Threshold For Inclusion Research Articles

An item bank to measure health-related quality of life among young children (0-5-years-old) affected by respiratory illnesses – expert stakeholders and end-users from the Western Cape, South Africa

BackgroundHealth-related quality of life (HRQoL) is a crucial patient-centred outcome for developing policy. However, there is a lack of appropriate HRQoL measures for young children (0-5-years), who are particularly vulnerable to respiratory illnesses like pulmonary tuberculosis (PTB) and other respiratory infections, especially in low- and middle-income countries (LMICs). We aimed to develop a disease-specific HRQoL item bank for young children with acute and chronic respiratory illnesses.MethodsAn exploratory sequential design with three phases was used to develop a HRQoL item bank. The content validity of the item bank was evaluated by local and international experts specialising in HRQoL and child health. The group included paediatric pulmonologists, researchers with expertise in respiratory illnesses, and experts in scale development. Cognitive interviews with 37 caregivers of children with TB, pneumonia, adenovirus respiratory infection, other lower respiratory tract infections, reactive airway disease, and protracted bronchitis in Cape Town, South Africa, and consultations with 22 stakeholders were conducted for final revisions. The item bank was progressively refined at each phase of the study.FindingsThe Delphi experts recommended dividing the item bank into two age groups (0-2-years and 3-5-years) and using a 5-point Likert scale. Overall, 41 items (42%) met the predetermined > 70% threshold for inclusion in the item bank. Cognitive interviews confirmed that the domains were relevant. Minor modifications were made to five items in cohort 1 (0-2-years) and seven in cohort 2 (3-5-years), with 8 items (13%) and 14 items (22%) excluded. Phase 3 consultations emphasised the importance of including all seven domains and expanding the items to cover early childhood development, play, social interactions, and care routines. The final item bank includes versions for both age groups and incorporates these refinements.ConclusionAn item bank was developed as a first step to develop a comprehensive disease-specific HRQoL tool for young children with respiratory illnesses in an LMIC. Input from caregivers and content experts was crucial in creating two HRQoL item banks tailored to the developmental differences between 0 and 2 and 3-5-year age groups. Their contributions ensured the tool effectively captures age-appropriate aspects of HRQoL. Future studies should focus on assessing the validity and reliability of these item banks.

Exploring the Potential of Microservices in Internet of Things: A Systematic Review of Security and Prospects.

With the rapid growth of Internet of Things (IoT) systems, ensuring robust security measures has become paramount. Microservices Architecture (MSA) has emerged as a promising approach for enhancing IoT systems security, yet its adoption in this context lacks comprehensive analysis. This systematic review addresses this research gap by examining the incorporation of MSA in IoT systems from 2010 to 2024. From an initial pool of 4388 studies, selected articles underwent thorough quality assessment with weighted critical appraisal questions and a defined inclusion threshold. This study represents the first comprehensive systematic review to investigate the potential of microservices in IoT, with a particular focus on security aspects. The review explores the merits of MSA, highlighting twelve benefits, eight key challenges, and eight security risks. Additionally, the eight best practices for implementing MSA in IoT systems are extracted. The findings underscore MSA's utility in fortifying IoT security while also acknowledging complexities and potential vulnerabilities. Moreover, the study calls attention to the importance of incorporating complementary technologies including blockchain and machine learning to address identified gaps effectively. Finally, we propose a taxonomic classification for Microservice-based IoT security patterns, facilitating the categorization and organization of security measures in this context. Such a review can help researchers and practitioners identify existing gaps, highlight potential research directions, and provide guidelines for designing secure and efficient microservice-based IoT systems.

Screen Failures and Causes in Inflammatory Bowel Disease Randomized Controlled Trials: A Study of 16913 Screened Patients.

While recruitment rates in inflammatory bowel disease (IBD) trials are continuously decreasing, the underlying reasons are likely multifactorial but remain poorly defined. Screen failure (SF) proportions and causes have not been extensively explored in IBD. We assessed SF proportions and underlying SF reasons in IBD phase 2 and 3 clinical trials. We analyzed SF-related data from 17 randomized controlled phase 2 or 3 IBD trials. Twelve trials were in ulcerative colitis (UC) and 5 trials were in Crohn's disease (CD) operated by a single contract research organization, IQVIA. Differences between patient groups were tested for significance by Mann-Whitney and Fisher's tests when appropriate. We analyzed a total of 11 161 patients with UC and 5752 patients with CD. The mean SF proportion was 0.43 per trial in UC. The primary reason for SFs in UC was not meeting the overall (modified) Mayo score inclusion threshold and/or the endoscopic subscore of at least 2 (33.8% of all SF). In CD clinical trials, the mean SF proportion was at 0.53. The primary cause for SFs was not meeting the CDAI eligibility criteria (23.1% of all SFs). SF proportions were significantly higher in CD versus UC trials (P = .027). Clostridium difficile or any other intestinal infection and not meeting tuberculosis screening criteria were other major reasons for SFs both in UC and CD. High SF proportion in IBD clinical trials, particularly for CD studies, pose obstacles to patient recruitment. While underlying causes are diverse, arbitrarily defined clinical and/or endoscopic eligibility criteria remain the major limiting factors.

Quality of life and its determinants in patients with chronic respiratory diseases in the Fes-Meknes region, Morocco.

Chronic respiratory diseases (CRDs) pose a serious public health issue, affecting social functioning and psychological well-being and leading to a deterioration in the quality of life. The aim of this study was to assess the quality of life of patients with CRDs and determine the factors associated with their impairment in Morocco. A cross-sectional study was conducted in the Pulmonology Department of the Hassan II University Hospital in Fez in 2021. Data collection was carried out using an anonymous questionnaire containing sociodemographic, clinical, and therapeutic information. We employed the Moroccan version of the 12-item short-form (SF-12) scale to assess the mental and physical quality of life of patients. Bivariate analysis was performed to investigate the association between various factors and quality of life, using tests appropriate to the types of variables studied. Subsequently, multivariate analysis through multiple linear regression was employed to determine factors associated with quality of life, taking into account confounding factors. The threshold for inclusion in the model was set at 20%. Significant associations are presented as β values along with their 95% confidence intervals (CI). Our study included 209 patients, with 50.7% being female and 74.2% aged over 50 years. The most frequent clinical symptom was coughing. The average physical quality of life was estimated at 34.45±13.78, and the mental quality of life was 33.72±19.79. Multivariate analysis revealed that the deterioration of physical quality of life was associated with marital status (single) [β=-6.84; 95% CI (-11.43; -2.25); p=0.004], stage II dyspnea on the Modified Medical Research Council scale [β=-4.94; 95% CI (-9.41; -0.52); p=0.029], and the presence of cyanosis [β=-9.65; 95% CI (-15.64; -3.67); p=0.002]. The factors negatively associated with mental health in our patients were age ≥50 [β=-7.84; 95% CI (-15.05; -0.62); p=0.033], marital status (single) [β=-7.81; 95% CI (-15.14; -0.48); p=0.037], and presence of cyanosis [β=-10.70; 95% CI (-20.08; -1.32); p=0.026]. The SF-12 calculation reflected an impairment in the quality of life of patients with CRDs. It is imperative to integrate the assessment of quality of life into the management strategy for this pathology.

Sex and Population-Specific 99th Percentiles of Troponin for Myocardial Infarction in the Danish Population (DANSPOT).

Sex- and population-specific 99th percentiles of high-sensitivity cardiac troponin (hs-cTn) are recommended in guidelines although the evidence for a clinical utility is sparse. The DANSPOT trial will investigate the clinical effect of sex- and population-specific 99th percentiles of cTn. We report the 99th percentiles derived from this trial and their dependency on kidney function. We used samples from healthy Danish blood donors and measured hemoglobin A1c, N-terminal pro-brain natriuretic peptide and creatinine, and calculated an estimated glomerular filtration rate (eGFR). We compared 2 cutoffs for the eGFR of healthy participants (60 vs 90 mL/min/1.73 m2). The cTn assays investigated were Siemens Atellica and Dimension Vista hs-cTnI, Abbott hs-cTnI, and Roche hs-cTnT. A total of 2287 participants were sampled, of which 71 (3.1%) were excluded due to a history of heart disease (n = 4), insufficient material (n = 7), or a screening biomarker (n = 60). Of the remaining 2216 participants, 1325 (59.8%) had an eGFR ≥90 mL/min/1.73 m2. Compared to a cutoff of 60 mL/min/1.73 m2 for eGFR, using 90 mL/min/1.73 m2 resulted in lower 99th percentiles for females; Siemens Vista (46 vs 70 ng/L), Abbott (14 vs 18 ng/L), and Roche cTnT (10 vs 13 ng/L), and decreased the number of measurements above the manufacturers' 99th percentiles for all assays. We present reference values for 4 cTn assays for eGFR cutoffs of 60 and 90 mL/min/1.73 m2. These cutoffs differ based on the eGFR threshold for inclusion indicating that any chosen cutoff is also valuable with moderately reduced kidney function.

71 Exploring DNA-methylation and DNA-hydroxymethylation in clear cell renal cell carcinoma using Dirichlet multinomial regression

Abstract Background DNA methylation alterations have been found related to clear cell renal cell carcinoma (ccRCC). In addition, DNA methylation has been used to identify cell heterogeneity at the tumor level using cell deconvolution methods. Other cytosine modifications are less studied in the field. In this study, we aim to explore the use of compositional method, Dirichlet multinomial regression1, to simultaneously explore DNA methylation and DNA hydroxymethylation in ccRCC. Methods A total of 243 clear cell renal cell carcinoma (ccRCC) samples were collected from the Dartmouth Renal Tumor Biobank. DNA methylation analysis was conducted using the Infinium MethylationEPIC BeadChip, using tandem bisulfite (BS) and oxidative bisulfite (oxBS) treatments to differentiate between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) states. Beta values were calculated for all the arrayed samples. Quality control was performed using the ENmix pipeline to ensure the inclusion of high-quality samples using a stringent pOOBHA <0.05. The oxBS maximum likelihood estimate (oxBS-MLE) method was applied to assess 5mC and 5hmC levels based on paired BS and oxBS datasets. To determine the inclusion threshold for 5hmC beta values in the Dirichlet analysis, the R package oxBSCut was used to mask values close to zero2. Missing 5hmC values and those values masked below the detection limit were imputed using a compositional approach and a Tobit regression model to retain the model properties. The Dirichlet model was applied to analyze three methylation states: unmethylated, methylated, and hydroxymethylated, providing comprehensive insights into the methylation landscape of ccRCC samples. Results Here, we analyzed the top 1% most variable methylated sites (n=3020). When comparing tumor vs normal adjacent samples we tested the cytosine modifications in the same model adjusting for sex, age at diagnosis, tumor stage, and grade. For this exploratory analysis, we selected those results that passed an FDR<0.01 and an absolute difference >0.2 for further exploration. Four sites were hyperhydroxymethylated related to MYO5A, DLG2, ANKRD33B, and one open sea site. A total of 23 sites were significantly hypermethylated. Using eForge-TF, these sites tracked to transcription factors targeting estrogen receptors, retinoic acid receptors alpha and gamma, and FOXC1 among others3. Conclusions In this preliminary analysis, using a new modeling approach to interrogate cytosine modifications simultaneously, we found some intriguing results consistent with previous literature. We will expand this analysis to evaluate the relation between extreme changes in hydroxymethylation in particular in relation to alternative splicing alterations. Reference 1. Tsagris, M., Stewart, C. A Dirichlet Regression Model for Compositional Data with Zeros. Lobachevskii J Math39, 398–412 (2018). https://doi.org/10.1134/S1995080218030198 2. Zhang Z, Lee MK, Perreard L, Kelsey KT, Christensen BC, Salas LA. Navigating the hydroxymethylome: experimental biases and quality control tools for the tandem bisulfite and oxidative bisulfite Illumina microarrays. Epigenomics. 2022;14(3):139-152. doi:10.2217/epi-2021-0490 3. Charles E Breeze, Alex P Reynolds, Jenny van Dongen, Ian Dunham, John Lazar, Shane Neph, Jeff Vierstra, Guillaume Bourque, Andrew E Teschendorff, John A Stamatoyannopoulos, Stephan Beck, eFORGE v2.0: updated analysis of cell type-specific signal in epigenomic data, Bioinformatics, Volume 35, Issue 22, November 2019, Pages 4767–4769, https://doi.org/10.1093/bioinformatics/btz456

Variability in performance of genetic-enhanced DXA-BMD prediction models across diverse ethnic and geographic populations: A risk prediction study.

Osteoporosis is a major global health issue, weakening bones and increasing fracture risk. Dual-energy X-ray absorptiometry (DXA) is the standard for measuring bone mineral density (BMD) and diagnosing osteoporosis, but its costliness and complexity impede widespread screening adoption. Predictive modeling using genetic and clinical data offers a cost-effective alternative for assessing osteoporosis and fracture risk. This study aims to develop BMD prediction models using data from the UK Biobank (UKBB) and test their performance across different ethnic and geographical populations. We developed BMD prediction models for the femoral neck (FNK) and lumbar spine (SPN) using both genetic variants and clinical factors (such as sex, age, height, and weight), within 17,964 British white individuals from UKBB. Models based on regression with least absolute shrinkage and selection operator (LASSO), selected based on the coefficient of determination (R2) from a model selection subset of 5,973 individuals from British white population. These models were tested on 5 UKBB test sets and 12 independent cohorts of diverse ancestries, totaling over 15,000 individuals. Furthermore, we assessed the correlation of predicted BMDs with fragility fractures risk in 10 years in a case-control set of 287,183 European white participants without DXA-BMDs in the UKBB. With single-nucleotide polymorphism (SNP) inclusion thresholds at 5×10-6 and 5×10-7, the prediction models for FNK-BMD and SPN-BMD achieved the highest R2 of 27.70% with a 95% confidence interval (CI) of [27.56%, 27.84%] and 48.28% (95% CI [48.23%, 48.34%]), respectively. Adding genetic factors improved predictions slightly, explaining an additional 2.3% variation for FNK-BMD and 3% for SPN-BMD over clinical factors alone. Survival analysis revealed that the predicted FNK-BMD and SPN-BMD were significantly associated with fragility fracture risk in the European white population (P < 0.001). The hazard ratios (HRs) of the predicted FNK-BMD and SPN-BMD were 0.83 (95% CI [0.79, 0.88], corresponding to a 1.44% difference in 10-year absolute risk) and 0.72 (95% CI [0.68, 0.76], corresponding to a 1.64% difference in 10-year absolute risk), respectively, indicating that for every increase of one standard deviation in BMD, the fracture risk will decrease by 17% and 28%, respectively. However, the model's performance declined in other ethnic groups and independent cohorts. The limitations of this study include differences in clinical factors distribution and the use of only SNPs as genetic factors. In this study, we observed that combining genetic and clinical factors improves BMD prediction compared to clinical factors alone. Adjusting inclusion thresholds for genetic variants (e.g., 5×10-6 or 5×10-7) rather than solely considering genome-wide association study (GWAS)-significant variants can enhance the model's explanatory power. The study highlights the need for training models on diverse populations to improve predictive performance across various ethnic and geographical groups.

What Is Love? A Factor Analysis of Established Frameworks and a Semantic Analysis of Individual Western Beliefs

The assessment of the construct of love has been attempted with various self-reporting questionnaires but there is no evidence that these measures are assessing the same construct. This research is attempting to develop a culturally sensitive definition for the construct of love. This research is a two-part study. The first part of the research sets out to validate eight of the widely used love (or related area) self-reporting measures. We hypothesized that there would be high collinearity between the various measures and that they would be related to the individual’s perception of love. 565 adults were surveyed and were given each of the love measures, demographic questions, an overall rating of love (0-100), as well as an open-ended question to explain their definition of love. Factor analysis revealed that several of the measures had more factors than they reported, the items were plagued with high collinearity, or they had items that did not meet the minimum threshold for model inclusion. The second study addressed the attitudes toward love in Western society using an Implicit Association Test (IAT). We hypothesized that cognitive load would vary by the categorizations of love words. 1102 individuals in the United States and Europe were given a list of 158 words and asked if the word was associated to love or not love while cognitive load, measured as latency, was recorded. The results indicated that love words are identified faster than not love words. Conclusions are consistent with Prospect Theory and the Theory of Constructed Emotions.

Nonlinear impact of financial inclusion on tax revenue: evidence from the Monte-Carlo simulation algorithm under the Bayesian approach

PurposeThis article aims to study the nonlinear effect of financial inclusion on tax revenue of 21 low financial development countries (LFDCs) and 22 high financial development countries (HFDCs) from 2004 to 2020.Design/methodology/approachThe study calculates the world average financial development index (FD̅) for all countries using data from the IMF. The average FD of HFDCs is higher than (FD̅). On the other hand, the average FD of LFDCs is lower than (FD̅). Data of 21 LFDCs and 22 HFDCs cover the period 2004–2020. With the small sample problem, we applied the Bayesian method to examine the nonlinear effect of financial inclusion on the tax revenue of the two groups of countries.FindingsUsing the Bayesian method, the results show that financial inclusion negatively impacts tax revenue with an absolute probability of 100% in LFDCs and a lower probability of 92.45% in HFDCs. Additionally, the financial inclusion threshold at LFDCs is 18.90. Below this threshold, financial inclusion promotes tax revenue with a 100% probability. On the contrary, when financial inclusion exceeds the threshold, it will have a negative effect on tax revenue. Similarly, the financial inclusion threshold at HFDCs is 20.14, with a probability of 92.45%.Originality/valueTo the best of the authors’ knowledge, this is the first paper to examine the nonlinear impact of financial inclusion on tax revenue in high and low financial development countries.

International Classification System for Ocular Complications of Anti-VEGF Agents in Clinical Trials

Complications associated with intravitreal anti-VEGF therapies are reported inconsistently in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. Systematic review and Delphi consensus process. Twenty-five international retinal specialists participated in the Delphi consensus survey. A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists who voted on inclusion, exclusion, rephrasing, and addition of complications. Furthermore, surveys determined specifiers for the selected complications. This iterative process helped to refine the final classification system. The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. After screening 18 229 articles, 130 complications were categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 complications (70%) after 3 rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 complications (52%) in the final list. A total of 14 complications (11%) met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds also were excluded from the final classification system after the Delphi process terminated. In addition, 47 of 75 proposed complication specifiers (63%) were included based on participant agreement. Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Current diagnostic guidelines and perpetuation of inequities in ovarian cancer: A National Cancer Database study.

11027 Background: International guidelines use cancer antigen 125 (CA-125) thresholds to recommend which patients with pelvic masses should undergo evaluation by gynecologic oncologists for ovarian cancer and which patients can be observed without intervention. However, CA-125 thresholds were developed from white populations, and CA-125 levels have been shown to be 10-29% lower in healthy Black women than white women. If CA-125 levels also differ among patients with cancer, current guidelines may contribute to missed or delayed ovarian cancer diagnoses among Black women. Our objective was to examine CA-125 levels at cancer diagnosis by patient race and associations of CA-125 elevation with timely treatment. Methods: We conducted a retrospective cohort study of patients with ovarian cancer ages 0 to 90+ years diagnosed from 2018-2020 using the National Cancer Database. CA-125 was defined as positive/borderline or negative/normal by each site. We report descriptive CA-125 elevated by patient characteristics. We use multivariate logistic regression models to examine the association of patient characteristics with CA-125 level overall and for epithelial and high-grade serous cancers. We used generalized linearized models to examine the association of CA-125 with days from diagnosis to chemotherapy start for patients with Stage II-IV disease. Results: Of 38,707 patients diagnosed with ovarian cancer and with reported CA-125, 13.4% of patients did not have an elevated CA-125 at diagnosis. Patients who identified as Black, Asian, or Hispanic were less likely to have an elevated CA-125 at ovarian cancer diagnosis as were patients with early-stage disease. Among patients with high-grade serous cancer (n=18,151), 8% of Black patients had normal CA-125 at diagnosis compared to 6% of white patients. In multivariate analyses, being Black remained associated with lower odds of elevated CA-125 (OR 0.71, 95%CI 0.63-0.81), after adjustment for menopausal status, comorbidities, and stage. Even among patients with high-grade serous ovarian cancer, being black was associated with lower odds of having an elevated CA-125 (OR 0.78, 95%CI 0.64-0.96). Patients with Stage II-IV ovarian cancer who had a normal CA-125 at diagnosis had 12 days longer on average to chemotherapy initiation compared to patients with elevated CA-125. Conclusions: Current thresholds for CA-125 and gynecologic oncology referral likely miss Black patients with ovarian cancer and may delay timely treatment. Work is needed to develop inclusive CA-125 thresholds and guidelines for ovarian cancer diagnosis and not compound disparities.

Exploring predictors of Treatment Attendance in Patients with PTSD and Comorbid Personality Disorders: Secondary Analysis of a Randomized Controlled Trial

IntroductionPosttraumatic stress disorder (PTSD) and personality disorders (PD) often co-occur and treatment dropout remains a challenging problem for both disorders. The literature on predictors of treatment dropout is highly mixed and few reliable predictors have been identified for both PTSD and PD treatments separately, let alone for concurrent PTSD and PD treatment.ObjectivesThe aim of the present study was to identify predictors of treatment attendance among a wide range of variables in patients with PTSD and comorbid PD who received trauma-focused treatment with and without concurrent PD treatment.MethodsData were used from the prediction and outcome study in comorbid PTSD and personality disorders (PROSPER), a study consisting of two randomized clinical trials (RCT) testing the effectiveness of trauma-focused treatment (eye movement desensitization and reprocessing or imagery rescripting) with versus without concurrent PD treatment (dialectical behavior therapy or group schema therapy). 256 patients with PTSD and comorbid personality disorder participated in the study. The potential predictors included demographic (e.g. work status), patient severity (e.g. PTSD severity), patient-therapist (e.g. working alliance) and therapist (e.g. therapist experience) variables. The ordinal outcome variable was treatment attendance (0, 1-7, 8-11, 12+ trauma-focused treatment sessions). Relevant predictors were identified by a series of ordinal regression analyses (threshold for inclusion p &lt; .10). Relevant predictors were then entered together in a final ordinal regression model. Multiple imputation was used to handle missing data.ResultsThe final model included ten predictor variables and provided a good fit for the data (pooled R2Nagelkerke = .29). Higher education level (OR = 1.22, p = .009), self-rated PTSD severity (OR = 1.04, p = .036) and working alliance (OR = 1.72, p = .047) were associated with a larger number of attended sessions. Higher levels of inadequate social support from a friend (OR = 0.90, p = .042) and being randomized in the concurrent treatment condition (OR = 0.52, p = .022) were associated with a smaller number of attended sessions.ConclusionsIn terms of treatment attendance rates, the results suggest that trauma-focused treatment is preferred over concurrent trauma-focused and personality disorder treatment for patients presenting with PTSD and PD. Clinicians should further be aware of the risk of lower treatment attendance for patients with a lower educational background and those reporting inadequate social support. Enhancing working alliance may protect against early treatment termination. Finally, patients with higher levels of PTSD severity at baseline may need a larger number of treatment sessions.Disclosure of InterestNone Declared

(060) Epigenetic and Gene Expression Profiles in Non-Plaque Tissues from Men with Peyronie’s Disease

Abstract Introduction Peyronie’s Disease (PD) can significantly impact sexual function. A hereditary predisposition to PD suggests that genetic variants may exist, and gene expression may modulate the penetrance of the disease. Identification of changes in epigenetic and gene expression profiles will facilitate a deeper understanding of the disease and provide insight for more targeted therapies. Objective Our objective is to determine if PD is correlated with epigenetic variations and/or gene expression changes, as indicated by DNA methylation assessment and RNA sequencing. Methods Penile tunica albuginea samples (not from fibrotic plaques) were obtained from men with PD undergoing penile prosthesis placement. Control samples were collected from men with erectile dysfunction (ED) without PD undergoing penile prosthesis placement. DNA methylation analyses were performed on homogenized penile tissue samples via an Illumina Human MethylationEPIC BeadChip v2 array. Using the minfi package in R, beta values were produced for all 936,990 CpG sites for each sample and SWAN normalization was applied. Differentially methylated regions (DMR) were found via USEQ with a threshold Wilcoxon FDR score of 40. Gene expression levels were examined in PD and ED samples via RNA-sequencing. Gene expression data was compared against epigenetic data to determine if any epigenetics changes identified affected gene expression profiles. Results A total of 24 tissue samples were collected: 12 ED and 12 PD. USEQ yielded 36 total DMRs with an FDR score of 40 or greater (p-value&amp;lt;0.0001). Of these 36 DMRs, a Stanford GREAT analysis revealed 60 total gene-region associations and five implicated biological processes: anterior/posterior pattern specification, chordate embryonic development, embryo development (ending in birth or egg hatching), somitogenesis, and pattern specification process. Furthermore, differential gene expression analysis identified 76 genes with significant expression changes between PD and ED groups, of which 17 genes were upregulated while 59 were downregulated. Long noncoding RNAs and the keratocan gene showed notable expression differences between PD and ED groups. GO enrichment analysis revealed significant terms related to DNA binding and protein binding. None of the differentially regulated genes overlapped with identified DMRs. Conclusions This study identified distinct gene expression and DNA methylation patterns between PD and ED groups, despite PD samples not being taken from plaque regions, suggesting that more systemic changes may be present. Upregulated genes in PD included long noncoding RNAs and the keratocan gene, suggesting their involvement in disease pathogenesis. Long noncoding RNA overexpression may serve a regulatory function in gene expression or cell processes while overexpression of the keratocan gene may promote collagen accumulation and remodeling, leading to fibrous plaque formation. Likewise, DMRs and their region-gene associations suggest a role in early embryonic development for pathogenesis. Although RNA-seq did not indicate any significant differentially expressed genes that matched with gene-region associations correlated with DMRs, the significance and quantity of DMRs between ED and PD sample groups is indicative of affected biological processes that manifest in distinct pathophysiologies. Further research is needed to investigate if differentially regulated genes exist in DMRs that exhibited changes but did not meet the criteria threshold for inclusion here. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Contraline, Techfields Inc, Alto Neurosciences, Curebase.

Enhancing high-performance concrete sustainability: integration of waste tire rubber for innovation

This study extensively explored the impact of integrating waste tire rubber into high-performance concrete (HPC) by substituting natural sand. Different fractions of rubber particles—5%, 10%, and 15% replacements of the fine aggregate—were rigorously investigated. Properties from fresh to hardened concrete were assessed, including compressive and tensile strength, modulus of elasticity, workability, and damping coefficient. Replacing up to 10% of sand with 0.6 mm rubber particles showed minimal strength compromise compared to standard HPC. However, at a 15% replacement rate, a noticeable decline in strength became evident, highlighting an optimal threshold for inclusion. Additionally, rubber incorporation notably enhanced concrete ductility and damping, marking a substantial improvement in dynamic properties. Efforts to offset strength reduction through increased fines content and mineral admixture could not counteract the decline at the 15% replacement level, suggesting limitations in compensatory measures. Methodological refinements enhanced data accuracy, including capping and surface treatments during compression testing. The study underlined the viability of controlled rubber substitution for bolstering HPC's dynamic attributes. Despite strength reductions at higher replacement rates, controlled waste tire rubber integration proves promising for enhancing HPC's dynamics without compromising structural integrity, advocating its suitability across diverse construction applications.

Trends in contact sensitization, results, and implications from a contact dermatitis clinic in Israel.

The baseline series includes common allergens, evolves over time, and differs by location. Our study aims to characterize allergen sensitization trends among the Israeli population during the last two decades, compare our results to American and European registries, as well as to highlight significant allergens in additional series outside the European baseline series (OEBS). We analysed patch test results of 2086 patients from a designated contact dermatitis clinic in Tel Aviv between 2019 and 2022, compared them to European and North American registries and to 2156 patch test results conducted in Israel two decades ago. 38.6% of patients had at least one positive reaction to an allergen in the European baseline series (EBS), nickel sulphate (14.6%), fragrance mix I (4.6%), and Methylchloroisothiazolinone methylisothiazolinone (MCI/MI; 3.7%) were the most common among them. N-Isopropyl N-Phenyl-4-Phenylenediamine (NIPPD; 0%), Propolis (0.1%), Sesquiterpene lactone mix (0.1%), and Budesonide (0.1%) elicited a sensitization frequency significantly lower than the proposed threshold for baseline inclusion. Chi-square test revealed a statistically significant decrease (p < 0.05) in the sensitization frequency of fragrance mix I, Formaldehyde, Potassium dichromate, Neomycin sulphate, Myroxylon pereirae, Sesquiterpene lactone, and NIPPD during the last two decades. The overall sensitization frequency to the majority of allergens was lower in our cohort in comparison to the North American and European registries. MCI/MI and 2-hydroxyethyl methacrylate-2 (HEMA) are common, relevant allergens, with high SPIN (significance and prevalence index number) and should be better regulated by the authorities. While among the EBS, NIPPD, Propolis, Sesquiterpene lactone, and Budesonide usually do not elicit a positive reaction and therefore should be reconsidered in baseline series, among the OEBS, Chloramphenicol, Quaternium 15, Propyl gallate, and Amerchol L101 have elicited high SPIN values and should be vigilantly examined in the suitable clinical scenario. Significantly lower sensitization frequency to propolis raises the possibility of a protective effect due to early oral exposure among the Israeli population.

(059) Epigenetic Profiles of Men with Peyronie’s Disease

Abstract Introduction Peyronie’s Disease (PD) can significantly impact sexual function. A hereditary predisposition to PD suggests that genetic variants may exist, and gene expression may modulate the penetrance of the disease. Identification of changes in epigenetic or gene expression profiles would facilitate a deeper understanding of the disease and provide insight for more targeted therapies. Objective Our objective is to determine if predisposition to PD is correlated with epigenetic variations and/or gene expression changes, as indicated by DNA methylation assessment and RNA sequencing. Methods Penile tunica albuginea samples were obtained from men with PD undergoing penile prosthesis placement. Penile sample from these men were not from fibrotic plaques. Control samples were collected from men with erectile dysfunction (ED) without PD undergoing penile prosthesis placement. DNA methylation analyses were performed on homogenized penile tissue samples via an Illumina Human MethylationEPIC BeadChip v2 array. Using the minfi package in R, beta values were produced for all 936,990 CpG sites for each sample and SWAN normalization was applied. Differentially methylated regions (DMR) were found via USEQ with a threshold Wilcoxon FDR score of 40. Gene expression levels were examined in PD and ED samples via RNA-sequencing. Gene expression data was compared against epigenetic data to determine if any epigenetics changes identified affected gene expression profiles. Results A total of 24 tissue samples were collected: 12 ED and 12 PD. USEQ yielded 36 total DMRs with a FDR score of 40 or greater (p-value&amp;lt;0.0001). Of these 36 DMRs, a Stanford GREAT analysis revealed 60 total gene-region associations and five implicated biological processes: anterior/posterior pattern specification, chordate embryonic development, embryo development (ending in birth or egg hatching), somitogenesis, and pattern specification process. Furthermore, differential gene expression analysis identified 76 genes with significant expression changes between PD and ED groups, of which 17 genes were upregulated while 59 were downregulated. Long noncoding RNAs and the keratocan gene showed notable expression differences between PD and ED groups. GO enrichment analysis revealed significant terms related to DNA binding and protein binding. None of the differentially regulated genes overlapped with identified DMRs. Conclusions This study identified distinct gene expression and DNA methylation patterns between PD and ED groups, despite PD samples not being taken from plaque regions. Upregulated genes in PD included long noncoding RNAs and the keratocan gene, suggesting their involvement in disease pathogenesis. Long noncoding RNA overexpression may serve a regulatory function in gene expression or cell processes while overexpression of the keratocan gene may promote collagen accumulation and remodeling, leading to fibrous plaque formation in the affected area. Likewise, DMRs and their region-gene associations suggest a role in early embryonic development for pathogenesis. Although RNA-seq did not indicate any significant differentially expressed genes that matched with gene-region associations correlated with DMRs, the significance and quantity of DMRs between ED and PD sample groups is indicative of affected biological processes that manifest in distinct pathophysiologies. Further research is needed to investigate if differentially regulated genes exist in DMRs that exhibited changes but did not meet the criteria threshold for inclusion here. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Paterna bio, Firmtech, Turtle health, Maximus, Carrot, Contraline, endo pharmaceuticals, inherent biosciences, techfields inc, macro trials, alto neurosciences, curebase, vivify medical.

Development of entrustable professional activities for emergency medicine medical education fellowships: A modified Delphi study.

It is essential that medical education (MedEd) fellows achieve desired outcomes prior to graduation. Despite the increase in postgraduate MedEd fellowships in emergency medicine (EM), there is no consistently applied competency framework. We sought to develop entrustable professional activities (EPAs) for EM MedEd fellows. From 2021 to 2022, we used a modified Delphi method to achieve consensus for EPAs. EM education experts generated an initial list of 173 EPAs after literature review. In each Delphi round, panelists were asked to make a binary choice of whether to include the EPA. We determined an inclusion threshold of 70% agreement a priori. After the first round, given the large number of EPAs meeting inclusion threshold, panelists were instructed to vote whether each EPA should be included in the "20 most important" EPAs for a MedEd fellowship. Modifications were made between rounds based on expert feedback. We calculated descriptive statistics. Seventeen experts completed four Delphi rounds each with 100% response. After Round 1, 87 EPAs were eliminated and two were combined. Following Round 2, 46 EPAs were eliminated, seven were combined, and three were included in the final list. After the third round, one EPA was eliminated and 13 were included. After the fourth round, 11 EPAs were eliminated. The final list consisted of 16 EPAs in domains of career development, education theory and methods, research and scholarship, and educational program administration. We developed a list of 16 EPAs for EM MedEd fellowships, the first step in implementing competency-based MedEd.

Common design and data elements reported in active mechanical thrombectomy trials focusing on distal medium vessel occlusions and minor strokes: a systematic review

BackgroundDistal medium vessel occlusions (DMVOs) and minor strokes represent emerging frontiers in mechanical thrombectomy (MT). Although several randomized clinical trials (RCTs) are underway, the design characteristics of these trials and...

Association of human brain‐age with genetically predicted plasma levels of brain rejuvenating and aging factors identified in mice

AbstractBackgroundAging is the primary risk factor for Alzheimer’s disease. Experiments in mice have identified circulating proteins with an “aging/rejuvenating” effect on the brain. However, whether these proteins have an effect on the human brain remains unknown. Here, we leverage genetic data to study links between the predicted plasma levels of these proteins and human brain age.MethodsThis study includes 1,394 cognitively unimpaired individuals of the ALFA study. Plasma proteins with an effect on mice brain aging were identified through a systematic review [Figure 1]. Summary statistics data of protein quantitative trait loci (pQTLs) associated to these proteins in human (inclusion threshold&lt;5×10−5) were acquired from a previous study (Pietzner et al.,2021), and used for computing protein genetic scores (pPRS). For each ALFA cohort participant, DeltaAge scores was calculated by subtracting chronological age from MRI‐based estimation of brain age (Cumplido et al.,2022). Positive values are interpreted as brain age older than chronological age, and viceversa. The associations between brain DeltaAge measurements and pPRSs were assessed through general linear regression models stratified by sex, amyloid‐β (Aβ) status (CSF‐Aβ42/40&lt;0.071 [Milà‐Alomà et al.,2020]) and APOE‐ε4 carriership. Results were reported for nominal and group‐correction (two experimental aging groups) level of significance (p&lt;0.05, p&lt;0.025, respectively). All pQTLs included in the significant pPRS were functionally annotated and an enrichment analysis was performed.ResultsGenetically predicted plasma levels of CSF2, VCAM1, HP, GHRH and BGLAP were associated with negative values of brain DeltaAge, while KLOTHO with positive values. Results for GHRH (Aβ+ and APOE‐ε4 non‐carriers) and BGLAP (APOE‐ε4 carriers) remained significant after p‐value correction, with an effect in agreement with their brain rejuvenation role as found in mice [Figure 2]. Enrichment analysis found immune response and complement activation processes associated with negative values of DeltaAge [Figure 3].ConclusionsThese results show that plasma levels of the brain aging/rejuvenating proteins discovered in mice may also influence human brain aging. In particular, genetically predicted levels of two rejuvenating factors in mice (BGLAP and GHRH) were associated with a younger brain age than chronological age. Follow‐up analyses will include protein level measurements to unravel the molecular complexity of brain aging.

Bioinformatic investigation of discordant sequence data for SARS-CoV-2: insights for robust genomic analysis during pandemic surveillance.

The COVID-19 pandemic has necessitated the rapid development and implementation of whole-genome sequencing (WGS) and bioinformatic methods for managing the pandemic. However, variability in methods and capabilities between laboratories has posed challenges in ensuring data accuracy. A national working group comprising 18 laboratory scientists and bioinformaticians from Australia and New Zealand was formed to improve data concordance across public health laboratories (PHLs). One effort, presented in this study, sought to understand the impact of the methodology on consensus genome concordance and interpretation. SARS-CoV-2 WGS proficiency testing programme (PTP) data were retrospectively obtained from the 2021 Royal College of Pathologists of Australasia Quality Assurance Programmes (RCPAQAP), which included 11 participating Australian laboratories. The submitted consensus genomes and reads from eight contrived specimens were investigated, focusing on discordant sequence data and findings were presented to the working group to inform best practices. Despite using a variety of laboratory and bioinformatic methods for SARS-CoV-2 WGS, participants largely produced concordant genomes. Two participants returned five discordant sites in a high-Cτ replicate, which could be resolved with reasonable bioinformatic quality thresholds. We noted ten discrepancies in genome assessment that arose from nucleotide heterogeneity at three different sites in three cell-culture-derived control specimens. While these sites were ultimately accurate after considering the participants' bioinformatic parameters, it presented an interesting challenge for developing standards to account for intrahost single nucleotide variation (iSNV). Observed differences had little to no impact on key surveillance metrics, lineage assignment and phylogenetic clustering, while genome coverage <90 % affected both. We recommend PHLs bioinformatically generate two consensus genomes with and without ambiguity thresholds for quality control and downstream analysis, respectively, and adhere to a minimum 90 % genome coverage threshold for inclusion in surveillance interpretations. We also suggest additional PTP assessment criteria, including primer efficiency, detection of iSNVs and minimum genome coverage of 90 %. This study underscores the importance of multidisciplinary national working groups in informing guidelines in real time for bioinformatic quality acceptance criteria. It demonstrates the potential for enhancing public health responses through improved data concordance and quality control in SARS-CoV-2 genomic analysis during pandemic surveillance.