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Research on kidney diseases is being transformed by the rapid expansion and innovations in omics technologies. The analysis, integration, and interpretation of big data, however, have been an impediment to the growing interest in applying these technologies to understand kidney function and failure. Targeting this urgent need, the University of Michigan O’Brien Kidney Translational Core Center (MKTC) and its Administrative Core established the Applied Systems Biology Core. The Core provides need-based support for the global kidney community centered on enabling incorporation of systems biology approaches by creating web-based, user-friendly analytic and visualization tools, like Nephroseq and Nephrocell, guiding with experimental design, and processing, analysis, and integration of large data sets. The enrichment core supports systems biology education and dissemination through workshops, seminars, and individualized training sessions. Meanwhile, the Pilot and Feasibility Program of the MKTC provides pilot funding to both early-career and established investigators new to the field, to integrate a systems biology approach into their research projects. The relevance and value of the portfolio of training and services offered by MKTC are reflected in the expanding community of young investigators, collaborators, and users accessing resources and engaging in systems biology-based kidney research, thereby motivating MKTC to persevere in its mission to serve the kidney research community by enabling access to state-of-the-art data sets, tools, technologies, expertise, and learning opportunities for transformative basic, translational, and clinical studies that will usher in solutions to improve the lives of people impacted by kidney disease.

OBJECTIVE To define the relationship between glucose and C-peptide during the progression to type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS We longitudinally studied glucose and C-peptide response curves (GCRCs), area under curve (AUC) for glucose, and AUC C-peptide from oral glucose tolerance tests (OGTTs), and Index60 (which integrates OGTT glucose and C-peptide values) in Diabetes Prevention Trial–Type 1 (DPT-1) (n = 72) and TrialNet Pathway to Prevention Study (TNPTP) (n = 82) participants who had OGTTs at baseline and follow-up time points before diagnosis. RESULTS Similar evolutions of GCRC configurations were evident between DPT-1 and TNPTP from baseline to 0.5 years prediagnosis. Whereas AUC glucose increased throughout from baseline to 0.5 years prediagnosis, AUC C-peptide increased from baseline until 1.5 years prediagnosis (DPT-1, P = 0.004; TNPTP, P = 0.012) and then decreased from 1.5 to 0.5 years prediagnosis (DPT-1, P = 0.017; TNPTP, P = 0.093). This change was mostly attributable to change in the late AUC C-peptide response (i.e., 60- to 120-min AUC C-peptide). Median Index60 values of DPT-1 (1.44) and TNPTP (1.05) progressors to T1D 1.5 years prediagnosis (time of transition from increasing to decreasing AUC C-peptide) were used as thresholds to identify individuals at high risk for T1D in the full cohort at baseline (5-year risk of 0.75–0.88 for those above thresholds). CONCLUSIONS A transition from an increase to a decrease in AUC C-peptide ∼1.5 years prediagnosis was validated in two independent cohorts. The median Index60 value at that time point can be used as a pathophysiologic-based threshold for identifying individuals at high risk for T1D.

OBJECTIVE Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish continuous glucose monitoring (CGM) metrics that could predict imminent progression to diabetes. RESEARCH DESIGN AND METHODS In the Autoimmunity Screening for Kids study, 91 children who were persistently islet autoantibody positive (median age 11.5 years; 48% non-Hispanic White; 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range 0.2–34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range 0.4–29) months. RESULTS Compared with children who did not progress to clinical diabetes (nonprogressors), those who did (progressors) had significantly higher average sensor glucose levels (119 vs. 105 mg/dL, P < 0.001) and increased glycemic variability (SD 27 vs. 16, coefficient of variation, 21 vs. 15, mean of daily differences 24 vs. 16, and mean amplitude of glycemic excursions 43 vs. 26, all P < 0.001). For progressors, 21% of the time was spent with glucose levels >140 mg/dL (TA140) and 8% of time >160 mg/dL, compared with 3% and 1%, respectively, for nonprogressors. In survival analyses, the risk of progression to diabetes in 1 year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. Performance of prediction by receiver operating curve analyses showed area under the curve of ≥0.89 for both individual and combined CGM metric models. CONCLUSIONS TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year in autoantibody-positive children. CGM should be included in the ongoing monitoring of high-risk children and could be used as potential entry criterion for prevention trials.

Longitudinal changes in gene expression during islet autoimmunity (IA) may provide insight into biological processes that explain progression to type 1 diabetes (T1D). We identified individuals from Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, autoantibodies present on two or more visits. Illumina’s NovaSeq 6000 was used to quantify gene expression in whole blood. With linear mixed models we tested for changes in expression after IA that differed across individuals who progressed to T1D (progressors) (n = 25), reverted to an autoantibody-negative stage (reverters) (n = 47), or maintained IA positivity but did not develop T1D (maintainers) (n = 66). Weighted gene coexpression network analysis was used to identify coexpression modules. Gene Ontology pathway analysis of the top 150 differentially expressed genes (nominal P < 0.01) identified significantly enriched pathways including leukocyte activation involved in immune response, innate immune response, and regulation of immune response. We identified a module of 14 coexpressed genes with roles in the innate immunity. The hub gene, LTF, is known to have immunomodulatory properties. Another gene within the module, CAMP, is potentially relevant based on its role in promoting β-cell survival in a murine model. Overall, results provide evidence of alterations in expression of innate immune genes prior to onset of T1D.

AIMS/HYPOTHESES: Physical inactivity may contribute to islet autoimmunity and progression to clinical type 1 diabetes. To test this hypothesis, we evaluated physical activity, assessed by accelerometer, as an independent risk factor for progression to clinical diabetes among genetically at risk for type 1 diabetes children and youth with islet autoimmunity. METHODS: Accelerometer data were obtained for 95 children and youth participating in the Diabetes Autoimmunity Study in the Young who had islet autoimmunity. Islet autoimmunity was defined as the presence of islet autoantibodies to insulin, glutamic acid decarboxylase, tyrosine phosphatase-like protein IA-2, or zinc transporter 8. RESULTS: During prospective follow-up for up to 7 years, 13 of the 95 participants progressed to clinical diabetes. In multivariable survival analysis, none of the physical activity parameters examined predicted a higher risk of developing diabetes. In survival analysis with time-varying physical activity parameters, none of the physical activity parameters over time were associated with the risk of developing type 1 diabetes. CONCLUSIONS/INTERPRETATION: It does not appear that low physical activity is a risk factor for progression from islet autoantibodies to diabetes in children and youth at high genetic risk for type 1 diabetes.

The overall survival rate of prostate cancer (PCa) has improved over the past decades. However, huge socioeconomic and racial disparities in overall and prostate cancer-specific mortality exist. The neighborhood-level factors including socioeconomic disadvantage and lack of access to care may contribute to disparities in cancer mortality. This study examines the impact of neighborhood deprivation on mortality among PCa survivors.North Carolina-Louisiana Prostate Cancer Project (PCaP) data were used. A total of 2113 men, 1046 AA and 1067 EA, with PCa were included in the analysis. Neighborhood deprivation was measured by the Area Deprivation Index (ADI) at the census block group level using data from the US Census Bureau. Quintiles of ADI were created. Cox proportional hazards and competing risk models with mixed effects were performed to estimate the effect of neighborhood deprivation on all-cause and PCa-specific mortality adjusted for age, race, study site, insurance status, and comorbidities.Participants living in the most deprived neighborhoods had an increased risk for all-cause mortality (quintiles 4 + 5: adjusted hazard ratio [aHR] = 1.51, 95% confidence interval [CI] = 1.16-1.96) compared to those in the least deprived (quintile 1) neighborhoods. The risk of prostate cancer-specific mortality was also higher among those living in the deprived neighborhoods (quintiles 4 + 5: aHR = 1.90, 95% CI = 1.10-3.50) than those in the least deprived neighborhood.The findings suggest neighborhood-level resources or health interventions are essential to improve survival among men with PCa. Additional research should focus on the mechanisms of how the neighborhood environment affects mortality.

Objective Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes. Methods We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA)] and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses. Results Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05). Conclusions ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

T cell receptor (TCR) sequences are exceptionally diverse and can now be comprehensively measured with next-generation sequencing technologies. However, a thorough investigation of longitudinal TCR repertoires throughout childhood in health and during development of a common childhood disease, type 1 diabetes (T1D), has not been undertaken. Here, we deep sequenced the TCR-β chain repertoires from longitudinal peripheral blood DNA samples at 4 time points beginning early in life (median age of 1.4 years) from children who progressed to T1D (n = 29) and age/sex-matched islet autoantibody-negative controls (n = 25). From 53 million TCR-β sequences, we show that the repertoire is extraordinarily diverse early in life and narrows with age independently of disease. We demonstrate the ability to identify specific TCR sequences, including those known to recognize influenza A and, separately, those specific for insulin and its precursor, preproinsulin. Insulin-reactive TCR-β sequences were more common and frequent in number as the disease progressed in those who developed T1D compared with genetically at risk nondiabetic children, and this was not the case for influenza-reactive sequences. As an independent validation, we sequenced and analyzed TCR-β repertoires from a cohort of new-onset T1D patients (n = 143), identifying the same preproinsulin-reactive TCRs. These results demonstrate an enrichment of preproinsulin-reactive TCR sequences during the progression to T1D, highlighting the importance of using disease-relevant TCR sequences as powerful biomarkers in autoimmune disorders.

Diet, inflammation, and oxidative stress may be important in breast carcinogenesis, but evidence on the role of the inflammatory and pro-oxidative potential of dietary patterns is limited. Energy adjusted-Dietary Inflammatory Index (E-DII TM ) and dietary oxidative balance score (D-OBS) were calculated for 43,563 Sister Study cohort participants who completed a Block 1998 food frequency questionnaire at enrollment in 2003-2009 and satisfied eligibility criteria. D-OBS was validated using measured F2 -isoprostanes and metabolites. High E-DII score and low D-OBS represent a more pro-inflammatory and pro-oxidant diet, respectively, and associations of quartiles of each index with breast cancer (BC) risk were estimated using multivariable Cox proportional hazards regression. There were 2,619 BCs diagnosed at least 1 year after enrollment (mean follow-up 8.4 years). There was no overall association between E-DII and BC risk, whereas there was a suggestive inverse association for the highest versus lowest quartile of D-OBS (HR 0.92 [95% CI, 0.81-1.03]). The highest quartile of E-DII was associated with risk of triple-negative BC (HR 1.53 [95% CI, 0.99-2.35]). When the two indices were combined, a pro-inflammatory/pro-oxidant diet (highest tertile of E-DII and lowest tertile of D-OBS) was associated with increased risk for all BC (HR 1.13 [95% CI, 1.00-1.27]) and for triple-negative BC (1.72 [95% CI, 1.10-2.70]), compared with an anti-inflammatory/anti-oxidant diet (lowest tertile of E-DII and highest tertile of D-OBS). Diets with increased inflammatory potential and reduced oxidative balance were positively associated with overall and triple-negative BC.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor–stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβD849V) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβD849V also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβD849V was observed within a subset of astrocytes, and aged mice expressing PDGFRβD849V exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβD849V in their stromal cells as a preclinical model of breast cancer–associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. Significance: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients. See related article by Wyss and colleagues, p. 594

OBJECTIVE: Large-scale screening of the general population for islet autoantibodies (IAbs) to detect type 1 diabetes (T1D) has started worldwide. The standard screening method of separate radio-binding assay (RBA) for each IAb is an inefficient bottleneck. Furthermore, most positive results by RBA in screening of general population individuals without a clinical diagnosis of T1D are low-affinity and not predictive of future diabetes. RESEARCH DESIGN AND METHODS: We have developed and validated a novel 6-Plex assay based on electrochemiluminescence (ECL) technology that combines in a single well high-affinity IAbs (to insulin, GAD, IA-2, and ZnT8), transglutaminase autoantibodies for celiac disease, and severe acute respiratory syndrome coronavirus 2 antibodies. The Autoimmunity Screening for Kids (ASK) provided 880 serum samples, from 828 children aged 1–17 years without diabetes who were previously tested for IAbs using single ECL assays and RBA assays. RESULTS: Levels of all six antibodies in the 6-Plex ECL assay correlated well with respective single ECL assay levels. Similar to single ECL assays, the 6-Plex ECL assay positivity was congruent with the RBA in 95% (35/37) of children who later developed T1D and in 88% (105/119) high-risk children with multiple IAbs. In contrast, only 56% (86/154, P

Kidney Precision Medicine Project (KPMP) is building a spatially specified human kidney tissue atlas in health and disease with single-cell resolution. Here, we describe the construction of an integrated reference map of cells, pathways, and genes using unaffected regions of nephrectomy tissues and undiseased human biopsies from 56 adult subjects. We use single-cell/nucleus transcriptomics, subsegmental laser microdissection transcriptomics and proteomics, near-single-cell proteomics, 3D and CODEX imaging, and spatial metabolomics to hierarchically identify genes, pathways, and cells. Integrated data from these different technologies coherently identify cell types/subtypes within different nephron segments and the interstitium. These profiles describe cell-level functional organization of the kidney following its physiological functions and link cell subtypes to genes, proteins, metabolites, and pathways. They further show that messenger RNA levels along the nephron are congruent with the subsegmental physiological activity. This reference atlas provides a framework for the classification of kidney disease when multiple molecular mechanisms underlie convergent clinical phenotypes.

Dietary factors play an important role in promoting nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) development through regulation of metabolism and inflammation. However, so far there was no evidence regarding how dietary factors may influence different disease outcomes in the NAFLD to HCC progression. Our study aimed to comprehensively evaluate the role of dietary factors on the risk of progression from NAFLD to HCC.A comprehensive literature research was conducted in PubMed, Web of Science and Embase databases to identify case-control and cohort studies published up to March 15, 2022 in English. We included studies investigating associations of food and beverage items (excluding alcohol), food groups, dietary patterns, and dietary habits with incidence risk of four main chronic liver diseases involved in the NAFLD-to-HCC progression (i.e., NAFLD, liver fibrosis, liver cirrhosis, and HCC). Three researchers independently performed the literature search, selected eligible articles, performed data abstraction and evaluated study quality. After evaluating adequacy and credibility of the associations reported for each dietary factor and each liver disease outcome, we summarized and evaluated the consistency of associations based on a priori determined criteria considering study design and the proportion of significant associations.There were 109 studies included in this review (47 on NAFLD, 1 on liver fibrosis, 6 on liver cirrhosis, and 55 on HCC). Consistent evidence suggested that higher dietary inflammatory potential was associated with increased risk of both NAFLD and HCC whereas Mediterranean diet was associated with lower risk of both diseases. Additionally, greater conformity to the Healthy Eating Index, Dietary Approaches to Stop Hypertension score, and Mediterranean Diet Score, and dietary patterns with high dietary antioxidant capacity reduced NAFLD risk. Some specific foods including soft drinks and red and/or processed meat were associated with increased NAFLD risk while total vegetables and spinach were associated with reduced NAFLD risk. Coffee and white meat consumption were inversely related to HCC risk.Dietary patterns or individual foods representing a more anti-inflammatory potential were associated with reduced risk of both NAFLD and HCC, which implied diet-induced inflammation may impact NAFLD progression towards HCC.

BACKGROUND Sezary syndrome is a leukaemic variant of cutaneous T-cell lymphoma with poor prognosis. With the exception of stem cell transplantation, current treatments for SS are not curative. Rather, they aim at reducing disease burden and improving quality of life. Yet, pruritus - the major cause for impaired quality of life in these patients - is notoriously difficult to treat. Thus, supportive treatments addressing agonizing pruritus are urgently needed. OBJECTIVES To explore the clinical and immunological effects of type 2 cytokine blockade with dupilumab as supportive treatment in Sezary syndrome. METHODS A Sezary syndrome patient with stable disease but intractable pruritus was treated with dupilumab in combination with continued extracorporeal photopheresis. Close clinical and immunological monitoring on blood and skin samples from the patient was performed over 44 weeks. In vitro assays with patient's lymphoma cells were performed to address effects of dupilumab on Sezary cell's response to Th2 cytokines. RESULTS Clinically, dupilumab treatment induced rapid and sustained reduction in itch and improvement of skin and lymph node involvement. In both blood and skin, a reduction in Th2 bias was observed. Intriguingly, lymphocyte counts and Sezary cells in blood increased and later stabilized under dupilumab treatment. In vitro, dupilumab abrogated the anti-apoptotic and activating effects of Th2 cytokines on Sezary cells. CONCLUSIONS In this Sezary patient, inhibition of IL-4 and IL-13 signalling was associated with striking clinical benefit in terms of quality of life, pruritus and use of topical corticosteroids. While safety remains an important concern, our data support the future exploration of Th2 modulation for supportive care in Sezary Syndrome.

PURPOSE National epidemiologic data on melanoma are scarce in Brazil. The current work presents final demographic, clinical, and pathologic results from the Brazilian Melanoma Group database to detail how patients with melanoma present at diagnosis. METHODS The online database includes patients diagnosed between 1982 and 2015 and evaluated at their centers of origin between 2001 and 2016. The primary objective was to describe the demographic, clinical, and pathologic characteristics of the patients, and secondary objectives were to investigate the association between clinical and pathologic variables of interest. RESULTS A total of 1,596 patients were included. Median age was 52 years, 57% were women, and the majority were identified as white. Invasive melanoma was diagnosed in 1,297 patients, mostly localized, whereas 299 (19%) had in situ disease (TisN0M0). Only 165 patients had initial lymph node involvement. Fitzpatrick skin types I or II were slightly more frequent with in situ melanoma (73%) than with invasive disease (67%; P = .054). The median Breslow thickness was 0.95 mm, Clark levels 2 and 3 comprised nearly 70% of cases, and ulceration was present in 18% of patients. The mitotic rate was significantly associated with the presence of ulceration and both vascular and perineural invasion but not with margin positivity, whereas histologic regression was associated with both intratumoral and peritumoral inflammatory infiltrates. CONCLUSION Despite the limitations of an observational, registry-based study, the current results provide a general profile of patients with cutaneous melanoma in Brazil at the time of diagnosis.

Context Understanding factors involved in the rate of C-peptide decline is needed to tailor therapies for type 1 diabetes (T1D). Objective Evaluate factors associated with rate of C-peptide decline after a T1D diagnosis in young children. Design Observational study. Setting Academic centers. Participants A total of 57 participants from the Environmental Determinants of Diabetes in the Young (TEDDY) study who were enrolled at 3 months of age and followed until T1D, and 56 age-matched children diagnosed with T1D in the community. Intervention A mixed meal tolerance test was used to measure the area under the curve (AUC) C-peptide at 1, 3, 6, 12, and 24 months postdiagnosis. Outcome Factors associated with rate of C-peptide decline during the first 2 years postdiagnosis were evaluated using mixed effects models, adjusting for age at diagnosis and baseline C-peptide. Results Adjusted slopes of AUC C-peptide decline did not differ between TEDDY subjects and community controls (P = 0.21), although the former had higher C-peptide baseline levels. In univariate analyses combining both groups (n = 113), younger age, higher weight and body mass index z-scores, female sex, an increased number increased number of islet autoantibodies, and IA-2A or ZnT8A positivity at baseline were associated with a higher rate of C-peptide loss. Younger age, female sex, and higher weight z-score remained significant in multivariate analysis (all P < 0.02). At 3 months after diagnosis, higher HbA1c became an additional independent factor associated with a higher rate of C-peptide decline (P < 0.01). Conclusion Younger age at diagnosis, female sex, higher weight z-score, and HbA1c were associated with a higher rate of C-peptide decline after T1D diagnosis in young children.

Advances in molecular methods and the ability to share large population-based datasets are uncovering heterogeneity within diabetes types, and some commonalities between types. Within type 1 diabetes, endotypes have been discovered based on demographic (e.g. age at diagnosis, race/ethnicity), genetic, immunological, histopathological, metabolic and/or clinical course characteristics, with implications for disease prediction, prevention, diagnosis and treatment. In type 2 diabetes, the relative contributions of insulin resistance and beta cell dysfunction are heterogeneous and relate to demographics, genetics and clinical characteristics, with substantial interaction from environmental exposures. Investigators have proposed approaches that vary from simple to complex in combining these data to identify type 2 diabetes clusters relevant to prognosis and treatment. Advances in pharmacogenetics and pharmacodynamics are also improving treatment. Monogenic diabetes is a prime example of how understanding heterogeneity within diabetes types can lead to precision medicine, since phenotype and treatment are affected by which gene is mutated. Heterogeneity also blurs the classic distinctions between diabetes types, and has led to the definition of additional categories, such as latent autoimmune diabetes in adults, type 1.5 diabetes and ketosis-prone diabetes. Furthermore, monogenic diabetes shares many features with type 1 and type 2 diabetes, which make diagnosis difficult. These challenges to the current classification framework in adult and paediatric diabetes require new approaches. The ‘palette model’ and the ‘threshold hypothesis’ can be combined to help explain the heterogeneity within and between diabetes types. Leveraging such approaches for therapeutic benefit will be an important next step for precision medicine in diabetes. Since the first remedies for ‘honey urine’ were described over 25 centuries ago, untangling the pathways that lead to what we call today diabetes has enabled better treatments. The current classification of diabetes recognises the major forms of type 1 diabetes, type 2 diabetes, gestational diabetes and other less common types, such as monogenic diabetes (including neonatal diabetes and MODY), diseases of the exocrine pancreas (e.g. cystic fibrosis-related diabetes and pancreatogenic [or type 3c] diabetes) or drug-induced diabetes (Table 1) [1]. Advances in molecular biology and genetic methods during the past decades have facilitated the discovery of a myriad of genetic associations that suggest diverse pathophysiology within each of those types, as well as some commonalities between types. The recent acceleration in the ability to share large population-based datasets has further increased the evidence for heterogeneity within and between diabetes types [2]. Integrating our understanding of genetics, immunology and metabolic abnormalities in each type of diabetes will boost the ability to use precision medicine to tailor treatments and improve health outcomes.

Introduction The Autoimmunity Screening for Kids (ASK) study is a large scale pediatric screening study in Colorado for celiac disease (CD) and type 1 diabetes. This is a report of the CD outcomes for the first 9,973 children screened through ASK. Methods ASK screens children aged 1-17 years for CD using 2 highly sensitive assays for tissue transglutaminase autoantibodies (TGA): a radiobinding (RBA) assay for IgA TGA and an electrochemiluminescence (ECL) assay that detects all TGA isotypes. Children who test positive on either assay are asked to return for confirmatory testing. Those with a confirmed RBA TGA level ≥ 0.1 (twice the upper limit of normal) are referred to the Colorado Center for Celiac Disease for further evaluation; all others are referred to primary care. Results Of the initial 9,973 children screened, 242 children were TGA+ by any assay. Of those initially positive, 185 children (76.4%) have completed a confirmation blood draw with 149 children (80.5%) confirming positive by RBA TGA. Confirmed RBA TGA+ was associated with a family history of CD (odds ratio [OR] = 1.83; 95% confidence interval 1.06-3.16), non-Hispanic white ethnicity (OR = 3.34; 2.32-4.79), and female sex (OR = 1.43; 1.03-1.98). Gastrointestinal symptoms of CD, assessed at the initial screening, were reported equally often among the RBA TGA+ vs TGA- children (32.1% vs 30.5%, P = 0.65). Discussion The initial results of this ongoing mass-screening program confirm a high prevalence of undiagnosed CD autoimmunity in a screened US population. Symptoms at initial screening were not associated with TGA status (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/AJG/B587).

The purpose of this study was to evaluate the impact of implementing community-based prostate health education programs in rural communities. Prostate cancer (PrCA) remains one of the most common cancers among men, and a growing body of literature demonstrates that large interracial differences in PrCA incidence and mortality rates consistently disfavor African Americans in comparison to European Americans. It also is evident despite the overall decrease in cancer death rates in the United States in recent decades, rural areas are experiencing a reduction in death rates much more slowly. In this study, education session content focused on PrCA risk factors, symptoms, screening, healthy diet and exercise, treatment options, and provider communication strategies. Forty individuals participated and completed pre/post-education program surveys to assess changes in PrCA knowledge and cancer decision making. Participants showed improvements in education and awareness following the session and overall impressions of the program were consistently positive as exhibited by participants’ answers on a satisfaction survey. The findings demonstrate the real need both in terms of research to understand the underlying problem and to provide practical solutions that can be implemented to reverse the current situation. The results obtained support community-based education programs as an effective means of delivering PrCA prevention, screening, and treatment information to rural communities.

Background Hematology-oncology patients often require blood and blood product transfusions, including platelets (PLTs), to maintain stability. Administering PLTs in a shorter timeframe may prove beneficial by possibly raising platelet counts to a higher level faster, and allowing patients to be disconnected from IV pumps sooner. Objective To evaluate the optimal (safe and effective) transfusion time by comparing standard administration of PLTs over 2–4 h to the investigational administration of PLTs over 30–45 min in the pediatric hematology-oncology inpatient population. Methodology A pilot trial was conducted using a convenience sample of hematology-oncology children. Children prescribed a PLT transfusion while admitted to an inpatient unit were eligible. If randomized to the intervention group, the nurse administered the PLTs over 30–45 min. If randomized to the standard group, the nurse administered the PLTs over 2–4 h. Post transfusion PLTcount was drawn 30 min after completion. The child was monitored closely for adverse reactions. Results Eleven participants were enrolled in the study and 20 PLT infusions administered. No adverse events were noted. There was not a significant difference in changes in PLT counts by group (post minus pre), p = 0.082. There was not a significant difference in post infusion PLT counts, p = 0.727. There was a significant difference in the rate of change in PLT counts by groups, p = 0.003. Nursing implications This pilot study provides preliminary evidence that PLTs may be safely and effectively administered over 30–45 min in pediatric hematology-oncology patients. With quicker PLT administration, patients can be disconnected from IV pumps sooner.

The antiplatelet landscape for the secondary prevention of ischemic stroke has changed significantly over the past decade. Poststroke dual antiplatelet regimens are becoming increasingly routine as supported by recent literature and guideline recommendations. Dual antiplatelet therapy after stroke generally consists of aspirin and clopidogrel and is considered in the short term after stroke in select populations including those with mild stroke or transient ischemic attack and in patients with severe intracranial atherosclerosis. When initiating dual antiplatelet therapy, factors that may increase a patient's risk of bleeding must be weighed against the patient's risk of future ischemic events. This review focuses on antiplatelet medications available in the United States with the aim to provide a summary of the available literature on poststroke dual antiplatelet therapy, pharmacological nuances of the agents, and reversal of antiplatelets in the setting of intracerebral hemorrhage.

OBJECTIVE To assess the costs and project the potential lifetime cost-effectiveness of the ongoing Autoimmunity Screening for Kids (ASK) program, a large-scale, presymptomatic type 1 diabetes screening program for children and adolescents in the metropolitan Denver region. RESEARCH DESIGN AND METHODS We report the resource utilization, costs, and effectiveness measures from the ongoing ASK program compared with usual care (i.e., no screening). Additionally, we report a practical screening scenario by including utilization and costs relevant to routine screening in clinical practice. Finally, we project the potential cost-effectiveness of ASK and routine screening by identifying clinical benchmarks (i.e., diabetic ketoacidosis [DKA] events avoided, HbA1c improvements vs. no screening) needed to meet value thresholds of $50,000–$150,000 per quality-adjusted life-year (QALY) gained over a lifetime horizon. RESULTS Cost per case detected was $4,700 for ASK screening and $14,000 for routine screening. To achieve value thresholds of $50,000–$150,000 per QALY gained, screening costs would need to be offset by cost savings through 20% reductions in DKA events at diagnosis in addition to 0.1% (1.1 mmol/mol) improvements in HbA1c over a lifetime compared with no screening for patients who develop type 1 diabetes. Value thresholds were not met from avoiding DKA events alone in either scenario. CONCLUSIONS Presymptomatic type 1 diabetes screening may be cost-effective in areas with a high prevalence of DKA and an infrastructure facilitating screening and monitoring if the benefits of avoiding DKA events and improved HbA1c persist over long-run time horizons. As more data are collected from ASK, the model will be updated with direct evidence on screening effects.

Most screening programs to identify individuals at risk for type 1 diabetes have targeted relatives of people living with the disease to improve yield and feasibility. However, ~90% of those who develop type 1 diabetes do not have a family history. Recent successes in disease modifying therapies to impact the course of early-stage disease have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk. Existing population screening programs rely on genetic or autoantibody (AA) screening, and these have yielded significant information about disease progression and approaches for timing for screening in clinical practice. At the March 2021 Type 1 Diabetes TrialNet Steering Committee meeting, a session was held in which ongoing efforts for screening in the general population were discussed. This report reviews the background of these efforts and the details of those programs. Additionally, we present hurdles that need to be addressed for successful implementation of population screening and provide initial recommendations for individuals with positive screens so that standardized guidelines for monitoring and follow-up can be established.

Plant-based and animal-based protein intake have differential effects on various aging-related health outcomes, but less is known about the health effect of isocaloric substitution of plant-based and animal-based protein. This systematic review summarized current evidence of the isocaloric substitutional effect of plant-based and animal-based protein on aging-related health outcomes. PubMed and Embase databases were searched for epidemiologic observational studies published in English up to 15 March 2021. Studies that included adults ≥18 years old; use of a nutritional substitution model to define isocaloric substitution of plant protein and animal protein; health outcomes covering mortality, aging-related diseases or indices; and reported association estimates with corresponding 95% confidence intervals were included. Nine cohort studies and 3 cross-sectional studies were identified, with a total of 1,450,178 subjects included in this review. Consistent and significant inverse association of substituting plant protein for various animal proteins on all-cause mortality was observed among 4 out of 5 studies with relative risks (RRs) from 0.54 to 0.95 and on cardiovascular disease (CVD) mortality among all 4 studies with RRs from 0.58 to 0.91. Among specific animal proteins, the strongest inverse association on all-cause and CVD mortality was identified when substituting plant protein for red and/or processed meat protein, with the effect mainly limited to bread, cereal, and pasta protein when replacing red meat protein. Isocaloric substitution of plant-based protein for animal-based protein might prevent all-cause and CVD-specific mortality. More studies are needed on this topic, particularly for cancer incidence and other specific aging-related diseases.

Background and aims Recent reports indicate that African Americans have higher mortality rates from SARS-CoV-2 coronavirus disease 19 (COVID-19) compared to Caucasians, with more marked differences in the Midwest region of the US. This study was performed to study differences in COVID-19 related mortality and hospital length of stay (LOS) between African Americans and Caucasians in Midwest setting, and identify factors associated with mortality and LOS. Methods Data were collected from the electronic health records (EHR) of patients admitted to hospitals in Midwest region of the US. EHR of 471 COVID-19 patients were reviewed. Results Approximately 63% were African Americans and 34% Caucasians. One hundred sixteen variables were tested. There was no significant difference in hospital mortality between African Americans and Caucasians (OR 1, 95% CI 0.48–1.94). Older age, Chronic kidney disease, mental status change, mechanical ventilation, vasopressor support, high neutrophil count, elevated AST and ALT, high lung involvement severity score and elevated CRP were associated with mortality in a univariate analysis (P

OBJECTIVE The Environmental Determinants of Diabetes in the Young (TEDDY) study is uniquely capable of investigating age-specific differences associated with type 1 diabetes. Because age is a primary driver of heterogeneity in type 1 diabetes, we sought to characterize by age metabolic derangements prior to diagnosis and clinical features associated with diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS The 379 TEDDY children who developed type 1 diabetes were grouped by age at onset (0–4, 5–9, and 10–14 years; n = 142, 151, and 86, respectively) with comparisons of autoantibody profiles, HLAs, family history of diabetes, presence of DKA, symptomatology at onset, and adherence to TEDDY protocol. Time-varying analysis compared those with oral glucose tolerance test data with TEDDY children who did not progress to diabetes. RESULTS Increasing fasting glucose (hazard ratio [HR] 1.09 [95% CI 1.04–1.14]; P = 0.0003), stimulated glucose (HR 1.50 [1.42–1.59]; P < 0.0001), fasting insulin (HR 0.89 [0.83–0.95]; P = 0.0009), and glucose-to-insulin ratio (HR 1.29 [1.16–1.43]; P < 0.0001) were associated with risk of progression to type 1 diabetes. Younger children had fewer autoantibodies with more symptoms at diagnosis. Twenty-three children (6.1%) had DKA at onset, only 1 (0.97%) of 103 with and 22 (8.0%) of 276 children without a first-degree relative (FDR) with type 1 diabetes (P = 0.008). Children with DKA were more likely to be nonadherent to study protocol (P = 0.047), with longer duration between their last TEDDY evaluation and diagnosis (median 10.2 vs. 2.0 months without DKA; P < 0.001). CONCLUSIONS DKA at onset in TEDDY is uncommon, especially for FDRs. For those without familial risk, metabolic monitoring continues to provide a primary benefit of reduced DKA but requires regular follow-up. Clinical and laboratory features vary by age at onset, adding to the heterogeneity of type 1 diabetes.

Background Becoming unemployed is associated with poorer health, including weight gain. Middle- and older-age adults are a growing segment of workforces globally, but they are also more vulnerable to changes to employment status, especially during economic shocks. Expected workforce exits over the next decade may exacerbate both the obesity epidemic and the economic burden of obesity. This review extends current knowledge on economic correlates of health to assess whether employment transitions impact body weight by sex/gender among middle-aged and older adults. Methods Eight bibliometric databases were searched between June and July 2021, supplemented by hand-searches, with no restriction on publication date or country. Longitudinal studies, or reviews, were eligible when examining body weight as a function of employment status change in adults ≥50 years. Data extraction and quality appraisal used predefined criteria; reported findings were analysed by narrative synthesis. Results We screened 6,001 unique abstracts and identified 12 articles that met inclusion criteria. All studies examined retirement; of which two also examined job-loss. Overall, studies showed that retirement led to weight gain or no difference in weight change compared to non-retirees; however, reported effects were not consistent for either women or men across studies or for both women and men within a study. Reported effects also differed by occupation: weight gain was more commonly observed among retirees from physical occupations but not among retirees from sedentary occupations. Few studies assessed the role of health behaviours; sleep was the least studied. Most studies were medium quality. Conclusions Existing studies do not provide a clear enough picture of how employment transitions affect body weight. Firm conclusions on the impact of employment transitions on weight cannot be made without further high-quality evidence that considers the role of gender, job-type, other health behaviours, and other transitions, like job-loss.

An understanding of the ethical underpinnings of human subjects research that involves some risk to participants without anticipated direct clinical benefit-such as the kidney biopsy procedure as part of the Kidney Precision Medicine Project (KPMP)-requires a critical examination of the risks as well as the diverse set of countervailing potential benefits to participants. This kind of deliberation has been foundational to the development and conduct of the KPMP. Herein, we use illustrative features of this research paradigm to develop a more comprehensive conceptualization of the types of benefits that may be important to research participants, including respecting pluralistic values, supporting the opportunity to act altruistically, and enhancing benefits to a participant's community. This approach may serve as a model to help researchers, ethicists, and regulators to identify opportunities to better respect and support participants in future research that entails some risk to these participants as well as to improve the quality of research for people with kidney disease.

Background: The use of ultrasound-guided ablation procedures to treat both benign and malignant thyroid conditions is gaining increasing interest. This document has been developed as an international interdisciplinary evidence-based statement with a primary focus on radiofrequency ablation and is intended to serve as a manual for best practice application of ablation technologies. Methods: A comprehensive literature review was conducted to guide statement development and generation of best practice recommendations. Modified Delphi method was applied to assess whether statements met consensus among the entire author panel. Results: A review of the current state of ultrasound-guided ablation procedures for the treatment of benign and malignant thyroid conditions is presented. Eighteen best practice recommendations in topic areas of preprocedural evaluation, technique, postprocedural management, efficacy, potential complications, and implementation are provided. Conclusions: As ultrasound-guided ablation procedures are increasingly utilized in benign and malignant thyroid disease, evidence-based and thoughtful application of best practices is warranted.

PURPOSE: We examined the associations between intake of meat and fish by preparation methods and breast cancer in the Carolina Breast Cancer Study, a racially diverse population-based case-control study. METHODS: African American (AA) and European American (EA) women aged 20–74 years with a first diagnosis of invasive or in situ breast cancers were frequency matched by race and age group to controls identified through the North Carolina Division of Motor Vehicles and Medicare lists [AA: 548 cases, 452 controls; EA: 858 cases, 748 controls]. Participants self-reported meat preparation methods and intake frequencies. Adjusted odds ratios (OR) and 95% CIs (CI) were calculated using multivariable logistic regression adjusted for age, race, alcohol intake, body mass index, family income, lactation, marital status, use of oral contraceptives, postmenopausal hormone use, smoking status, and offsets. RESULTS: Positive associations with breast cancer were observed for intakes of grilled/barbecued hamburger (≥ once/week, OR: 1.28; 95% CI: 1.01, 1.63), and pan-fried/oven-broiled beef steak (≥ once/week, OR: 1.36; 95% CI: 1.08, 1.72). Inverse associations were observed for pan-fried fish (≥ once/week, OR: 0.77; 95% CI: 0.60, 0.98), and for grilled/barbecued pork chops (>0 time/week OR: 0.81, 95% CI: 0.68, 0.97). Associations tended to be stronger among EA women than among AA women. CONCLUSION: More frequent consumption of beef prepared with high temperature methods was associated with higher odds of breast cancer while more frequent consumption of pan-fried fish or grilled/barbecued pork chops was associated with lower odds of breast cancer.