Social Determinants of Health Impacting Access to Renal Dialysis for Racial/Ethnic Minorities.

Although widespread, the burden of disease presented by chronic kidney disease (CKD) is not equally distributed among all demographics. Examining the social determinants of health (SDOH) that relate to barriers to renal dialysis care in CKD can help to prevent future disparities. There has not been a study addressing the social factors that create barriers to care for ethnic minority patients with CKD. The aim of this scoping review is to address the SDOH that affects access to renal dialysis for ethnic minority patients in the United States. This study was based on the protocol published by the Joanna Briggs Institute. A total of 349 studies were identified from PubMed, EBSCOhost, and Embase. Each article was screened against population, concept, and context criteria in order to be considered for inclusion. The population was determined to be adults of all genders from underrepresented minority populations. The selected concept was SDOH. The context of this study was the United States population. From the articles selected by the search criteria, neighborhood of residence, mental health care access, glomerular filtration rate (GFR) methodology, socioeconomic status (SES), language barriers, immigration status, and military rank were identified as SDOH affecting access to renal dialysis care. While this study identified four social determinants, more research is needed for the investigation of other possible SDOH contributing to disparities related to CKD and access to renal dialysis care.

Learning How to Learn: An Innovative Medical School Orientation Activity.

PROBLEM: In 2018, Creighton University School of Medicine initiated a multiyear strategy to redesign the pedagogic approach of its educational program, transitioning from large-group, lecture-based experiences to small-group, active learning experiences using case-based learning (CBL) as required prework for team-based learning (TBL). In July 2019, the authors introduced their first-year medical students to the pedagogic and empiric underpinnings of the new curriculum they would experience. Initially, and ironically, this introduction was presented as a 30-minute didactic lecture, and students' ability to assimilate this information in any meaningful way was challenged. In addition, students required several sessions of the CBL-TBL activities during the official curriculum before they were able to effectively function as a team of learners. The authors created a novel introduction to their educational program that was active, meaningful, and efficient. APPROACH: In 2022, the authors created a 2-hour, small-group CBL activity using a fictional narrative of a medical student encountering their curriculum. During development, the authors recognized that the narrative was conducive to introduction of affective responses to medical education stressors, such as imposter phenomenon and Stanford duck syndrome. The CBL activity was given 4 hours during the formal 2022 orientation; 230 students participated. The CBL activity occurred on the second day of orientation and the TBL activity on the third (final) day of orientation. OUTCOMES: The results of the TBL activity indicate that students acquired a fundamental understanding of the attributes of active learning, features of imposter syndrome, substance abuse associated with Stanford duck syndrome, and peer evaluation. NEXT STEPS: This CBL-TBL activity will become a permanent part of orientation. The authors hope to evaluate the qualitative outcomes of this innovation on students' professional identity formation, institutional affiliation, and motivation. The authors will assess for any negative impact of this experience and the overall orientation.

Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6, CXCR5, and lnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.

Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses.

OBJECTIVE: Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjDRo+) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised. METHODS: Whole blood RNA-sequencing (RNA-seq) was performed on SjD cases (n=23 Ro/SSA negative (SjDRo-); n=27 Ro/SSA positive (SjDRo+) and healthy controls (HCs; n=27). Bioinformatics and pathway analyses of differentially expressed (DE) transcripts (log2 fold change ≥2 or ≤0.5; padj<0.05) were used to predict lncRNA function. LINC01871 was characterised by RNA-seq analyses of HSB-2 cells with CRISPR-targeted LINC01871 deletion (LINC01871-/ -) and in vitro stimulation assays. RESULTS: Whole blood RNA-seq revealed autoantibody-specific transcription profiles and disproportionate downregulation of DE transcripts in SjD cases relative to HCs. Sixteen DE lncRNAs exhibited correlated expression with the interferon (IFN)-regulated gene, RSAD2, in SjDRo+ (r≥0.65 or ≤-0.6); four antisense lncRNAs exhibited IFN-regulated expression in immune cell lines. LINC01871 was upregulated in all SjD cases. RNA-seq and pathway analyses of LINC01871-/ - cells implicated roles in cytotoxic function, differentiation and IFNγ induction. LINC01871 was induced by IFNγ in a myeloid cell line and regulated by calcineurin/NFAT pathway and T cell receptor (TCR) signalling in primary human T cells. CONCLUSION: LINC01871 influences expression of many immune cell genes and growth factors, is IFNγ inducible, and regulated by calcineurin signalling and TCR ligand engagement. Altered LINC01871 expression may influence the dysregulated T cell inflammatory pathways implicated in SjD.

Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.

Detection of congestive heart failure by mitral annular displacement in cats with hypertrophic cardiomyopathy - concordance between tissue Doppler imaging-derived tissue tracking and M-mode.

INTRODUCTION: The left ventricular systolic longitudinal function, traditionally measured by M-mode-derived mitral annular plane systolic excursion (MAPSE), is reduced in feline hypertrophic cardiomyopathy (HCM) and further reduced in cats with left-sided congestive heart failure (CHF). The objectives of this study were to compare longitudinal displacement measured by tissue tracking (TT-LD) and MAPSE in feline HCM and assess these methods' ability to differentiate CHF from preclinical HCM. A further objective was to provide preliminary reference intervals for TT-LD. ANIMALS: Eighty-five client-owned cats. METHODS: A retrospective case-control study. Anatomical M-mode was used to record MAPSE, and TT-LD was recorded by tissue tracking. RESULTS: Reduced longitudinal displacement measured by either MAPSE or TT-LD was significantly associated with CHF in cats with HCM (p < 0.036). Receiver-operating characteristic analysis indicated that TT-LD (AUC: 92.9%-97.9%) was more sensitive and specific than MAPSE (AUC: 85.8%-89.1%) for the detection of CHF. A diagnostic cut-off of 2.89 mm for maximal TT-LD in the left ventricular septum resulted in a sensitivity and specificity of 100% and 83.3%, while a diagnostic cut-off of 2.41 mm in the left ventricular posterior wall resulted in a sensitivity of 100% and a specificity of 90%. CONCLUSIONS: M-mode-derived mitral annular plane systolic excursion and TT-LD were strongly correlated, but not interchangeable. Longitudinal displacement measured by tissue tracking decreased more with disease severity than traditional MAPSE. Longitudinal displacement may help detect CHF in cats with HCM - with the maximal TT-LD of the left ventricular posterior wall achieving the highest AUC value.

Adherence to the infant vitamin D supplementation policy in Ireland.

PURPOSE: From September 2010 until November 2019, Ireland's infant vitamin D supplementation policy recommended administration of 5 µg/day of vitamin D3 from birth to 12 months to all infants, regardless of feeding method. This study aims to examine policy adherence. METHODS: In the prospective COMBINE birth cohort study (recruited 2015-2017), detailed longitudinal supplement data were examined in 364 infants across the first year of life, according to product type, dose, frequency, and duration. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was compared with the BASELINE cohort (recruited 2008-2011, n = 1949). RESULTS: In COMBINE, 92% of infants initiated supplementation at birth. The median supplementation duration was 51 (40, 52) weeks, with a range of 3-52 weeks. While supplementing, most parents (92%) used an exclusive vitamin D supplement as recommended and 88% gave 5 µg/day. Half (51%) gave vitamin D daily and a further 33% supplemented at least 3-6 times/week. Overall, 30% adhered fully to the policy, providing 5 µg vitamin D3 daily from birth to 12 months. A further 16% were broadly compliant, giving 5 µg frequently for the full 12 months. Vitamin D supplement use at 2, 6, and 12 months in COMBINE was 93%, 89%, and 72%, considerably higher than our earlier BASELINE cohort at 49%, 64%, and 44% at the same time points (all P < 0.001). CONCLUSIONS: We report a high level of vitamin D supplementation initiation at birth, with full to broad policy adherence among more than half of infants. There is scope to improve overall compliance by focusing on supplementation frequency.

Vitamin D in pregnancy: Where we are and where we should go.

Vitamin D deficiency has been widely reported among pregnant women and infants around the world. Women with low sun exposure, high BMI, low vitamin D intakes and socioeconomic disadvantage with poor quality diets are at greatest risk of vitamin D deficiency, leading to very low serum concentrations of 25-hydroxyvitamin D (25(OH)D) in their offspring and an increased risk of nutritional rickets. Many observational studies, supported by compelling in vitro and in vivo data, have generated evidence suggesting that low vitamin D status in pregnancy may also contribute to the risk of adverse perinatal outcomes including hypertensive disorders (e.g., preeclampsia), fetal growth restriction, and preterm birth. However, the few large randomized controlled trials (RCTs) conducted to date have generated conflicting evidence for a role of vitamin D supplementation in improving perinatal outcomes. Vitamin D supplementation policies during pregnancy and implementation of policies vary within and between jurisdictions. Regulatory authorities have cited insufficient evidence to establish pregnancy-specific targets for serum 25(OH)D concentrations or prenatal vitamin D intake that effectively reduce the risks of adverse perinatal and infant outcomes. This paper arises from a Debate on Vitamin D Requirements during Pregnancy, held at the 22nd Vitamin D Workshop, 2019. From varied perspectives, our objectives were to evaluate the evidence for: vitamin D metabolism in pregnancy and the prevalence of gestational vitamin D deficiency worldwide; the translation of laboratory research findings to clinical studies on the role of vitamin D in perinatal health; the challenges of designing and conducting clinical trials to establish prenatal vitamin D requirements; and results to date of major large RCTs of prenatal vitamin D supplementation. Lastly, we explored potential next steps towards generating robust clinical data in this field to address both public health protection and patient care.

Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

Impact of maternal, antenatal and birth-associated factors on iron stores at birth: data from a prospective maternal-infant birth cohort.

BACKGROUND/OBJECTIVES: Low serum ferritin concentrations at birth, which reflect neonatal iron stores, track through to early childhood and have been associated with poorer neurodevelopmental outcomes. We aimed to identify maternal, antenatal and birth-associated factors that influence iron stores at birth in a prospective maternal-infant birth cohort. SUBJECTS/METHODS: In a population-based, longitudinal, birth cohort in Ireland, 413 maternal-infant dyads with prospectively collected lifestyle and clinical data from 15 weeks' gestation had umbilical cord serum ferritin concentrations measured. Regression models were developed to identify independent factors associated with cord ferritin concentrations. RESULTS: Median (IQR) cord ferritin concentrations were 185.7 (131.7, 385.5) µg/l, and 8% (n=33) of infants had low iron stores (ferritin <76 µg/l) at birth. Maternal obesity (BMI ⩾30 kg/m2) at 15 weeks' gestation (adj. estimate (95% confidence interval (CI)): -66.4 (-106.9, -25.9) µg/l, P<0.0001) and delivery by caesarean section (-38.8 (-70.2, -7.4) µg/l, P=0.016) were inversely associated with cord ferritin concentrations. In addition, maternal smoking at 15 weeks' gestation (adj. odds ratio (95% CI): 2.9 (1.2, 7), P=0.020) and being born small-for-gestational age (3.4 (1.3, 8.9), P=0.012) were associated with an increased risk of low iron stores (ferritin <76 µg/l) at birth. CONCLUSIONS: We have identified a number of potentially modifiable lifestyle factors that influence iron stores at birth, with the important role of overall maternal health and lifestyle during pregnancy highlighted. Public health policies targeting women of child-bearing age to improve nutrition and health outcomes should be prioritised for the health of the next generation.

Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer?

The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1MET (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1MET was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1MET than p53 WT cells (p = 0.029). Furthermore, response (measured as IC50 value) correlated significantly with p53 protein level as measured by ELISA (p = 0.0089, r=-0.57, n = 19). In addition to inhibiting cell proliferation, PRIMA-1MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.

Single-cell analysis of glandular T cell receptors in Sjögren's syndrome.

CD4+ T cells predominate in salivary gland (SG) inflammatory lesions in Sjögren's syndrome (SS). However, their antigen specificity, degree of clonal expansion, and relationship to clinical disease features remain unknown. We used multiplex reverse-transcriptase PCR to amplify paired T cell receptor α (TCRα) and ß transcripts of single CD4+CD45RA- T cells from SG and peripheral blood (PB) of 10 individuals with primary SS, 9 of whom shared the HLA DR3/DQ2 risk haplotype. TCRα and ß sequences were obtained from a median of 91 SG and 107 PB cells per subject. The degree of clonal expansion and frequency of cells expressing two productively rearranged α genes were increased in SG versus PB. Expanded clones from SG exhibited complementary-determining region 3 (CDR3) sequence similarity both within and among subjects, suggesting antigenic selection and shared antigen recognition. CDR3 similarities were shared among expanded clones from individuals discordant for canonical Ro and La autoantibodies, suggesting recognition of alternative SG antigen(s). The extent of SG clonal expansion correlated with reduced saliva production and increased SG fibrosis, linking expanded SG T cells with glandular dysfunction. Knowledge of paired TCRα and ß sequences enables further work toward identification of target antigens and development of novel therapies.

Parental physical and lifestyle factors and their association with newborn body composition.

OBJECTIVE: To investigate the parental physical and lifestyle determinants of newborn body composition. DESIGN: Prospective cohort study. SETTING: Cork University Maternity Hospital, a tertiary referral hospital in Cork, Ireland. POPULATION: All babies were recruited as part of a prospective birth cohort, Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints (BASELINE). These babies were recruited from women who had participated in the Screening of Pregnancy Endpoints (SCOPE) study Ireland, a prospective, multicentre cohort study METHODS: Multivariate linear regression was used to analyse the effect of a range of maternal and paternal physical and lifestyle features on neonatal body fat percentage (BF%). MAIN OUTCOME MEASURES: Neonatal BF%. Neonatal adiposity was assessed within 48 hours of birth using air displacement plethysmography (PEAPOD(®) ). RESULTS: In all, 1243 infants were enrolled in the study. Increasing maternal body mass index (adjusted mean difference 0.09; 0.04, 0.15) and waist height ratio (adjusted mean difference 6.59; 0.27, 12.92) were significantly associated with increased neonatal BF%. In contrast, maternal smoking was associated with reduced neonatal BF% compared with non smokers (adjusted mean difference -0.55; -1.07, -0.03). Infant sex significantly altered neonatal BF%, with female infants having higher neonatal BF% compared with male infants (adjusted mean difference 1.98; 1.54, 2.53). No association was observed between paternal body mass index (BMI), paternal age or paternal smoking and neonatal BF%. CONCLUSIONS: Maternal smoking, BMI, waist height ratio and infant sex were associated with altered BF%. TWEETABLE ABSTRACT: Maternal smoking, BMI, waist height ratio and infant sex are associated with altered neonatal body fat percentage.

Development, validation and implementation of a quantitative food frequency questionnaire to assess habitual vitamin D intake.

BACKGROUND: A well-designed, validated quantitative food frequency questionnaire (FFQ) could offer an efficient and cost-effective method for assessing habitual vitamin D intake. The present study aimed to describe the development, validation and implementation of a vitamin D FFQ. METHODS: National food consumption survey data obtained from Irish adults (18-64 years) were used to identify foods that contribute 95% of vitamin D intake. A winter-based validation study was carried out for the resulting FFQ in 120 females, including 98 women [mean (SD) 65.0 (7.3) years] and 22 girls [12.2 (0.8) years], using a 14-day diet history (DH) as a comparator. Serum 25(OH)D concentrations were analysed. Validity coefficients were calculated using the method of triads. Cross-classification and Bland-Altman analysis were also performed. RESULTS: Median (interquartile range) vitamin D intakes (including the contribution from nutritional supplements) were 5.4 (3.7) and 3.7 (5.9) µg day(-1) from the FFQ and DH, respectively and intakes of vitamin D from food sources were 3.6 (3.1) and 2.4 (2.2) µg day(-1) . The FFQ and DH classified 86% and 87% of individuals into the same and adjacent thirds of wintertime serum 25(OH)D status, respectively. There was a strong association (r = 0.71, P < 0.0001) and no significant systematic or proportional bias observed for the difference between estimates from the FFQ and DH. The validity coefficient for the FFQ was 0.92 (95% confidence interval = 0.80-0.97). Repeatability analysis (n = 56) performed 6-12 months later showed no significant difference in estimates of vitamin D between administrations. CONCLUSIONS: The data obtained in the present study indicate high validity and good reproducibility of a short, interviewer-administered FFQ for vitamin D.

ePlantLIBRA: A composition and biological activity database for bioactive compounds in plant food supplements.

The newly developed ePlantLIBRA database is a comprehensive and searchable database, with up-to-date coherent and validated scientific information on plant food supplement (PFS) bioactive compounds, with putative health benefits as well as adverse effects, and contaminants and residues. It is the only web-based database available compiling peer reviewed publications and case studies on PFS. A user-friendly, efficient and flexible interface has been developed for searching, extracting, and exporting the data, including links to the original references. Data from over 570 publications have been quality evaluated and entered covering 70 PFS or their botanical ingredients.

Eating behaviour and weight status at 2 years of age: data from the Cork BASELINE Birth Cohort Study.

BACKGROUND/OBJECTIVES: To conduct an analysis of associations between eating behaviours and weight status in 2-year-old children. SUBJECTS/METHODS: Data were collected prospectively in the maternal-infant dyad Cork BASELINE Birth Cohort Study. The weight status of children aged 2 years (n=1189) was assigned using the International Obesity Task Force BMI cutoffs using measured heights and weights. Eating behaviours were assessed using the Children's Eating Behaviour Questionnaire (CEBQ). RESULTS: Eighty percent of children were of normal weight, 14% were overweight or obese and 6% were underweight. From the CEBQ, food approach behaviours including Enjoyment of Food (odds ratio (OR)=1.90, 95% confidence interval (CI)=1.46-2.48) and Food Responsiveness (OR=1.73, 95% CI=1.47-2.03) were associated with overweight/obesity (all P<0.001). The food avoidant behaviours of Satiety Responsiveness (OR=2.03, 95% CI=1.38-2.98) and Slowness in Eating (OR=1.44, 95% CI=1.01-2.04) were associated with underweight at 2 years (all P<0.05). CONCLUSIONS: Eating behaviours are associated with weight status as early as 2 years of age.

Vitamin D and muscle strength throughout the life course: a review of epidemiological and intervention studies.

The putative role of vitamin D in muscle function and strength throughout the life course is of interest because muscle strength is required for engagement in physical activity at all ages. As vitamin D deficiency is widely reported in the population, especially in countries at high latitude, the potential importance of vitamin D in muscle function throughout life, and the potential impacts on growth and development, participation in physical activity, and effects on skeletal and cardio-metabolic health, comprise an important topic for discussion. This review provides an overview of muscle function and summarises the role of the vitamin D receptor and the proposed molecular mechanisms of action of vitamin D in muscle cells. In addition, the review provides a comprehensive assessment of the clinical evidence surrounding the association between vitamin D and muscle strength. Among adults, particularly older adults, cross-sectional and cohort studies reported a positive association between vitamin D status and muscle strength. These associations have been largely confirmed by intervention studies. Limited research has been carried out in adolescents and children; two cross-sectional studies in adolescents have suggested an association between serum 25-hydroxyvitamin D concentrations and muscle strength. However, the two intervention studies in adolescents have yielded conflicting results. Other than a single observational study, data in young children are very limited and further investigation in under 12-year-olds is warranted.