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Background As diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States. Methods Six health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2. Results Across datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred 30%) in some datasets—limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis. Conclusion Our results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources–a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

Aims/hypothesisDiabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets.MethodsWe performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets.ResultsThe meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR9.3×10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p

Abstract Effective treatment may prevent kidney complications, but women might be underprescribed. Novel, data-driven insights into prescriptions and their relationship with kidney health in women with type 1 diabetes may help to optimize treatment. We identified six medication profiles in 1164 women from the FinnDiane Study with normal albumin excretion rate based on clusters of their baseline prescription data using a self-organizing map. Future rapid kidney function decline was defined as an annual estimated glomerular filtration rate (eGFR) loss > 3 ml/min/1.73 m2 after baseline. Two profiles were associated with future decline: Profile ARB with the highest proportion of angiotensin receptor blockers (odds ratio [OR] 2.75, P = 0.02) and highly medicated women in profile HighMed (OR 2.55, P = 0.03). Compared with profile LowMed (low purchases of all), profile HighMed had worse clinical characteristics, whereas in profile ARB only systolic blood pressure was elevated. Importantly, the younger women in profile ARB with fewer kidney protective treatments developed a rapid decline despite otherwise similar baseline characteristics to profile ACE & Lipids (the highest proportions of ACE inhibitors and lipid-modifying agents) without a future rapid decline. In conclusion, medication profiles identified different future eGFR trajectories in women with type 1 diabetes revealing potential treatment gaps for younger women.

Abstract Background Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits. Methods We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy. Results The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10−8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10−4), apolipoprotein B (p=5.6×10−4), and LDL cholesterol (p=9.5×10−4) concentrations. Conclusions We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

Summary: Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12, and CRYAB) to construct a transcriptional “stress score” that reflected long-term decline of kidney function and could even identify normoalbuminuric individuals showing early decline. We thus provide workflow and web resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.

Introduction and objectives: Cardiac amyloidosis (CA) is not a rare cause of heart failure (HF). In Spain, more than 60% of HF patients admitted to hospitals are treated in Internal Medicine Services. REGAMIC is a registry designed by the HF Working Group of the Spanish Society of Internal Medicine to improve the suspicion criteria and the selection of patients in whom CA must be ruled out. The main objective is to evaluate the differential characteristics between two groups of HF patients with suspicion of CA: confirmed vs ruled out cases. The secondary objectives are to evaluate the data on which investigators have based the suspicion of CA, and to identify prognostic differences between both groups. Methods: A multicenter, observational, prospective, cohort study of at least 600 patients, with a 2-year follow-up. Inclusion criteria: patients of Internal Medicine Services, aged ≥ 18 years, with HF and left ventricular hypertrophy (septum or posterior wall ≥ 12 mm), with suspicion of CA. Clinical, electrocardiographic, echocardiographic, and follow-up data will be compared between both groups of patients. Results and discussion: If the recommendations of the 2021 European Society of Cardiology Consensus on CA are followed, a large number of patients should be studied to rule out CA. REGAMIC can improve the selection of patients in whom CA will be ruled out and make the study more cost-effective. Conclusions: Our registry aims to improve the knowledge about differential characteristics between HF patients with clinical suspicion of CA and may increase knowledge of the natural history of the disease.

Abstract Prospective biomarker studies can be used to identify biomarkers predictive of disease onset. However, if serum biomarkers are measured years after their collection, the storage conditions might affect analyte concentrations. Few data exists concerning which metabolites and proteins are affected by storage at − 20 °C vs − 80 °C. Our objectives were to document analytes affected by storage of serum samples at − 20 °C vs − 80 °C, and to identify those indicative of the storage temperature. We utilized liquid chromatography tandem mass spectrometry and Luminex to quantify 300 analytes from serum samples of 16 Finnish individuals with type 1 diabetes, with split-aliquot samples stored at − 80 °C and − 20 °C for a median of 4.2 years. Results were validated in 315 Finnish and 916 Scottish individuals with type 1 diabetes, stored at − 20 °C and at − 80 °C, respectively. After quality control, we analysed 193 metabolites and proteins of which 120 were apparently unaffected and 15 clearly susceptible to storage at − 20 °C vs − 80 °C. Further, we identified serum glutamate/glutamine ratio greater than 0.20 as a biomarker of storage at − 20 °C vs − 80 °C. The results provide a catalogue of analytes unaffected and affected by storage at − 20 °C vs − 80 °C and biomarkers indicative of sub-optimal storage.

BackgroundAs diagnostic tests for COVID-19 were broadly deployed under Emergency Use Authorization, there emerged a need to understand the real-world utilization and performance of serological testing across the United States.MethodsSix health systems contributed electronic health records and/or claims data, jointly developed a master protocol, and used it to execute the analysis in parallel. We used descriptive statistics to examine demographic, clinical, and geographic characteristics of serology testing among patients with RNA positive for SARS-CoV-2.ResultsAcross datasets, we observed 930,669 individuals with positive RNA for SARS-CoV-2. Of these, 35,806 (4%) were serotested within 90 days; 15% of which occurred 30%) in some datasets-limiting our ability to examine differences in serological testing by race. In datasets where race/ethnicity information was available, we observed a greater distribution of White individuals among those serotested; however, the time between RNA and serology tests appeared shorter in Black compared to White individuals. Test manufacturer data was available in half of the datasets contributing to the analysis.ConclusionOur results inform the underlying context of serotesting during the first year of the COVID-19 pandemic and differences observed between claims and EHR data sources-a critical first step to understanding the real-world accuracy of serological tests. Incomplete reporting of race/ethnicity data and a limited ability to link test manufacturer data, lab results, and clinical data challenge the ability to assess the real-world performance of SARS-CoV-2 tests in different contexts and the overall U.S. response to current and future disease pandemics.

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.

Abstract Background Skeletal dysplasia is typically diagnosed using a combination of radiographic imaging, clinical examinations, and molecular testing. Identifying a molecular diagnosis for an individual with a skeletal dysplasia can lead to improved clinical care, guide future medical management and treatment, and inform assessment of risk for familial recurrence. The molecular diagnostic utility of multi-gene panel testing using next-generation sequencing (NGS) has not yet been characterized for an unselected population of individuals with suspected skeletal dysplasia. In this study, we retrospectively reviewed patient reports to assess the diagnostic yield, reported variant characteristics, impact of copy number variation, and performance in prenatal diagnostics of panel tests for variants in genes associated with skeletal dysplasia and growth disorders. Results Clinical reports of consecutive patients with a clinical indication of suspected skeletal dysplasia who underwent panel testing were examined. The 543 patients included in the study submitted samples for diagnostic genetic testing with an indication of suspected skeletal dysplasia or growth disorder and received one of three nested panel tests. A molecular diagnosis was established in 42.0% of patients (n = 228/543). Diagnostic variants were identified in 71 genes, nearly half of which (n = 35, 49.3%) contributed uniquely to a molecular diagnosis for a single patient in this cohort. Diagnostic yield was significantly higher among fetal samples (58.0%, n = 51/88) than postnatal samples (38.9%, n = 177/455; z = 3.32, p

IntroductionA reliable pediatric triage tool is essential for nurses working in pediatric emergency departments to quickly identify children requiring priority care (high-level emergencies) and those who can wait (low-level emergencies). In the absence of a gold standard in France, the objective of our study was to validate our 5-level pediatric triage tool –pediaTRI– against the reference tool: the Pediatric Early Warning Score (PEWS) System.Materials and MethodsWe prospectively included 100,506 children who visited the Pediatric Emergency Department at Lenval Children's Hospital (Nice, France) in 2016 and 2017. The performance of pediaTRI to identify high-level emergencies (severity levels 1 and 2) was evaluated in comparison with a PEWS ≥ 4/9. Data from 2018–19 was used as an independent validation cohort.ResultspediaTRI agreed with the PEWS score for 84,896 of the patients (84.5%): 15.0% (14.8–15.2) of the patients were over-triaged and 0.5% (0.5–0.6) under-triaged compared with the PEWS score. pediaTRI had a sensitivity of 76.4% (74.6–78.2), a specificity of 84.7% (84.4–84.9), and positive and negative likelihood ratios of 5.0 (4.8–5.1) and 0.3 (0.3–0.3), respectively, for the identification of high-level emergencies. However, the positive likelihood ratios were lower for patients presenting with a medical complaint [4.1 (4.0–4.2) v 10.4 (7.9–13.7 for trauma), and for younger children [1.2 (1.1–1.2) from 0 to 28 days, and 1.9 (1.8–2.0) from 28 days to 3 months].ConclusionpediaTRI has a moderate to good validity to triage children in a Pediatric Emergency Department with a tendency to over-triage compared with the PEWS system. Its validity is lower for younger children and for children consulting for a medical complaint.

Background Lung cancer invading outside a lobe centrally or peripherally, or presenting with synchronous or metachronous tumors, requires a special approach. Here, we aimed to evaluate the rate and outcomes of surgery of these patients in a medium‐volume practice using real‐world, population‐based data. Methods All patients (n = 269) on whom lung cancer surgery was performed in Central Finland and Ostrobothnia between January 2013 and December 2019 were included. A total of 40 patients with sleeve (n = 18) or other extended resections (n = 9), multifocal diseases (n = 14), and other operated synchronous cancers (n = 3) required an extended or otherwise special surgical approach (extended group). Short‐ and long‐term outcomes were compared to high‐risk (n = 72) and normal patient groups (n = 157). Results The rate of extended resection was 14.9%. The rates of PET‐CT (95%), invasive staging (35%), and brain imaging (42.5%) were highest in extended group compared to other groups. Extended group had larger and higher rate of stage III tumors than high‐risk and normal groups. All extended group patients underwent anatomic lung resection with better lymph node yield than the other two groups, with a neoadjuvant and/or adjuvant treatment rate of 70.0%. Major complications occurred in 7.5% in the extended group, 19.4% in the high‐risk group, and 6.4% in the normal group; at one year, alive and living at home rates were 88.2%, 83.3%, and 97.8%, and overall five‐year survival rates 75.6%, 62.4%, and 63.9% (P = 0.287), respectively. Conclusions After guideline‐based evaluation, a significant rate of these special cases can be resected with a low complication rate and good long‐term survival in real‐world practice. Key points Significant findings of the study Extended resections for lung cancer include tumors spreading outside the lung The rate of extended resection was 14.9% in a population‐based setting Major complications occurred in 7.5% and five‐year survival was 75.6% What this study adds Complication rate and long‐term outcome were similar compared to normal patients Guideline‐based evaluation results with excellent outcome in real‐world practice

Introduction With a population-based cohort in the video-assisted thoracoscopic surgery (VATS) era, we aimed to evaluate the value of the stair-climbing test (SCT) on short- and long-term outcomes of lung cancer surgery. Methods All patients operated due to primary lung cancer in Central Finland and Ostrobothnia from 2013 to June 2020 were included. For the analysis, clinical variables including the outcome of SCT and cause-specific mortality were available. Short- and long-term outcomes were compared between 12 m SCT (n=217) groups. Results Patients with poor performance (12 m group (94.2%), p=0.002. No difference was observed in cancer-specific 5-year survival. Non-cancer-specific survival (62.9% versus 83.1%, p12 m group. Poor exercise performance increases non-cancer-specific mortality. Being a major predictor of survival, exercise capacity should be included in prognostic models.

Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR. Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n = 49) and MMR-proficient (MMR-P, n = 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing. Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (IGF2, NEUROG1, CRABP1, and CDKN2A) and TSGs (SFRP1 and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas. Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. Fund: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid Juselius Foundation, and HiLIFE. Keywords: Lynch syndrome, Colorectal adenoma, DNA methylation, DNA mismatch repair, LINE-1 methylation, Mutation, Tumorigenesis, Tumor suppressor