Adjustment For Multiple Testing Research Articles

Burn Center Verification and Safety-net Status: Are There Differences in Discharge to Inpatient Rehabilitation?

Discharge to acute rehabilitation following major burn injury is crucial for patient recovery and quality of life. However, barriers to acute rehabilitation, including race and payor type impede access. The effect of burn center organizational structure on discharge disparities remains unknown. This study aims to investigate associations between patient demographics, burn center factors, and discharge to acute rehabilitation on a population level. Using the California Healthcare Access and Information Database, 2009-2019, all inpatient encounters at verified and non-verified burn centers were extracted. The primary outcome was the proportion of patients discharged to acute rehabilitation. Key covariates included age, race, burn center safety net status, diagnosis related group, American Burn Association (ABA) verification status, and American College of Surgeons (ACS) Level 1 trauma center designation. Logistic regression and mixed-effects modeling were performed, with Bonferroni adjustment for multiple testing. Among 27,496 encounters, 0.8% (228) were discharged to inpatient rehabilitation. By race/ethnicity, the proportion admitted to inpatient rehabilitation was 0.9% for White, 0.6% for Black, 0.7% for Hispanic, and 1% for Asian. After adjusting for burn severity and age, notable predictors for discharge to inpatient rehabilitation included Medicare as payor (OR 0.30-0.88, p=0.015) compared to commercial insurance, trauma center status (OR 1.45-3.43, p<.001), ABA verification status (OR 1.16-2.74, p=0.008), and safety-net facility status (OR 1.09-1.97, p=0.013). Discharge to inpatient rehabilitation varies by race, payor status, and individual burn center. Verified and safety-net burn centers had more patients discharge to inpatient rehabilitation adjusted for burn severity and demographics.

Promoting equity in clinical research: The role of social determinants of health

ObjectiveThis study aims to investigate the association between social determinants of health (SDoH) and clinical research recruitment outcomes and recommends evidence-based strategies to enhance equity. Materials and MethodsData were collected from the internal clinical study manager database, clinical data warehouse, and clinical research registry. Study characteristics (e.g., study phase) and sociodemographic information were extracted. Median neighborhood income, distance from the study location, and Area Deprivation Index (ADI) were calculated. Mixed effect generalized regression was used for clustering effects and false discovery rate adjustment for multiple testing. A stratified analysis was performed to examine the impact in distinct medical departments. ResultsThe study sample consisted of 3,962 individuals, with a mean age of 61.5 years, 53.6 % male, 54.2 % White, and 49.1 % non-Hispanic or Latino. Study characteristics revealed a variety of protocols across different departments, with cardiology having the highest percentage of participants (46.4 %). Industry funding was the most common (74.5 %), and digital advertising and personal outreach were the main recruitment methods (58.9 % and 90.8 %). DiscussionThe analysis demonstrated significant associations between participant characteristics and research participation, including biological sex, age, ethnicity, and language. The stratified analysis revealed other significant associations for recruitment strategies. SDoH is crucial to clinical research recruitment, and this study presents evidence-based solutions for equity and inclusivity. Researchers can tailor recruitment strategies to overcome barriers and increase participant diversity by identifying participant characteristics and research involvement status. ConclusionThe findings highlight the relevance of clinical research inequities and equitable representation of historically underrepresented populations. We need to improve recruitment strategies to promote diversity and inclusivity in research.

Racial Disparities in Glioblastoma Genomic Alterations: A Comprehensive Analysis of a Multi-Institution Cohort of 2390 Patients

Although molecular biomarkers have significantly advanced precision oncology in glioblastoma, the prevalence of these biomarkers by race remains underexplored. This study aims to characterize the genomic alterations in glioblastoma across Asian, Black, and White patients, offering insights into racial disparities that may influence treatment outcomes and disease progression. Analyzing data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange database V13.0, this study examined 2390 primary glioblastoma samples from unique patients. Genomic alterations in 566 cancer-related genes were assessed using targeted next-generation sequencing panels from 3 large cancer institutes. The patient cohort included 112 Asians, 67 Blacks, and 2211 Whites. Statistical significance of associations between genomic alterations and race was evaluated using the chi-squared test, with the Benjamini-Hochberg method applied to control for multiple testing adjustments. Significant racial differences were observed in the frequency of genomic alterations. Asians exhibited a higher frequency of TP53 alterations (52.68%, P < 0.001), Blacks showed more frequent alterations in NRAS (7.46%, P < 0.001), MTOR (10.45%, P= 0.039), and TET2 (8.96%, P=0.039), and Whites had a higher occurrence of PTEN alterations (48.67%, P= 0.045). Additionally, Black patientshad an elevated rate of RET deletions (14.29%, P<0.001). This study identifies significant racial disparities in the alteration frequencies of 6 key glioblastoma genes: NRAS, TP53, MTOR, TET2, PTEN, and RET. These findings underscore the need for racial considerations in glioblastoma treatment strategies and highlight potential avenues for targeted therapeutic interventions. Further research is needed to explore the clinical implications of these genomic disparities.

Caregiver Experiences and Burden in Moderate-Advanced Dementia With Lewy Bodies.

Dementia with Lewy bodies (DLB) is a common degenerative dementia, but research on caregiver experiences in late stages is lacking. This study aimed to investigate the caregiving experience in moderate-advanced DLB to identify opportunities for improving care and support. Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were recruited from specialty clinics, advocacy organizations, and research registries. The study collected demographics, disease-related measures, and measures of the caregiver experience relating to caregiver support, burden, grief, self-efficacy, depression, quality of life, and coping. Spearman correlation coefficients and Wilcoxon rank-sum tests evaluated the relationships of caregiver measures with patient and caregiver variables with adjustments for multiple testing. Caregivers (n = 143) were mostly women (83.5%) and spouses (84.7%) (mean age 68 years; range 37-85). Almost 40% reported high burden and/or depression. Caregiver measures correlated with fluctuation and behavioral symptom severity, sleepiness, and autonomic symptoms of the person with DLB. Higher burden correlated with worse caregiver quality of life, higher depression, and grief. Greater self-efficacy, social support, and resilience correlated with lower caregiver burden. The most frequently reported caregiver concerns were being unable to plan for the future, having to put the needs of the person with DLB ahead of the caregiver's own needs, and worry that the person with DLB would become too dependent on the caregiver, but many additional concerns were endorsed. Caregivers were generally satisfied with medical team support. The lowest reported satisfaction related to information regarding disease progression and how well medical teams shared information with each other. Various patient-related and caregiver-related factors influence caregiver experiences in moderate-advanced DLB. Clinicians can target caregiver needs by providing support resources and DLB education and treating bothersome patient symptoms. Future research should investigate what interventions can modify and improve caregiver experiences in advanced DLB and identify therapeutics for patient symptoms currently without adequate treatments (e.g., fluctuations, daytime sleepiness). NCT04829656.

Assessment of causal relationships between omega-3 and omega-6 polyunsaturated fatty acids in autoimmune rheumatic diseases: a brief research report from a Mendelian randomization study.

Currently, the association between the consumption of polyunsaturated fatty acids (PUFAs) and the susceptibility to autoimmune rheumatic diseases (ARDs) remains conflict and lacks substantial evidence in various clinical studies. To address this issue, we employed Mendelian randomization (MR) to establish causal links between six types of PUFAs and their connection to the risk of ARDs. We retrieved summary-level data on six types of PUFAs, and five different types of ARDs from publicly accessible GWAS statistics. Causal relationships were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the reliability of our research findings, we used four complementary approaches and conducted multivariable MR analysis (MVMR). Additionally, we investigated reverse causality through a reverse MR analysis. Our results indicate that a heightened genetic predisposition for elevated levels of EPA (ORIVW: 0.924, 95% CI: 0.666-1.283, P IVW = 0.025) was linked to a decreased susceptibility to psoriatic arthritis (PsA). Importantly, the genetically predicted higher levels of EPA remain significantly associated with an reduced risk of PsA, even after adjusting for multiple testing using the FDR method (P IVW-FDR-corrected = 0.033) and multivariable MR analysis (P MV-IVW < 0.05), indicating that EPA may be considered as the risk-protecting PUFAs for PsA. Additionally, high levels of LA showed a positive causal relationship with a higher risk of PsA (ORIVW: 1.248, 95% CI: 1.013-1.538, P IVW = 0.037). It is interesting to note, however, that the effects of these associations were weakened in our MVMR analyses, which incorporated adjustment for lipid profiles (P MV-IVW > 0.05) and multiple testing using the FDR method (P IVW-FDR-corrected = 0.062). Moreover, effects of total omega-3 PUFAs, DHA, EPA, and LA on PsA, were massively driven by SNP effects in the FADS gene region. Furthermore, no causal association was identified between the concentrations of other circulating PUFAs and the risk of other ARDs. Further analysis revealed no significant horizontal pleiotropy and heterogeneity or reverse causality. Our comprehensive MR analysis indicated that EPA is a key omega-3 PUFA that may protect against PsA but not other ARDs. The FADS2 gene appears to play a central role in mediating the effects of omega-3 PUFAs on PsA risk. These findings suggest that EPA supplementation may be a promising strategy for preventing PsA onset. Further well-powered epidemiological studies and clinical trials are warranted to explore the potential mechanisms underlying the protective effects of EPA in PsA.

A Comparison of Remote Versus in-Person Assessments of Substance Use and Related Constructs Among Adolescents

Objective: Underreporting of adolescent substance use is a known issue, with format of assessment (in-person vs. remote) a potentially important factor. We investigate whether being assessed remotely (via phone or videoconference) versus in-person affects youth report of substance use patterns, attitudes, and access, hypothesizing remote visits would garner higher levels of substance use reporting and more positive substance use attitudes. Methods: We used the Adolescent Brain and Cognitive DevelopmentSM [ABCD] Study data between 2021-2022 during the COVID-19 pandemic. Participants chose whether to complete assessments in-person (n=615; 49% female; meanage=13.9; 57% White) or remotely (n=1,467; 49% female, meanage=13.7; 49% White). Regressions predicted substance use patterns, attitudes, and access, by visit format, controlling for relevant sociodemographic factors. Effect sizes and standardized mean differences are presented. Results: 17% of adolescent participants reported any level of substance use. Youth interviewed remotely reported more negative expectancies of alcohol and cannabis. In addition, those queried remotely were less likely to endorse use), sipping alcohol, eating cannabis), and reported less curiosity or intent to try alcohol, though these differences did not survive an adjustment for multiple testing. Effect sizes ranged from small to medium. Conclusions: Preliminary evidence suggests youth completing remote visits were more likely to disclose negative expectancies toward alcohol and cannabis. Effect sizes were modest, though 37 of 39 variables examined trended toward restricted reporting during remote sessions. Thus, format of substance use assessment should be controlled for, but balanced by other study needs (e.g., increasing accessibility of research to all sociodemographic groups).

Abstract PO5-16-01: Clinicogenomic analysis reveals genomic associations of brain metastatic tropism in breast cancer

Abstract Introduction: Recent progress in imaging and therapeutics has led to improvements in the treatment of advanced breast cancer. However, the incidence of brain metastasis (BM) in breast cancer is increasing and continues to be associated with poor prognosis and significant morbidity. Herein, we describe genomic enrichments associated with brain tropism from a large institutional clinico-genomic cohort. Methods: Patients who underwent tumor and matched normal sequencing utilizing hybridization-capture based targeted exonic sequencing (MSK-IMPACT) from April 2014 to March 2023 were included in this analysis; this cohort included 6,377 samples from 5,135 patients. We analyzed genomic data to inform the full spectrum of somatic and germline mutations, copy number changes and structural variants enriched in samples in resected BM specimens (n = 179), compared to primary tumors (n = 2980), stratified by receptor status. Enrichment analysis was conducted using a Fisher exact test for each respective receptor status. Similar analyses were conducted between extracranial metastatic (ECM) sites (n = 3186) and primary tumors, to differentiate the unique genomic features driving the emergence of BM as compared to general metastatic propensity. Multiple hypothesis testing was performed using Benjamini-Hochberg. Further genomic analysis, including allele specific copy number changes and mutational signatures will be reported at the 2023 SABCS meeting. Results: Oncogenic alterations in several genes were found to be enriched in BM samples compared to primary tumor, with an odds ratio exceeding that of the corresponding ECM comparison. For example, in the HR+/HER2- subset (4329 samples from 3476 patients), pathogenic variants in the following genes were enriched in BM:Primary analysis: NF1 (OR 6.4 [2.9 – 13.7], q = 0.001, 15.5% of BM), MYC (OR 3.9 [2.0 – 7.4], q = 0.001, 24.4% of BM), AGO2 (5.2 [2.4 – 10.9], q= 0.002, 15.5% of BM), CDKN2A (OR 3.9 [1.6 – 9.4], q = 0.06, 10.3% of BM), ERBB2 (OR 3.6 [1.5 – 8.6], q = 0.06, 10.3% of BM), RB1 (OR 4.2 [1.5 – 11.4], q = 0.06, 8.6% of BM), TP53 (OR 2.0 [1.1 – 3.5], q = 0.07, 40% of BM). In contrast, ESR1 variants were enriched in BM:Primary (OR 14.0 [6.7 – 28.2], but at the same level as ECM:Primary (OR 12.3 [8.7 – 17.7]). When considering HER2+ tumors (919 samples from 739 patients), only NKX.3 was enriched in the BM:Primary comparison (OR 11.5 [3.2 – 42.3], q = 0.004, 11.6% of BM). Although no TNBC samples met significance thresholds after adjustment for multiple hypothesis testing, CDH1, NTRK1, EGFR, and TP53 emerged as putatively significant. Conclusions: In a large cohort of genomically-profiled breast cancer samples, we find recurrent involvement of genes involved in cell cycle regulation (RB1, CDKN2A, TP53); these have been found to be enriched in brain metastases from other cancer types and are implicated in resistance to common lineage-directed therapies. Our approach also uncovered several targets for which therapies are actively in development (ERBB2, MYC). Further study of genomic evolution of breast cancer in the context of brain metastasis and therapeutic resistance will uncover conserved site-specific genomic changes and will identify novel, rational therapeutic targets. Citation Format: Anton Safonov, Deborah Smith, Emanuela Ferraro, Junchao Shen, Ishaani Khatri, Rahul Kumar, Julia An, Mark Robson, Sarat Chandarlapaty, Adrienne Boire, Nikolaus Schultz, Nelson Moss, Luke Pike, Pedram Razavi. Clinicogenomic analysis reveals genomic associations of brain metastatic tropism in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-01.

Oral pathology following treatment of brain tumors in childhood

Relevance. The limited selectivity of antitumor therapy for central nervous system neoplasms entails the risk of dental morbidity in patients.The aim of the study is to assess the severity of damage to the dental hard tissues in patients with tumors of the posterior cranial fossa (medulloblastoma, astrocytoma) and other tumors of the central nervous system.Materials and methods. Three comparison groups were established based on the toxicity profiles of antitumor therapy among 251 patients at the "Russian Field" treatment and rehabilitation scientific center, to assess the characteristics of oral health status. The assessment of oral health status included diagnosing the carious process and calculating the DMFT index. The degree of damage to the dental hard tissues was evaluated on a four-point scale. The clinical manifestations of oral cavity pathology were compared using the Z-criterion for multiple pairwise comparisons of data, with adjustments for multiple testing (Multiple pairwise comparison Z-test for proportions with multiple testing correction) using the free R software version 3.5.2. The null hypothesis of equal indicators in the compared groups was rejected with a 95% confidence probability when comparing groups of patients.Results. Dental hard tissue pathology was significantly more prevalent in patients with medulloblastoma compared to those diagnosed with astrocytomas and other central nervous system tumors. Additionally, the prevalence of dental hard tissue pathology progressively decreased as the observation period following the completion of antitumor remission was extended.Conclusion. The most severe damage to dental hard tissues is observed in patients with medulloblastoma, who undergo more intensive antitumor therapy compared to those with CNS tumors of other histological types.

Linguistic dissection of nursing handoffs: Implications for patient safety in varied-acuity hospital settings.

This study examines the intricate language and communication patterns of nurse-to-nurse handoffs across three units with varying patient acuity levels and nurse-patient ratios, seeking to identify linguistic factors that may affect the quality of information transfer and patient outcomes. A mixed-methods cross-sectional design. This study used the Nurse-to-Nurse Transition of Care Communication Model to explore the content and meaning of language in nursing handoffs within a large academic medical centre. Data were collected on three units through digital audio recordings of 20 handoffs between June and September 2022, which were transcribed and analysed using the Linguistic Inquiry Word Count programme. Trustworthiness was established by adhering to COREQ and STROBE guidelines for qualitative and quantitative research, respectively. Analysis revealed a preference for casual, narrative language across all units, with ICU nurses demonstrating a higher confidence and leadership in communication. Cognitive processes such as insight and causation were found to be underrepresented, indicating a potential area for miscommunication. Communication motives driven by affiliation were more pronounced in ICU settings, suggesting a strong collaborative nature. No significant differences were observed among the units post multiple testing adjustments. Speech dysfluencies were most pronounced in ICU handoffs, reflecting possible stress and cognitive overload. The study highlights the need for improved communication strategies such as interventions to enhance language clarity and incorporating technological tools into handoff processes to mitigate potential miscommunications and errors. The findings advance nursing science by highlighting the critical role of nuanced language in varied-acuity hospital settings and the necessity for structured nurse education in handoff communication and standardized handoff procedures. This study underscores the critical role of language in nurse-to-nurse handoffs. It calls for enhanced communication strategies, technology integration and training to reduce medical errors, improving patient outcomes in high-acuity hospital settings. Nurses only.

Abstract LB098: Deep plasma proteome characterization in two independent clinical cohorts identifies clusters of biomarkers separating benign and malign tumors in women with suspicion of ovarian cancer

Abstract Early detection is essential for ovarian cancer survival but today’s biomarkers are not specific enough to clear benign from malignant tumors nor sensitive enough to be used in screening. Here we have used the proximity extension assay (PEA) Olink Explore HT to characterize 5416 plasma proteins. For a subset of the women, we have also characterized the transcriptional landscape in corresponding tumor tissue using total RNA-sequencing on the Illumina NovaSeq 6000 instrument. The plasma samples were from two independent Swedish clinical cohorts (N1 = 171, N2 = 233) and tumor RNA was extracted from 112 of the samples from the second cohort. Each cohort consisted of women who after suspicion of ovarian cancer were surgically diagnosed with either benign or malign tumors. All plasma samples were collected at time of diagnosis, before commencement of treatment. In the plasma protein analyses, the first cohort was used as a discovery and the second as replication. In the discovery cohort, we found a total of 328 plasma proteins differing significantly between women with benign tumors and; early stage (I-II), late stage (III-IV) or any stage(I-IV) malignant tumors. These associations were examined in the replication cohort, and were all found to have similar foldchange between women with benign and malignant tumors. 99.7% (327/328) differed significantly after adjustment for multiple hypothesis testing. The 328 associations corresponded to a total of 192 proteins out of which 26 (13.5%) were found to have a significant correlation with RNA-expression in the corresponding tumor. A correlation network analysis based on the 192 proteins identified 5 major clusters, consisting of 18 to 59 protein-protein couplings. 80% of these clusters contained proteins that are annotated with up to five major KEGG cancer pathways and several of these contained proteins correlating significantly with the tumor RNA-SEQ data. All except one cluster contained one or two proteins that are either currently approved FDA drug targets or listed as druggable in DrugBank by specific compounds. Ovarian cancer has a low 5-year survival and eludes the current treatment regimens if discovered late. By applying high-throughput proteomics in two independent cohorts, we identified a large number of affected proteins out of which only a few have corresponding changes in tumor RNA-expression. We also identified large highly co-regulated networks of proteins, suggesting large downstream systemic effects which could be a contributing factor to the difficulties in finding efficient treatments. Among these proteins, there are several druggable targets, however, not all the associated compounds are currently primarily used as anti-cancer drugs, highlighting the possibility of drug re-purposing for future use against ovarian cancer. Citation Format: Stefan Enroth, Mikaela Moskov, Julia Lindberg Hedlund, Svetlana Popova, Simn K. Forsberg, Klev Diamanti, Maria Lycke, Emma Ivansson, Anna Tolf, Karin Sundfeldt, Karin Stålberg, Ulf Gyllensten. Deep plasma proteome characterization in two independent clinical cohorts identifies clusters of biomarkers separating benign and malign tumors in women with suspicion of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB098.

The association of infant urinary adrenal steroids with the risk of childhood asthma development

BackgroundAdrenal steroids play important roles in early-life development. However, our understanding of the effects of perinatal adrenal steroids on the development of childhood asthma is incomplete. ObjectiveTo evaluate the associations between early-life adrenal steroid levels and childhood asthma. MethodsParticipants included the Infant Susceptibility to Pulmonary Infections and Asthma following Respiratory Syncytial Virus Exposure birth cohort children with untargeted urinary metabolomics data measured during early infancy (n = 264) and nasal immune mediator data measured concurrently at age 2 to 6 months (n = 76). A total of 11 adrenal steroid compounds were identified using untargeted metabolomics and 6 asthma-relevant nasal immune mediators from multiplex assays were a priori selected. Current asthma at ages 5 and 6 years was ascertained using validated questionnaires. Associations were tested using logistic and linear regression with confounders adjustment. ResultsPregnenetriol disulfate (adjusted odds ratio [aOR] = 0.20, 95% CI = 0.06-0.68) and 3a,21-dihydroxy-5b-pregnane-11,20-dione-21-glucuronide (aOR = 0.34, 95% CI = 0.14-0.75) were inversely associated with childhood asthma at 5 and 6 years after multiple testing adjustment. There was a significant interaction effect of pregnanediol-3-glucuronide by biological sex assigned at birth (aOR = 0.11, 95% CI = 0.02-0.51, for those with female sex) on childhood asthma. Pregnenetriol disulfate was inversely associated with granulocyte-macrophage colony-stimulating factor (β = −0.45, q-value = 0.05). 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide was inversely associated with interleukin [IL]-4 (β = −0.29, q-value = 0.02), IL-5 (β = −0.35, q-value = 0.006), IL-13 (β = −0.26, q-value = 0.02), granulocyte-macrophage colony-stimulating factor (β = −0.35, q-value = 0.006), and fibroblast growth factor-β (β = −0.24, q-value = 0.01) after multiple testing adjustment. ConclusionThe inverse association between adrenal steroids downstream of progesterone and 17-hydroxypregnenolone and the odds of childhood asthma and nasopharyngeal type 2 immune biomarkers suggest that increased early-life adrenal steroids may suppress type 2 inflammation and protect against the development of childhood asthma.

Selenotranscriptome network in Alzheimer’s disease

The interplay between selenoproteins, oxidative stress, and cell death pathways holds promise in unravelling novel therapeutic targets for Alzheimer’s disease (AD) in the future. Nonetheless, further comprehensive investigations are warranted to fully comprehend the precise contributions of selenoproteins in the aetiology and potential therapeutic strategies for Alzheimer’s disease. Previous work into gene expression networks in AD has included analysis of the entire transcriptome and, as of yet, has not yielded consistent insight into pathological pathways.1 Despite the comprehensive assessment of the transcriptome enabled by current technologies, one drawback of the whole transcriptome analysis is the risk of overlooking subtle yet significant variations in metabolic pathways.2 Thus, we aimed to assess gene expression of known selenoprotein and selenium-containing pathways in two different brain regions (dorsolateral prefrontal cortex (DPC) and posterior cingulate cortex (PCC)) across the AD spectrum. We used RNA sequencing data from The Rush University’s Religious Orders Study and Memory and Aging Project (ROSMAP) cohort available in the AD Knowledge Portal (https://www.synapse.org/).3 This study included data available for a total of 889 DPC and 647 PCC samples. Four pathological phenotypes were determined based on pathology (CERAD) and clinical (CDR) status: AD ([(+) pathology, (+) clinical], prodromal disease, corresponding to donors that have not received a clinical diagnosis despite the presence of pathological alterations ([(+) pathology, (−) clinical], controls ([(−) pathology, (−) clinical] and non-AD dementia [(+) pathology, (+) clinical]. This last group was excluded from the analysis as it is assumed they may have been misdiagnosed or presented with non-AD dementia. Six selenium or AD-related pathways were assessed, accounting for 421 unique genes. Group comparisons were performed using linear mixed modelling adjusted for age, sex, APOEe4 status and batch via DESeq2 package with Benjamini-Hochberg adjustment for multiple testing. A total of 18 genes significantly differed between AD and controls in both brain areas (same direction in both brain areas; P &lt; 0.05), including eight selenoprotein genes or genes directly associated with selenoprotein synthesis. Fifteen of them were also different (same direction) in PCC (seven selenoprotein/selenoprotein synthesis genes), and four were different in DPC (four selenoprotein/selenoprotein synthesis genes) between AD and prodromal. Only three genes significantly differed between prodromal and control samples (DPC), including the selenoprotein DIO3 and the transcription factor SP3. Our findings indicate a progressive change in gene expression across the different stages of AD. These findings shed light on critical genes involved in selenoprotein synthesis that play a role in AD pathogenesis. Restricting the analysis to a subset of pathways enabled the detection of smaller alterations between groups, which is particularly appropriate in trace element homeostasis, where small alterations may have significant downstream effects.

Efficacy and safety of ocrelizumab in patients with relapsing multiple sclerosis: Real-world experience of two Swiss multiple sclerosis centers

BackgroundOcrelizumab (OCR) is a humanized monoclonal antibody directed against CD-20 positive lymphocytes, mainly B-lymphocytes. OCR is approved for treatment of primary progressive (PPMS) and relapsing multiple sclerosis (RMS). This study aims to provide real-world safety and efficacy data of people with RMS treated with OCR in two Swiss Multiple Sclerosis (MS) centers. MethodsWe have conducted a retrospective data analysis using the patient cohorts from the Cantonal Hospital Aarau and Bern University Hospital (RMS: n = 235). Statistical analyses were performed with Mann–Whitney U-Test, Chi-squared test and Spearman-Rho-Correlation. Adjustment for multiple testing was performed by Bonferroni procedure. ResultsAfter initiation of OCR, there was a decrease in disease activity in RMS patients. In our study, 152/190 (80.0 %) RMS patients fulfilled the criteria for NEDA-3 12 months and 88/104 (84.6 %) showed NEDA-3 24 months after OCR initiation. The most frequent adverse events (AEs) in our study were infections, taking place in 78/235 (33.2 %) RMS patients. COVID-19 was the most common infection, followed by urinary infections and other respiratory infections and infectious adverse events occurred significantly more frequent in patients with reduced IgG serum concentration. ConclusionsOur real-world study showed OCR being associated with low rates of any type of MS disease activity as indicated by NEDA-3. The adverse event profile is comparable to the known events especially infections and an association between infections and reduced IgG serum concentration was found.

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Abstract P439: Atherosclerotic Cardiovascular Risk Factor Burden Among Marijuana Users in the US Population

Background: The prevalence of marijuana use in the US is increasing. Marijuana use has been associated with increased atherosclerotic cardiovascular disease (ASCVD) events. The ASCVD risk factor burden among marijuana users compared with non-users and tobacco users has not been defined. We sought to define ASCVD risk factor burden among marijuana users in a nationally representative sample of the US population. Methods: We analyzed cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) from the 2017-2018 cycle including 4991 participants aged 18-59 representing 223 million US adults. Participants were placed in 4 groups: marijuana and cigarette user (MS), exclusive marijuana user (M), exclusive cigarette user (S), and non-users (NS). ASCVD risk factors were assessed and compared using chi-squared and ANOVA with Tukey’s adjustment for multiple hypothesis testing. Results: The N=4991 participants representing 223 million US adults were a mean 51 years old, 54.82% female and BMI of 32.53. The N=1691 M-users were compared to the N=2552 NS, N=2439 S-users, and N=1020 MS users (Table 1). The M-users were younger, mean age (38.8 years) with a higher BMI (32.9 kg/m 2 ) compared to exclusive smokers, dual-users and non-users. Prevalent coronary heart disease differed by use-group (p &lt; 0.05). Conclusion: Exclusive M-users and dual users had higher prevalent CHD. ASCVD risk factor burden differed slightly between the groups.

Differential predictors of expressed emotion toward individuals with schizophrenia between families and halfway houses.

This study investigated patient- and caregiver-related predictors of expressed emotion (EE) toward individuals with schizophrenia in families and halfway houses and yet understudied differential effects across settings. We included 40 individuals with schizophrenia living with their families ("outpatients") and 40 "inpatients" in halfway houses and recorded the EE of 56 parents or 22 psychiatric nurses, respectively, through Five Minutes Speech Sample. Each outpatient was rated by one to two parents; each inpatient was rated by two to five nurses. As EE ratings had a multilevel structure, EE predictors were investigated in backward stepwise generalized linear mixed models using the "buildmer" R package. We first fitted models including either caregiver- or patient-related predictors in each setting and finally included both types of predictors. Setting-specific patient-related effects were investigated in interaction analyses. Adjustment for multiple tests identified the most robust associations. In multivariate models including either caregiver- or patient-related predictors, nurses' higher age, shorter work experience and lower inpatients' negative symptoms robustly predicted higher emotional overinvolvement (EOI). In the final models including both types of predictors, nurses robustly displayed lower EOI (i.e., reduced concern and disengagement) toward inpatients with higher negative symptoms. Several other features were nominally associated with criticism and EOI in each setting. However, no feature robustly predicted criticism in inpatients and criticism/EOI in outpatients after adjustment for multiple tests. In interaction analyses, higher negative symptoms differentially predicted lower EOI in nurses only. Our findings suggest setting-specific pathogenetic pathways of EOI and might help customize psychoeducational interventions to staff in halfway houses.

Epigenome-wide association study identifies neonatal DNA methylation associated with two-year attention problems in children born very preterm

Prior research has identified epigenetic predictors of attention problems in school-aged children but has not yet investigated these in young children, or children at elevated risk of attention problems due to preterm birth. The current study evaluated epigenome-wide associations between neonatal DNA methylation and attention problems at age 2 years in children born very preterm. Participants included 441 children from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study, a multi-site study of infants born < 30 weeks gestational age. DNA methylation was measured from buccal swabs collected at NICU discharge using the Illumina MethylationEPIC Bead Array. Attention problems were assessed at 2 years of adjusted age using the attention problems subscale of the Child Behavior Checklist (CBCL). After adjustment for multiple testing, DNA methylation at 33 CpG sites was associated with child attention problems. Differentially methylated CpG sites were located in genes previously linked to physical and mental health, including several genes associated with ADHD in prior epigenome-wide and genome-wide association studies. Several CpG sites were located in genes previously linked to exposure to prenatal risk factors in the NOVI sample. Neonatal epigenetics measured at NICU discharge could be useful in identifying preterm children at risk for long-term attention problems and related psychiatric disorders, who could benefit from early prevention and intervention efforts.

The effect of resolvin D1n-3 DPA on primary oral epithelial cell migration in vitro.

Specialized pro-resolving lipid mediators (SPMs) are known for their anti-inflammatory and pro-resolving actions. The aim of the present study was to find new functions of the SPM resolvin D1n-3 DPA (RvD1n-3 DPA) on oral epithelial cells. As a starting point, we used a dataset obtained by RNA high-throughput sequencing of oral epithelial cells exposed to TNF-α and RvD1n-3 DPA versus TNF-α alone. GOrilla enrichment analysis showed that the actin cytoskeleton was significantly overrepresented after adjustment for multiple hypothesis testing. As actin, amongst others, is closely related to cell migration, we then explored whether RvD1n-3 DPA can modulate oral epithelial cell migration. To this end, we used an in vitro cell migration model, including TNF-α treatment, to mimic an inflammatory cell state. The analysis revealed that RvD1n-3 DPA increased oral epithelial cell migration in the presence but not in the absence of TNF-α. Addition of RvD1n-3 DPA also induced F actin accumulation around the cell nucleus, indicating that RvD1n-3 DPA potentially can mediate processes of intracellular transport. This indicates that this lipid mediator may be a promising therapeutic candidate in oral mucosal wound healing.

Utilisation of Chronic Disease and Mental Health Management Services and Cardioprotective Medication Prescriptions in Primary Care for Patients With Cardiovascular Diseases and Cancer: A Cross-Sectional Study

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among cancer survivors. Mental health is considered an important risk factor affecting the treatment of cardiovascular disease. However, little is known about the use of secondary prevention strategies for CVD in patients with both cancer and CVD. This study aimed to compare the utilisation of primary care chronic disease management plans, mental health care and guideline-indicated cardioprotective medications among CVD patients with and without cancer. Retrospective cross-sectional study utilising clinical data of patients with CVD from 50 Australian primary care practices. Outcomes included the use of chronic disease management plans, mental health care, guideline-indicated cardioprotective medications and influenza vaccination. Logistic regression, accounting for demographic and clinical covariates and clustering effects by practices, was used to compare the two groups. Of the 15,040 patients with CVD, 1,486 patients (9.9%) concurrently had cancer. Patients with cancer, compared to those without, were older (77.6 vs 71.8 years, p<0.001), more likely to drink alcohol (62.6% vs 55.7%, p<0.001), have lower systolic (130.3±17.8 vs 132.5±21.1 mmHg, p<0.001) and diastolic (72.2±11 vs 75.3±34 mmHg, p<0.001) blood pressure. Although suboptimal for both groups, patients with cancer were significantly more likely to have general practice management plans (GPMPs) (51.4% vs 43.2%, p<0.001), coordination of team care arrangements (TCAs) (46.2% vs 37.0%, p<0.001), have a review of either GPMP or TCA (42.8% vs 34.7%, p<0.001), have a mental health treatment consultation (15.4% vs 10.5%, p=0.004) and be prescribed blood pressure-lowering medications (70.1% vs 66.0%, p=0.002). However, there were no statistical differences in the prescription of lipid-lowering or antiplatelet medications. After adjustments for covariates and multiple testing, patients with cancer did not show a difference in GPMPs, TCAs, and a review of either, but were more likely to receive mental health treatment consultations than those without cancer (odds ratio 1.76; 95% confidence interval 1.42-2.19). Less than half of patients with CVD had a GPMP, TCA or review of either. Although those patients with cancer were more likely to receive these interventions, still around half the patients did not. Medicare-funded GPMPs, TCAs and a review of either GPMP or TCA were underutilised, and future studies should seek to identify ways of improving access to these services.

The effect of metabolic factors on the association between hyperuricemia and chronic kidney disease: a retrospective cohort mediation analysis.

Hyperuricemia, hyperglycemia, hypertension, hyperlipidemia, and hyperhomocysteinemia are all established risk factors for chronic kidney disease (CKD), and their interplay could exacerbate CKD progression. This study aims to evaluate the potential mediation effects of hyperglycemia, hypertension, hyperlipidemia, and hyperhomocysteinemia on the association between hyperuricemia (HUA) and chronic kidney disease (CKD). We collected electronic medical record data from 2055 participants who underwent physical examinations at the Affiliated Hospital of Qingdao University. The data were utilized to investigate the mediating effect of various factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), homocysteine (HCY), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), blood glucose (Glu), and hemoglobin A1c (HbA1c) on the relationship between HUA and CKD. Upon adjusting for confounding variables, mediation analysis indicated that only HCY acted as a mediator in the HUA-CKD relationship (p value < 0.05), exhibiting a statistically significant mediation effect of 7.04%. However, after adjustment for multiple testing, none of these variables were statistically significant. Considering the observed associations between hyperuricemia, hyperglycemia, hypertension, hyperlipidemia, and CKD, none of the factors of interest remained statistically significant after adjusting for multiple testing as potential mediators of hyperuricemia on CKD.