain the main contributors to the burden, and lower-development countries demonstrate potential for reduction. Temporal trends vary by age, sex, and SDI, with projections indicating continued disparities to 2045.

Conclusions: Traumatic joint dislocations show marked heterogeneity in age, sex, and SDI, with the most significant differences in low-income regions. Research should prioritize policy development and targeted prevention and treatment strategies for groups at high-risk for joint dislocation to effectively mitigate the disease burden.

Background: Cardiovascular disease remains a major source of morbidity and mortality, and population imaging studies have yielded insights into disease etiology and risk.

Methods: In this study, we segment the heart, aorta, and vena cava from abdominal magnetic resonance imaging (MRI) scans using deep learning. We generate six image-derived phenotypes (IDP): heart volume, four aortic and one vena cava cross-sectional areas (CSA), from 44,541 UK Biobank participants, and explore their associations with disease outcomes, as well as genetic and environmental factors.

Results: Here we show concordance between our IDPs and related IDPs from cardiac magnetic resonance imaging, the current gold standard, and replicate previous findings related to sex differences and age-related changes in heart and vessel dimensions. We identify a significant association between infrarenal descending aorta CSA and incident abdominal aortic aneurysm, and between heart volume and several cardiovascular disorders. In a genome-wide association study, we identify 72 associations at 59 loci (15 novel). We derive a polygenic risk score for each trait and demonstrated an association with thoracic aneurysm diagnosis, pointing to a potential screening opportunity. We demonstrate substantial genetic correlation with cardiovascular traits including aneurysms, varicose veins, dysrhythmia, and cardiac failure. Finally, heritability enrichment analysis implicates vascular tissue in the heritability of these traits.

Conclusions: This study illustrates the value of non-specific abdominal MRI for exploring cardiovascular disease risk in cohort studies, and identifies novel genetic associations with vascular dimensions.

Background: Gliomas, the most common brain tumors, present significant challenges in treatment, particularly glioblastoma multiforme (GBM), due to their infiltrative nature and difficulty in achieving gross total resection (GTR). Accurate assessment of surgical resection extent is critical for patient prognosis and survival. This study investigates the utility of cerebrospinal fluid (CSF) cell-free DNA (cfDNA) as a quantitative biomarker for evaluating glioma resection extent and patient prognosis.

Methods: Next-generation sequencing (NGS) was used to profile genomic alterations in tumor DNA and CSF cfDNA obtained before and after surgery. Concordance between mutations detected in tumor tissue and CSF cfDNA was assessed. Post-operative changes in mean mutant allele frequency (MAF) and tumor mutational burden (TMB) were evaluated, and their associations with overall survival (OS) were analyzed.

Results: A high concordance rate (83.50%) exists between CSF cfDNA and tumor tissue, particularly for key somatic mutations such as TERT, TP53, PTEN, and IDH1. Post-operative cfDNA analysis shows a significant reduction in mean MAF and TMB. Apart from non-GTR and multiple lesions, patients who exhibit a ≥ 90% reduction in mean MAF or in the MAF of driver mutations post-surgery demonstrate significantly improved OS.

Conclusions: These findings suggest that CSF cfDNA effectively represents the genetic profile of gliomas and serves as a sensitive measure for surgical resection efficacy and patient prognosis, highlighting its potential as a non-invasive biomarker for enhancing post-operative management in glioma patients.

Background: In tumors, reciprocal spatial interactions between immune cells, their mediators, the extracellular matrix, and mutated neoplastic cells impact all aspects of treatment resistance. The operational mechanisms of these interactions are foundational for developing insights and targets for cancer therapy and prevention. Spatial quantification of the tumor microenvironment system from image data has untapped potential for patient stratification.

Methods: Here, we present SparTile, a powerful computational approach for the analysis of multiplex proteomics images to reveal clinically relevant structural organization in the tumor microenvironment. SparTile enables robust and unbiased identification and characterization of tumor microenvironments based on spatial relationships among protein markers without the need for cell segmentation or classification.

Results: Applied to tissues of patients with triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer, SparTile identifies repeatable microenvironments with specific cellular relationships. Several microenvironments are characterized by risk markers such as Ki67+ (p-value = 0.052) and vimentin+ (p-value < 0.01) tumor cells, which correlate with poor survival. Furthermore, myeloid markers in an MX1-positive tumor environment correlate with shorter survival (p-value = 0.04). Finally, the relative distance between tumor and myeloid cell markers is a strong prognostic risk factor in multivariate Cox models (p-value < 0.01). This distance metric is externally validated on two datasets of breast cancer multiplex images (p-values < 0.01).

Conclusions: Our results show that unbiased protein-based and segmentation-free spatial analysis is effective for identifying clinically relevant biomarkers from multiplex tumor images and identifying predictive biology.

Background: Idiopathic Multicentric Castleman Disease, Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Organomegaly (iMCD-TAFRO) is a rare cytokine storm syndrome with high mortality. Pathogenesis of Castleman disease (CD) remain largely unknown. We aim to unravel the role of Mediterranean fever gene MEFV variants, the key gene variants implicated in familial Mediterranean fever, in CD.

Methods: Clinical data from a retrospective cohort of 37 patients with CD were collected. Blood and/or lymph node biopsy specimens were obtained for whole-exome sequencing. In vitro lipopolysaccharide stimulation experiment and single-cell RNA-sequencing (scRNA-seq) were performed to characterize the immune signature using peripheral blood mononuclear cells from an adolescent TAFRO patient, his asymptomatic parents, and a healthy control. The relative gene expression were examined by quantitative PCR. Cytokine levels were assessed using Luminex. Statistics were performed by SPSS and GraphPad Prism.

Results: Here we show an adolescent TAFRO patient with familial MEFV mutations demonstrates responsiveness to anti-IL-6 containing therapy. Through comprehensive analysis of a cohort of 37 CD patients, we observe a high prevalence of MEFV mutations (76%, 28/37). Notably, the MEFV E148Q-P369S-R408Q variant is present in 19% (7/37) of all patients and 50% (2/4) of the TAFRO subtype, with variant carriers exhibiting more severe disease course. Inflammation responses experiments and scRNA landscape reveal that MEFV expression is dominant in CD16⁺ monocytes and correlated with IL-6 pathway activation likely via the interaction with naïve B/memory B cells in the TAFRO.

Conclusions: This study presents one of the largest cohorts demonstrating the high prevalence of MEFV variants in CD, providing important insights for understanding and treating CD, particularly TAFRO.

Background: Relatively few studies have investigated HIV-1 persistence in tissues, especially in healthy people-living-with-HIV-1 (PLWH) on a successful antiretroviral regimen containing second generation integrase inhibitors.

Methods: In the ANRS EP64 DOLUVOIR, we explore HIV-1 persistence in five accessible anatomical sites in 20 PLWH on an efficient first-line ART regimen containing dolutegravir with virological load <50 copies/mL: PBMCs, rectum, adipose tissue, lymph node and sperm. We quantify total HIV-DNA and cell-associated HIV-1 RNA in different compartments. We sequence HIV-1 DNA for searching drug resistance mutations (DRM) (in RT and INT) and for studying HIV diversity within tissues (ENV). Intact proviral DNA is estimated in PBMCs with an adapted IPDA assay.

Results: Broad ranges of total HIV-DNA and transcripts levels are detected in lymph nodes, PBMCs, adipose tissue and rectum with the highest levels being found in lymph nodes (2.77 log copies HIV-1-DNA/10⁶ cells and 1.50 log copies of HIV-1 cell-associated-RNA/µg RNA). HIV-1 DNA is undetected in all sperm samples (n = 19) except for one (1.52 log copies HIV-1-DNA/106 cells). No difference is noted between the diversity in the four compartments. DRMs to the current regimen are found archived in compartments of six participants. Only two major DRMs to dolutegravir (G118R and R263K) are found archived in two participants. They are the results of APOBEC hypermutations.

Conclusions: Despite ongoing transcriptional activity, persistence of HIV-1 in deep tissues is not associated with the selection of DRMs to dolutegravir on intact proviruses. Our results suggest that the detectable transcriptional activity stems predominantly from defective proviral DNA.