Distinct Patterns Of Association Research Articles

Riparian woody plant communities in the Romanian Carpathians: Species diversity and community structure of Salix and Hippophaë communities.

Riparian woody plant communities, including shrubs and trees, are essential for maintaining biodiversity, protecting against floods, reducing erosion, and transporting nutrients. However, these habitats are greatly threatened by human activities, particularly agricultural land acquisition, and the introduction of invasive species. This study examined species diversity and interspecific association in riparian woody plant communities along rivers in the Romanian Carpathians. The study focused on communities of Salix purpurea, S. alba, and Hippophaë rhamnoides in mountain regions, with varying sampling efforts at different sites for each species. A total of 174 plant species were found, predominantly herbaceous (77.9%), followed by trees (11.6%) and shrubs (10.5%). While S. alba and S. purpurea communities show high species richness and abundance, S. alba has slightly higher diversity (H' ≈ 2.23, SD = 0.28) than S. purpurea (H' ≈ 1.69, SD = 0.42). Contrarily, significant differences exist between H. rhamnoides and S. alba communities in species richness (p = .007) and Shannon diversity (p = .004). PCA analysis elaborated on distinct distribution patterns of plant associations within habitats S. purpurea community, H. rhamnoides community, and S. alba community. Four invasive species (Oenothera biennis L. and Oxalis stricta L. in S. alba communities, Reynoutria sachalinensis Nakai in both S. purpurea and H. rhamnoides communities, and Erigeron canadensis L. in H. rhamnoides communities) were identified, as requiring conservation efforts. Hemicryptophytes dominate species richness, while microphanerophytes and megaphanerophytes significantly contribute to plant abundance. H. rhamnoides formed Hippophaë rhamnoides dunes (2160) Natura 2000 habitat, while S. alba created galleries within the 92A0 Salix alba and Populus alba habitat. In conclusion, the findings from this study highlight the importance of preserving riparian habitats because their value goes beyond local or regional considerations and extends to the global scale due to their unique characteristics.

Trace element status in canine endocrine diseases

A balanced trace element status is essential for the optimal functioning of all organisms. However, their concentrations are often altered in diverse medical conditions. This study investigated the trace element profiles in plasma samples of dogs with endocrine diseases and used chemometric techniques to explore their associations with biochemical data. Thirteen elements (As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Ni, Pb, Se and Zn) were measured in 40 dogs with hyperadrenocorticism (HAC), 29 dogs with diabetes mellitus (DM), 11 dogs with hypothyroidism (HT) and 30 control dogs using inductively coupled plasma mass spectrometry (ICP-MS). Statistically significant differences were observed for As, Cu, Mo, Se and Zn. In comparison with the control group, the HT patients had higher As and lower Se levels, while the HAC group had higher concentrations of Mo. All three disease groups had higher Cu and Zn concentrations than the control group, with the DM group having higher Cu concentrations and the HAC group higher Zn concentrations than the other endocrinopathy groups. The chemometric analysis revealed distinctive association patterns for discriminating each pathology group and the control group. Moreover, the analysis revealed the following associations: Mo with glucose levels and Cu with fructosamine levels in the DM group, As with cortisol levels in the HAC group, and Se with TT4 levels and As with TSH levels in the HT group. The study findings provide valuable insights into the complex relationships between trace elements and endocrinopathies, elucidating the associations with biochemical markers in these diseases. Larger-scale studies are necessary to fully understand the observed relationships and explore the potential clinical applications.

Potential Role of Circulating PD-L1+ Leukocytes as a Predictor of Response to Anti-PD-(L)1 Therapy in NSCLC Patients.

PD-(L)1 inhibitors are part of the treatment strategy for non-small cell lung cancer (NSCLC) although its efficacy is limited to certain patients. Our study aimed to identify patients who might benefit from anti-PD-(L)1 inhibitors by analyzing the PD-L1 expression on circulating leukocytes and its evolution during treatment. One hundred thirteen NSCLC patients, according to their radiological response after 10-12 weeks of treatment, were classified into responders, stable, and progressive disease. Percentages of circulating PD-L1+ leukocytes, PD-L1+ platelets (PLTs), and leukocyte-PLT complexes were assessed using flow cytometry, and plasma concentrations of soluble immunomodulatory factors were quantified by ELISA. Responders exhibited significantly higher pre-treatment percentages of PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs than progressors. The percentages of these populations decreased in responders post-treatment, contrasting with stables and progressors. PLTs notably contributed to PD-L1 expression in CD14+ cells and neutrophils. Plasma cytokine analysis revealed baseline differences only in IL-17 concentration among groups, whereas network analyses highlighted distinct association patterns between plasma molecules and PD-L1+ leukocytes after 10-12 weeks of treatment. Our findings suggest that pre-treatment assessment of circulating PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs may be helpful in identifying NSCLC patients who are potential candidates for anti-PD-(L)1 therapy.

OA09 Significant association between disease duration in axial spondyloarthritis and the occurrence of uveitis and inflammatory bowel disease, with no such association found for psoriasis

Abstract Background/Aims Axial spondyloarthritis is a chronic inflammatory condition primarily impacting the spine and sacroiliac joints. In addition to spinal inflammation and peripheral symptoms, it frequently presents with extra-musculoskeletal manifestations such as inflammatory bowel disease, psoriasis, and anterior uveitis, collectively adding to the overall disease burden. Although existing research has explored the heightened risk of ophthalmological manifestations with prolonged disease duration, there is a paucity of literature examining the association between disease duration in axial spondyloarthritis and the onset of inflammatory bowel disease and psoriasis. Aim: To investigate the relationship between axial spondyloarthritis disease duration and the development of extra-musculoskeletal manifestations. Methods This is a retrospective cohort study with data obtained from the Ankylosing Spondylitis Registry of Ireland (ASRI), which is a large cross-sectional, multicentre cohort study. Using both univariate and multivariate regression analyses, we examined the relationship between axial spondyloarthritis disease duration and extra musculoskeletal manifestations. In the multivariate analysis, several covariates including gender, body mass index, smoking, and HLA-B27 status were considered to account for their potential influence on the observed associations. Results Demographic details were available for 912 patients included at the time of analysis. The median disease duration in years for our cohort was 16. Table 1 presents relevant general characteristics of the ASRI cohort and the results of our regression analysis. Uveitis exhibited a highly significant association (P < 0.001) with AxSpA duration in both univariate and multivariate analyses, even after accounting for covariates. Inflammatory bowel disease also showed a significant association with AxSpA duration in both univariate and multivariate analyses (P < 0.003). In our analysis, psoriasis showed no significant relationship with AxSpA disease duration in both univariate (P = 0.298) and multivariate analyses (P1 = 0.249). Conclusion Our study, using a large data set, reveals distinct patterns of association between axial spondyloarthritis disease duration and inflammatory bowel disease and uveitis. Conversely, psoriasis demonstrates no significant link to disease duration when considering confounding factors. Clinically, these insights are crucial for tailored management strategies, emphasising the need for improved diagnostic time and multidisciplinary care to address the diverse manifestations of AxSpA and optimise patient outcomes. Disclosure B. Dinneen: None. M. Kenyon: None. F. O'Shea: None.

Strangers and Foreigners: Trust and Attitudes toward Citizenship in Sub-Saharan Africa

Abstract This study explores the factors that shape natives’ attitudes toward citizenship acquisition for foreigners. The hypothesis is that, in Sub-Saharan Africa, the slave trade represents a deep determinant of contemporary attitudes toward citizenship, through a proximate determinant which is the level of trust. Accordingly, individuals belonging to ethnic groups with higher exposure to historical slave exports are more likely to exhibit a sense of distrust toward strangers, and are consequently more likely to oppose citizenship laws that favor the inclusion of foreigners. The findings indicate that individuals with higher levels of trust toward other people do exhibit more favorable attitudes regarding the acquisition of citizenship at birth for children of foreigners, that these attitudes are also negatively related to the intensity of the slave trade, and that the underlying inverse relationship between trust and the slave trade is confirmed. Other factors such as conflict, kinship tightness, and witchcraft beliefs, which could also influence attitudes toward citizenship through the channel of trust, do not yield the same distinct pattern of associations as observed with the slave trade.

Neural correlates of the revised reinforcement sensitivity theory: A cross-sectional structural neuroimaging study in middle-aged adults.

The revised reinforcement sensitivity theory (RST) proposes that neurobiological systems control behavior: the fight-flight-freeze (FFFS) for avoidance of threat; behavioral approach/activation (BAS) for approach to rewards; and behavioral inhibition (BIS) for conflict resolution when avoidance and approach are possible. Neuroimaging studies have confirmed some theoretical associations between brain structures and the BAS and BIS; however, little representative population data are available for the FFFS. We investigated the neural correlates of the revised RST in a sample of 404 middle-aged adults (Mage = 47.18 (SD = 1.38); 54.5% female). Participants underwent structural magnetic resonance imaging and completed health questionnaires and the BIS/BAS/FFFS scales. We used multiple regression analyses to investigate the association between scale scores and volumes of a priori theoretically linked regions of interest while controlling for sex, age, intracranial volume, and cardio-metabolic variables; and conducted exploratory analyses on cortical thickness. The BIS was negatively associated with hippocampus laterality. At standard significance levels, the fear component of the FFFS was positively associated with anterior cingulate cortex; the BAS was positively associated with bilateral caudate; and the BIS was positively associated with posterior cingulate cortex volume. Furthermore, these neurobiological systems showed distinct patterns of association with cortical thickness though future work is needed. Our results showed that the neurobiological systems of the revised RST characterized in rodents can also be identified in the human brain.

Abstract 6158: Tumor genomic heterogeneity in non-small cell lung cancer (NSCLC) patients from Latin America

Abstract Motivation: Life prospects of non-small cell lung cancer (NSCLC) patients have greatly improved over the last decades with the adoption of tumor genomic profiling. A better understanding of the mutational landscape has allowed for a more precise molecular characterization and the development of more effective treatment alternatives. However, tumors present a widespread heterogeneity, and many challenges remain to fully comprehend the influencing factors. Of particular importance is the Latin America population which i) is commonly underrepresented in clinical trials and large-scale epidemiological studies, ii) presents higher incidence and mortality rates in comparison to the developed world, and iii) is constituted by a genetically admixed population. Our research attempts to close this gap by investigating the interplay between sociodemographic, clinical, and lifestyle factors, and the effect these exert on the mutational profiles of Latin-American NSCLC patients. Methodology: The study population is derived from the NIRVANA study, a cross-sectional multicenter observational study aiming to characterize and validate molecular diagnostic technologies for NSCLC patients in Chile, Brazil, and Peru. Between July 2015 to October 2018, 5030 NSCLC patients were recruited from 37 centers, meeting inclusion criteria of age ≥18, histologically or cytological proven NSCLC diagnostic, and naïve treatment. Exclusion criteria included prior chemotherapy treatment and refusal to give informed consent. Primary or metastatic NSCLC samples were collected during standard of care biopsy and processed for the DNA and RNA isolation. Next Generation Sequencing (NSG) genomics profiles were obtained using the Oncomine Focus Assay (OFA). Covariates of interest, including sociodemographic, clinical, and lifestyle factors, were assessed at enrollment. QC-approved genomic profiles were obtained for 1864 participants. Results and Conclusions: The prevalence of mutations and fusions in the eight most relevant NSCLC genes (EGFR, KRAS, ALK, MET, RET, BRAF, ROS1 and ERBB2) varies based on sociodemographic, clinical and lifestyle characteristics. Clear distinctions emerged in the prevalence of EGFR, KRAS and ERBB2 mutations among the three countries (EGFR: 20.9%, 17.6%, 35.3%; KRAS: 21.8%, 15.6%, 10.3%; ERBB2: 2.8%, 3.3%, 4.4% for Brazil, Chile, and Peru, respectively). Furthermore, distinct association patterns were identified between the prevalence of genetic alterations and the studied factors, with attributes such as sex, tobacco use and ethnicity mostly influencing the occurrence of EGFR, ALK and ROS1 alterations. These findings provide novel insights into NSCLC studies among Latin-American patients, potentially serving as guidelines for more tailored strategies in the overall management of this underrepresented population. Citation Format: Javiera Garrido, Evelin González, Gonzalo Sepúlveda-Hermosilla, Matias Freire, Alejandro Blanco, Solange Rivas, Katherine Marcelain, Gareth I. Owen, Carolina Ibañez, Alejandro Corvalan, Marcelo Garrido, Rodrigo Assar, Rodrigo Lizana, Javier Cáceres-Molina, Diego Ampuero, Liliana Ramos, Paola Pérez, Osvaldo Aren, Sara Chernilo, Cristina Fernández, María Loreto Spencer, Jacqueline Flores, Giuliano Bernal, Mónica Ahumada, Germán Rasse, Carolina Sánchez, Maria Galli de Amorim, Gabriela Branco, Diana Noronha Nunes, Emmanuel Dias-Neto, Helano C. Freitas, NIRVANA team, Ricardo Armisén. Tumor genomic heterogeneity in non-small cell lung cancer (NSCLC) patients from Latin America [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6158.

Global analysis of T-cell groups reveals immunological features and common antigen targets of digestive tract tumors

BackgroundT cells are key players in the tumor immune microenvironment (TIME), as they can recognize and eliminate cancer cells that express neoantigens derived from somatic mutations. However, the diversity and specificity of T-cell receptors (TCRs) that recognize neoantigens are largely unknown, due to the high variability of TCR sequences among individuals.MethodsTo address this challenge, we applied GLIPH2, a novel algorithm that groups TCRs based on their predicted antigen specificity and HLA restriction, to cluster the TCR repertoire of 1,702 patients with digestive tract cancer. The patients were divided into five groups based on whether they carried tumor-infiltrating or clonal-expanded TCRs and calculated their TCR diversity. The prognosis, tumor subtype, gene mutation, gene expression, and immune microenvironment of these groups were compared. Viral specificity inference and immunotherapy relevance analysis performed for the TCR groups.ResultsThis approach reduced the complexity of TCR sequences to 249 clonally expanded and 150 tumor-infiltrating TCR groups, which revealed distinct patterns of TRBV usage, HLA association, and TCR diversity. In gastric adenocarcinoma (STAD), patients with tumor-infiltrating TCRs (Patients-TI) had significantly worse prognosis than other patients (Patients-nonTI). Patients-TI had richer CD8+ T cells in the immune microenvironment, and their gene expression features were positively correlated with immunotherapy response. We also found that tumor-infiltrating TCR groups were associated with four distinct tumor subtypes, 26 common gene mutations, and 39 gene expression signatures. We discovered that tumor-infiltrating TCRs had cross-reactivity with viral antigens, indicating a possible link between viral infections and tumor immunity.ConclusionBy applying GLIPH2 to TCR sequences from digestive tract tumors, we uncovered novel insights into the tumor immune landscape and identified potential candidates for shared TCRs and neoantigens.

Characterizing major depressive disorder and substance use disorder using heatmaps and variable interactions: The utility of operant behavior and brain structure relationships.

Rates of depression and addiction have risen drastically over the past decade, but the lack of integrative techniques remains a barrier to accurate diagnoses of these mental illnesses. Changes in reward/aversion behavior and corresponding brain structures have been identified in those with major depressive disorder (MDD) and cocaine-dependence polysubstance abuse disorder (CD). Assessment of statistical interactions between computational behavior and brain structure may quantitatively segregate MDD and CD. Here, 111 participants [40 controls (CTRL), 25 MDD, 46 CD] underwent structural brain MRI and completed an operant keypress task to produce computational judgment metrics. Three analyses were performed: (1) linear regression to evaluate groupwise (CTRL v. MDD v. CD) differences in structure-behavior associations, (2) qualitative and quantitative heatmap assessment of structure-behavior association patterns, and (3) the k-nearest neighbor machine learning approach using brain structure and keypress variable inputs to discriminate groups. This study yielded three primary findings. First, CTRL, MDD, and CD participants had distinct structure-behavior linear relationships, with only 7.8% of associations overlapping between any two groups. Second, the three groups had statistically distinct slopes and qualitatively distinct association patterns. Third, a machine learning approach could discriminate between CTRL and CD, but not MDD participants. These findings demonstrate that variable interactions between computational behavior and brain structure, and the patterns of these interactions, segregate MDD and CD. This work raises the hypothesis that analysis of interactions between operant tasks and structural neuroimaging might aide in the objective classification of MDD, CD and other mental health conditions.

Psychosis superspectrum I: Nosology, etiology, and lifespan development.

This review describes the Hierarchical Taxonomy of Psychopathology (HiTOP) model of psychosis-related psychopathology, the psychosis superspectrum. The HiTOP psychosis superspectrum was developed to address shortcomings of traditional diagnoses for psychotic disorders and related conditions including low reliability, arbitrary boundaries between psychopathology and normality, high symptom co-occurrence, and heterogeneity within diagnostic categories. The psychosis superspectrum is a transdiagnostic dimensional model comprising two spectra-psychoticism and detachment-which are in turn broken down into fourteen narrow components, and two auxiliary domains-cognition and functional impairment. The structure of the spectra and their components are shown to parallel the genetic structure of psychosis and related traits. Psychoticism and detachment have distinct patterns of association with urbanicity, migrant and ethnic minority status, childhood adversity, and cannabis use. The superspectrum also provides a useful model for describing the emergence and course of psychosis, as components of the superspectrum are relatively stable over time. Changes in psychoticism predict the onset of psychosis-related psychopathology, whereas changes in detachment and cognition define later course. Implications of the superspectrum for genetic, socio-environmental, and longitudinal research are discussed. A companion review focuses on neurobiology, treatment response, and clinical utility of the superspectrum, and future research directions.

Emotion dysregulation and reward responsiveness as predictors of autonomic reactivity to an infant cry task among substance-using pregnant and postpartum women.

Maternal substance use may interfere with optimal parenting, lowering maternal responsiveness during interactions with their children. Previous work has identified maternal autonomic nervous system (ANS) reactivity to parenting-relevant stressors as a promising indicator of real-world parenting behaviors. However, less is known about the extent to which individual differences in emotion dysregulation and reward processing, two mechanisms of substance use, relate to maternal ANS reactivity in substance-using populations. The current study examined associations among emotion dysregulation, reward responsiveness, and ANS reactivity to an infant cry task among 77 low-income and substance-using women who were either pregnant (n=63) or postpartum (n=14). Two indicators of ANS functioning were collected during a 9min computerized infant cry task (Crybaby task): respiratory sinus arrhythmia (RSA) and pre-ejection period. Mothers also completed self-reported measures of emotion dysregulation and reward responsiveness. Analyses revealed that trait emotion regulation was associated with RSA reactivity to the Crybaby task, such that greater emotion dysregulation was associated with greater RSA reduction during the infant cry task than lower emotion dysregulation. Reward responsiveness was not significantly associated with either indicator of ANS reactivity to the task. Findings revealed distinct patterns of associations linking emotion dysregulation with ANS reactivity during a parenting-related computerized task, suggesting that emotion regulation may be a key intervention target for substance-using mothers.

The Contributions of the Cerebellar Peduncles and the Frontal Aslant Tract in Mediating Speech Fluency

Abstract Fluent speech production is a complex task that spans multiple processes, from conceptual framing and lexical access, through phonological encoding, to articulatory control. For the most part, imaging studies portraying the neural correlates of speech fluency tend to examine clinical populations sustaining speech impairments and focus on either lexical access or articulatory control, but not both. Here, we evaluated the contribution of the cerebellar peduncles to speech fluency by measuring the different components of the process in a sample of 45 neurotypical adults. Participants underwent an unstructured interview to assess their natural speaking rate and articulation rate, and completed timed semantic and phonemic fluency tasks to assess their verbal fluency. Diffusion magnetic resonance imaging with probabilistic tractography was used to segment the bilateral cerebellar peduncles (CPs) and frontal aslant tract (FAT), previously associated with speech production in clinical populations. Our results demonstrate distinct patterns of white matter associations with different fluency components. Specifically, verbal fluency is associated with the right superior CP, whereas speaking rate is associated with the right middle CP and bilateral FAT. No association is found with articulation rate in these pathways, in contrast to previous findings in persons who stutter. Our findings support the contribution of the cerebellum to aspects of speech production that go beyond articulatory control, such as lexical access, pragmatic or syntactic generation. Further, we demonstrate that distinct cerebellar pathways dissociate different components of speech fluency in neurotypical speakers.

DNA methylation clustered by predicted chromatin state reveals distinct association patterns with neuropathologic and biochemical measures in the AD brain

AbstractBackgroundAlzheimer’s disease (AD) is neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often quantified by Thal phase and Braak stage, respectively. Aβ also frequently deposits in the cerebrovasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. These and related measures often show high variability within AD suggesting distinct underlying mechanisms, the identification of which may reveal important biological insights into AD pathophysiology. We hypothesize that, within the AD brain, neuropathology and levels of core AD‐related proteins are influenced by variations in DNA methylation (DNAm). To test this, we performed epigenome‐wide association studies (EWAS) using DNAm clusters from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathologic measures (Braak, Thal, and CAA) and brain biochemical levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodsDNAm from neuropathologically‐confirmed AD cases available through the Mayo Clinic brain bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Neuropathology was scored by an experienced neuropathologist. TCX levels of five AD‐related proteins from three tissue fractions (buffer‐, detergent‐, and in‐soluble) were measured by ELISA (Liu 2020). CpG methylation (CpGm) was binned by a 15‐state chromatin model (Kundaje 2015) and averaged. Averaged CpGm clusters were tested for their association with each endophenotype through multi‐variable linear regression. The influence of CpGm clusters on expression levels of nearby genes was also investigated through multi‐variable regression.ResultsOur innovative binning method demonstrated expected and biologically relevant CpGm patterns. We identified multiple epigenome‐wide significant CpGm clusters unique to each AD‐related endophenotype and brain region. Comparisons between the TCX and CER further revealed brain region‐specific enrichment of distinct CpGm clusters. Significant CpGm clusters were further characterized by their influence on gene expression.ConclusionsAlthough all neuropathologic and biochemical endophenotypes tested are core to AD pathophysiology, our results suggest each has a distinct epigenetic architecture underlying their variability in the AD brain. By discovering brain region‐specific DNAm changes that contribute to each neuropathologic or biochemical outcome, we can identify core components of complex mechanisms that individually and jointly contribute to AD.

Systematic Prediction of Minor Histocompatibility Antigens to Inform GvHD Outcomes after Allogeneic Stem Cell Transplantation

T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms (SNPs, indels, frameshifts), is at the core of the therapeutic effect of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite the crucial role of mHAgs in graft-versus-leukemia and graft-versus-host (GvHD) reactions, it has not been possible thus far to consistently link patient-specific mHAg repertoires to clinical outcomes. As a result, only D-R HLA matching and the activity of GvHD prophylaxis strategies are currently available to help clinicians in this challenge. We hypothesized that post-transplant outcomes could be impacted by genome-wide mHAg load, delineated in an organ- and malignancy-specific fashion. We have therefore devised an analytic framework to systematically identify autosomal and Y-encoded mHAgs, based on the integration of polymorphism detection by whole-exome sequencing (WES) of germline DNA from D-R pairs together with organ-specific transcriptional- and proteome-level expression together with HLA class I epitope prediction. A critical component of the pipeline was building a reliable expression atlas for acute or chronic GvHD-targeted tissues. To capture less frequent but biologically relevant cell types consistently underestimated in bulk RNA expression profiles, we evaluated multiple external single-cell datasets of healthy human skin, liver, lung, GI, oral mucosa, and lacrimal gland. For each tissue, we merged the corresponding single-cell data sets and then clustered and annotated tissue-resident cell types, for which specific expressed genes were then identified, totaling 13,512 genes expressed in ≥1 GvHD target tissue. To determine how mHAg load related to GvHD risk, we applied our mHAg pipeline to paired WES (≥85% target base coverage at ≥20x depth) generated from 220 D-R pairs treated with a matched-related donor allo-HSCT for AML/MDS. We considered the impact of diagnosis, prognostic risk score, status at transplant, conditioning regimen, and graft source against median mHAg load on risk for acute and chronic GvHD. Across these patients, only total autosomal mHAg load > median was associated with increased risk of developing grade II-IV aGvHD (HR = 2.54, 95% confidence interval: 1.03 - 6.26, p = 0.043). While the total autosomal mHAg load was not associated with development of cGvHD, subgroup analysis of 55 FàM transplants revealed that a combined score of autosomal and Y-encoded mHAgs > median was associated with development of NIH moderate/severe cGvHD (p = 0.042). We next asked whether organ-specific mHAg load could predict the risk for organ-restricted acute or chronic GvHD. By evaluating organ-specific GvHD occurrence across deciles of mHAg load, we identified 2 distinct patterns of association. In the case of lung cGvHD, all 14 positive cases occurred in patients with a lung-specific autosomal mHAg load > median. By logistic regression modelling, lung mHAg load > median was the sole factor associated with increased risk of lung cGvHD (OR = 17.22, 95% CI: 3.18 - 321.63, p = 0.008). In contrast, for aGvHD of the liver, we observed an opposite pattern, with 12 of 13 affected patients having a liver mHAg load < median. We hypothesized that a limited set of immunodominant liver mHAgs might drive the clinical manifestations in these patients. By analyzing the mHAg landscape of patients affected by liver aGvHD, we observed an enriched representation of 7 polymorphisms in genes with preferential expression in liver. Notably, these SNPs were less frequent in patients developing aGvHD without liver involvement (p = 0.002) and co-occurred at a lower frequency in patients experiencing liver cGvHD (p = 0.0002). For one patient experiencing liver aGvHD, we could trace ex vivo T cells specific for 1 (of the 3 predicted) driver liver mHAgs. Overall, our findings indicate that molecular characterization of D-R pairs to define GvHD risk could facilitate the design of personalized post-HSCT treatments to minimize this highly morbid condition, including incorporation of additional immunosuppressive therapies, introduced early for high-risk patients, or reduced-intensity approaches in low-risk settings. This is particularly valuable for lung GvHD, which is associated with the highest morbidity and mortality.

Sociodemographic characteristics and longitudinal progression of multimorbidity: A multistate modelling analysis of a large primary care records dataset in England.

Multimorbidity, characterised by the coexistence of multiple chronic conditions in an individual, is a rising public health concern. While much of the existing research has focused on cross-sectional patterns of multimorbidity, there remains a need to better understand the longitudinal accumulation of diseases. This includes examining the associations between important sociodemographic characteristics and the rate of progression of chronic conditions. We utilised electronic primary care records from 13.48 million participants in England, drawn from the Clinical Practice Research Datalink (CPRD Aurum), spanning from 2005 to 2020 with a median follow-up of 4.71 years (IQR: 1.78, 11.28). The study focused on 5 important chronic conditions: cardiovascular disease (CVD), type 2 diabetes (T2D), chronic kidney disease (CKD), heart failure (HF), and mental health (MH) conditions. Key sociodemographic characteristics considered include ethnicity, social and material deprivation, gender, and age. We employed a flexible spline-based parametric multistate model to investigate the associations between these sociodemographic characteristics and the rate of different disease transitions throughout multimorbidity development. Our findings reveal distinct association patterns across different disease transition types. Deprivation, gender, and age generally demonstrated stronger associations with disease diagnosis compared to ethnic group differences. Notably, the impact of these factors tended to attenuate with an increase in the number of preexisting conditions, especially for deprivation, gender, and age. For example, the hazard ratio (HR) (95% CI; p-value) for the association of deprivation with T2D diagnosis (comparing the most deprived quintile to the least deprived) is 1.76 ([1.74, 1.78]; p < 0.001) for those with no preexisting conditions and decreases to 0.95 ([0.75, 1.21]; p = 0.69) with 4 preexisting conditions. Furthermore, the impact of deprivation, gender, and age was typically more pronounced when transitioning from an MH condition. For instance, the HR (95% CI; p-value) for the association of deprivation with T2D diagnosis when transitioning from MH is 2.03 ([1.95, 2.12], p < 0.001), compared to transitions from CVD 1.50 ([1.43, 1.58], p < 0.001), CKD 1.37 ([1.30, 1.44], p < 0.001), and HF 1.55 ([1.34, 1.79], p < 0.001). A primary limitation of our study is that potential diagnostic inaccuracies in primary care records, such as underdiagnosis, overdiagnosis, or ascertainment bias of chronic conditions, could influence our results. Our results indicate that early phases of multimorbidity development could warrant increased attention. The potential importance of earlier detection and intervention of chronic conditions is underscored, particularly for MH conditions and higher-risk populations. These insights may have important implications for the management of multimorbidity.

Dose-response associations of maternal age with pregnancy complications and multimorbidity among nulliparas and multiparas: A multicentric retrospective cohort study in southern China.

Advanced maternal age is becoming an increasingly common issue worldwide, presenting substantial health risks to pregnant women. However, dose-response associations of maternal age with a comprehensive range of pregnancy complications and their multimorbidity remain unclear. We conducted a retrospective cohort study using data from China's National Maternal Near Miss Surveillance System for 2017-2018, including 18 hospitals in southern China. We included 135 274 pregnant women aged 15-54 years with a singleton birth. We used multivariable logistic regression and restricted cubic spline to examine dose-response associations between maternal age and various pregnancy complications, as well as multimorbidity. We employed the Apriori algorithm to mine the association rules among pregnancy complications and identify frequent multimorbidity patterns. We found three distinct patterns of associations between maternal age and specific pregnancy complications. In relation to increasing maternal age, gestational diabetes mellitus, preeclampsia, and gestational hypertension showed nonlinear increasing trends for both nulliparas and multiparas, as did multimorbidity in nulliparas. Conversely, we observed linear increasing trends for placental previa in both nulliparas and multiparas, placental abruption in nulliparas, and multimorbidity in multiparas. Infection and severe anaemia had an approximate J-shaped curve among nulliparas, while postpartum haemorrhage exhibited a similar curve in both nulliparas and multiparas. Advanced maternal age was linked to an elevated risk of multimorbidity during pregnancy or postpartum period, exhibiting more complicated patterns. The most common multimorbidity patterns in this age group were "preeclampsia + gestational diabetes mellitus", "gestational hypertension + gestational diabetes mellitus", "infection + gestational diabetes mellitus", and "placental previa + gestational diabetes mellitus". Maternal age was associated with pregnancy complications and multimorbidity in three broad dose-response manners, including approximate J-shaped curves, as well as nonlinear and linear increasing trends, depending on the specific outcome and parity, which may suggest different underlying biological mechanisms. Women with advanced maternal age had a higher risk and more complicated patterns of multimorbidity during pregnancy or postpartum, suggesting that this group should be targeted for more intensive health care.

Pathway-specific polygenic scores for Alzheimer's disease are associated with changes in brain structure in younger and older adults.

Genome-wide association studies have identified multiple Alzheimer's disease risk loci with small effect sizes. Polygenic risk scores, which aggregate these variants, are associated with grey matter structural changes. However, genome-wide scores do not allow mechanistic interpretations. The present study explored associations between disease pathway-specific scores and grey matter structure in younger and older adults. Data from two separate population cohorts were used as follows: the Avon Longitudinal Study of Parents and Children, mean age 19.8, and UK Biobank, mean age 64.4 (combined n = 18 689). Alzheimer's polygenic risk scores were computed using the largest genome-wide association study of clinically assessed Alzheimer's to date. Relationships between subcortical volumes and cortical thickness, pathway-specific scores and genome-wide scores were examined. Increased pathway-specific scores were associated with reduced cortical thickness in both the younger and older cohorts. For example, the reverse cholesterol transport pathway score showed evidence of association with lower left middle temporal cortex thickness in the younger Avon participants (P = 0.034; beta = -0.013, CI -0.025, -0.001) and in the older UK Biobank participants (P = 0.019; beta = -0.003, CI -0.005, -4.56 × 10-4). Pathway scores were associated with smaller subcortical volumes, such as smaller hippocampal volume, in UK Biobank older adults. There was also evidence of positive association between subcortical volumes in Avon younger adults. For example, the tau protein-binding pathway score was negatively associated with left hippocampal volume in UK Biobank (P = 8.35 × 10-05; beta = -11.392, CI -17.066, -5.718) and positively associated with hippocampal volume in the Avon study (P = 0.040; beta = 51.952, CI 2.445, 101.460). The immune response score had a distinct pattern of association, being only associated with reduced thickness in the right posterior cingulate in older and younger adults (P = 0.011; beta = -0.003, CI -0.005, -0.001 in UK Biobank; P = 0.034; beta = -0.016, CI -0.031, -0.001 in the Avon study). The immune response score was associated with smaller subcortical volumes in the older adults, but not younger adults. The disease pathway scores showed greater evidence of association with imaging phenotypes than the genome-wide score. This suggests that pathway-specific polygenic methods may allow progress towards a mechanistic understanding of structural changes linked to polygenic risk in pre-clinical Alzheimer's disease. Pathway-specific profiling could further define pathophysiology in individuals, moving towards precision medicine in Alzheimer's disease.

Conditions of Birth and Early Childhood Developmental Risk for Mental Disorders.

Distinct classes of children in the general population are at increased odds of later mental illness and other adverse outcomes according to patterns of early childhood developmental vulnerability. If certain risk factors known at the time of birth are reliably associated with membership in early childhood risk classes, then preventative interventions could be initiated in the earliest years of life. Associations between 14 factors known at the time of birth and membership in early childhood risk classes were examined in 66,464 children. Risk class membership was associated with maternal mental illness, parental criminal charges and being male; distinct patterns of association were shown for some conditions, for example, prenatal child protection notification was uniquely associated with misconduct risk'. These findings suggest that risk factors known at the time of birth could assist in very early detection of children who may benefit from early intervention in the first 2000days.

Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways

Genome-wide association studies (GWAS) have mapped thousands of susceptibility loci associated with immune-mediated diseases. To assess the extent of the genetic sharing across nine immune-mediated diseases we apply genomic structural equation modelling to GWAS data from European populations. We identify three disease groups: gastrointestinal tract diseases, rheumatic and systemic diseases, and allergic diseases. Although loci associated with the disease groups are highly specific, they converge on perturbing the same pathways. Finally, we test for colocalization between loci and single-cell eQTLs derived from peripheral blood mononuclear cells. We identify the causal route by which 46 loci predispose to three disease groups and find evidence for eight genes being candidates for drug repurposing. Taken together, here we show that different constellations of diseases have distinct patterns of genetic associations, but that associated loci converge on perturbing different nodes in T cell activation and signalling pathways.

Parsing the heterogeneity of brain-symptom associations in autism spectrum disorder via random forest with homogeneous canonical correlation

BackgroundAutism spectrum disorder (ASD) is a highly heterogeneous developmental disorder, but the neuroimaging substrates of its heterogeneity remain unknown. The difficulty lies mainly on the significant individual variability in the brain-symptom association. MethodsT1-weighted magnetic resonance imaging data from the Autism Brain Imaging Database Exchange (ABIDE) (NTDC = 1146) were used to generate a normative model to map brain structure deviations of cases (NASD = 571). Voxel-based morphometry (VBM) was used to compute gray matter volume (GMV). Singular Value Decomposition (SVD) was employed to perform dimensionality reduction. A tree-based algorithm was proposed to identify the ASD subtypes according to the pattern of brain-symptom association as assessed by a homogeneous canonical correlation. ResultsWe identified 4 ASD subtypes with distinct association patterns between residual volumes and a social symptom score. More severe the social symptom was associated with greater GMVs in both the frontoparietal regions for the subtype1 (r = 0.29–0.44) and the ventral visual pathway for the subtype3 (r = 0.19–0.23), but lower GMVs in both the right anterior cingulate cortex for the subtype4 (r = −0.25) and a few subcortical regions for the subtype2 (r = −0.31 to −0.20). The subtyping significantly improved the classification accuracy between cases and controls from 0.64 to 0.75 (p < 0.05, permutation test), which was also better than the accuracy of 0.68 achieved by the k-means-based subtyping (p < 0.01). LimitationsSample size limited the study due to the missing data. ConclusionsThese findings suggest that the heterogeneity of ASD might reflect changes in different subsystems of the social brain, especially including social attention, motivation, perceiving and evaluation.