198 research outputs found
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First Post-Operative Urinary Kidney Injury Biomarkers and Association with the Duration of AKI in the TRIBE-AKI Cohort
Background: We previously demonstrated that assessment of the duration of AKI, in addition to magnitude of rise in creatinine alone, adds prognostic information for long-term survival. We evaluated whether post-operative kidney injury biomarkers in urine collected immediately after cardiac surgery associate with duration of serum creatinine elevation. Methods: We studied 1199 adults undergoing cardiac surgery in a prospective cohort study (TRIBE-AKI) and examined the association between the levels of five urinary biomarkers individually at 0–6 hours after surgery: interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L-FABP) and albumin with duration of serum creatinine-based AKIN criteria for AKI (0 (no AKI), 1–2, 3–6, ≥7 days). Results: Overall, 407 (34%) patients had at least stage 1 AKI, of whom 251 (61.7%) had duration of 1–2 days, 118 (28.9%) had duration 3–6 days, and 38 (9.3%) had duration of ≥7 days. Higher concentrations of all biomarkers (per log increase) were independently associated with a greater odds of a longer duration of AKI; odds ratios and 95% confidence intervals using ordinal logistic regression were the following: IL-18: 1.22, 1.13–1.32; KIM-1: 1.36, 1.21–1.52; albumin 1.20, 1.09–1.32; L-FABP 1.11, 1.04–1.19; NGAL 1.06, 1.00–1.14). AKI duration of 7 days or longer was associated with a 5-fold adjusted risk of mortality at 3 years. Conclusions: There was an independent dose-response association between urinary levels of injury biomarkers immediately after cardiac surgery and longer duration of AKI. Duration of AKI was also associated with long term mortality. Future studies should explore the potential utility of these urinary kidney injury biomarkers to enrich enrollment of patients at risk for longer duration of AKI into trials of interventions to prevent or treat post-operative AKI.</p
Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer risk
BACKGROUND: Although per- and polyfluoroalkyl substances (PFAS) exposure is a potential contributor to the increasing thyroid cancer trend, limited studies have investigated the association between PFAS exposure and thyroid cancer in human populations. We therefore investigated associations between plasma PFAS levels and thyroid cancer diagnosis using a nested case-control study of patients with thyroid cancer with plasma samples collected at/before cancer diagnosis. METHODS: 88 patients with thyroid cancer using diagnosis codes and 88 healthy (non-cancer) controls pair-matched on sex, age (±5 years), race/ethnicity, body mass index, smoking status, and year of sample collection were identified in the BioMe population (a medical record-linked biobank at the Icahn School of Medicine at Mount Sinai in New York); 74 patients had papillary thyroid cancer. Eight plasma PFAS were measured using untargeted analysis with liquid chromatography-high resolution mass spectrometry and suspect screening. Associations between individual PFAS levels and thyroid cancer were evaluated using unconditional logistic regression models to estimate adjusted odds ratios (OR adj) and 95% confidence intervals (CI). FINDINGS: There was a 56% increased rate of thyroid cancer diagnosis per doubling of linear perfluorooctanesulfonic acid (n-PFOS) intensity (OR adj, 1.56, 95% CI: 1.17-2.15, P = 0.004); results were similar when including patients with papillary thyroid cancer only (OR adj, 1.56, 95% CI: 1.13-2.21, P = 0.009). This positive association remained in subset analysis investigating exposure timing including 31 thyroid cancer cases diagnosed ≥1 year after plasma sample collection (OR adj, 2.67, 95% CI: 1.59-4.88, P < 0.001). INTERPRETATION: This study reports associations between exposure to PFAS and increased rate of (papillary) thyroid cancer. Thyroid cancer risk from PFAS exposure is a global concern given the prevalence of PFAS exposure. Individual PFAS studied here are a small proportion of the total number of PFAS supporting additional large-scale prospective studies investigating thyroid cancer risk associated with exposure to PFAS chemicals. FUNDING: National Institutes of Health grants and The Andrea and Charles Bronfman Philanthropies
Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week.
Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).Dr Farkouh has received research grants from Amgen, Novo Nordisk,
and Novartis. Dr Stone has received speaker honoraria from Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Miracor, Neovasc, Abiomed, Ancora,
Vectorious, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics,
Impulse Dynamics, Cardiomech, Gore, and Amgen; and has equity/
options from Ancora, Cagent, Applied Therapeutics, Biostar family of
funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix,
and Xenter. Dr Godoy is supported by the Frederick Banting and
Charles Best Canada Graduate Scholarship (Doctoral Research Award)
from the Canadian Institutes of Health Research. All other authors
have reported that they have no relationships relevant to the contents of this paper to disclose.S
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Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.
Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size
Albuminuria Testing in Hypertension and Diabetes:An Individual-Participant Data Meta-Analysis in a Global Consortium
Albuminuria is an under-recognized component of chronic kidney disease definition, staging, and prognosis. Guidelines, particularly for hypertension, conflict on recommendations for urine albumin-to-creatinine ratio (ACR) measurement. Separately among 1 344 594 adults with diabetes and 2 334 461 nondiabetic adults with hypertension from the chronic kidney disease Prognosis Consortium, we assessed ACR testing, estimated the prevalence and incidence of ACR ≥30 mg/g and developed risk models for ACR ≥30 mg/g. The ACR screening rate (cohort range) was 35.1% (12.3%-74.5%) in diabetes and 4.1% (1.3%-20.7%) in hypertension. Screening was largely unrelated to the predicted risk of prevalent albuminuria. The median prevalence of ACR ≥30 mg/g across cohorts was 32.1% in diabetes and 21.8% in hypertension. Higher systolic blood pressure was associated with a higher prevalence of albuminuria (odds ratio [95% CI] per 20 mm Hg in diabetes, 1.50 [1.42-1.60]; in hypertension, 1.36 [1.28-1.45]). The ratio of undetected (due to lack of screening) to detected ACR ≥30 mg/g was estimated at 1.8 in diabetes and 19.5 in hypertension. Among those with ACR/g, the median 5-year incidence of ACR ≥30 mg/g across cohorts was 23.9% in diabetes and 21.7% in hypertension. Incident albuminuria was associated with initiation of renin-angiotensin-aldosterone system inhibitors (incidence-rate ratio [95% CI], diabetes 3.09 [2.71-3.53]; hypertension 2.87 [2.29-3.59]). In conclusion, despite similar risk of albuminuria to those with diabetes, ACR screening in patients with hypertension was low. Our findings suggest that regular albuminuria screening should be emphasized to enable early detection of chronic kidney disease and initiation of treatment with cardiovascular and renal benefits
Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study
BackgroundChronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study.MethodsWe assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity.ResultsThe GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry.ConclusionOur genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations
Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19.
BACKGROUND
Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results.
OBJECTIVES
We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19.
METHODS
Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group.
RESULTS
Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent.
CONCLUSIONS
Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).Dr Stone has received speaker honoraria from Medtronic, Pulnovo,
Infraredx, Abiomed, and Abbott; has served as a consultant to
Daiichi-Sankyo, Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Ancora, Elucid Bio, Occlutech,
CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore,
Amgen, Adona Medical, and Millennia Biopharma; and has equity/
options from Ancora, Cagent, Applied Therapeutics, Biostar family of
funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix,
and Xenter; his daughter is an employee at IQVIA; and his employer,
Mount Sinai Hospital, receives research support from Abbott,
Abiomed, Bioventrix, Cardiovascular Systems Inc, Phillips, BiosenseWebster, Shockwave, Vascular Dynamics, Pulnovo, and V-wave. Dr
Farkouh has received institutional research grants from Amgen,
AstraZeneca, Novo Nordisk, and Novartis; has received consulting
fees from Otitopic; and has received honoraria from Novo Nordisk. Dr
Lala has received consulting fees from Merck and Bioventrix; has
received honoraria from Zoll Medical and Novartis; has served on an
advisory board for Sequana Medical; and is the Deputy Editor for the
Journal of Cardiac Failure. Dr Moreno has received honoraria from
Amgen, Cuquerela Medical, and Gafney; has received payment for
expert testimony from Koskoff, Koskoff & Dominus, Dallas W. Hartman, and Riscassi & Davis PC; and has stock options in Provisio. Dr
Goodman has received institutional research grants from Bristol
Myers Squibb/Pfizer Alliance, Bayer, and Boehringer Ingelheim; has
received consulting fees from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL
Behring, Ferring Pharmaceuticals, HLS Therapeutics, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, and Sanofi; has received
honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim,
Bristol Myers Squibb, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, and Servier; has served on Data
Safety and Monitoring boards for Daiichi-Sankyo/American Regent
and Novo Nordisk A/C; has served on advisory boards for Amgen,
AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL
Behring, Eli Lilly, Ferring Pharmaceuticals, HLS Therapeutics, JAMP
Pharma, Merck, Novartis, Pendopharm/Pharmascience, Pfizer,
Regeneron, Sanofi, Servier, and Tolmar Pharmaceuticals; has a leadership role in the Novartis Council for Heart Health (unpaid); and
otherwise has received salary support or honoraria from the Heart
and Stroke Foundation of Ontario/University of Toronto (Polo) Chair,
Canadian Heart Failure Society, Canadian Heart Research Centre and
MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating
Centre for Clinical Research, Duke Clinical Research Institute, New
York University Clinical Coordinating Centre, PERFUSE Research
Institute, and the TIMI Study Group (Brigham Health). Dr Ricalde has
received consulting fees from Medtronic, Servier, and Boston Scientific; has received honoraria from Medtronic, Pfizer, Merck, Boston
Scientific, Biosensors, and Bayer; has served on an advisory board for
Medtronic; and has leadership roles in SOLACI and Kardiologen. Dr
Payro has received consulting fees from Bayer Mexico; has received
honoraria from Bayer, Merck, AstraZeneca, Medtronic, and Viatris;
has received payments for expert testimony from Bayer; has received
travel support from AstraZeneca; has served on an advisory board for
Bayer; and his institution has received equipment donated from
AstraZeneca. Dr Castellano has received consulting fees and honoraria from Ferrer International, Servier, and Daiichi-Sankyo; and has
received travel support from Ferrer International. Dr Hung has served
as an advisory board member for Pfizer, Merck, AstraZeneca, Fosun,
and Gilead. Dr Nadkarni has received consulting fees from Renalytix,
Variant Bio, Qiming Capital, Menarini Health, Daiichi-Sankyo, BioVie,
and Cambridge Health; has received honoraria from Daiichi-Sankyo
and Menarini Health; has patents for automatic disease diagnoses
using longitudinal medical record data, methods, and apparatus for
diagnosis of progressive kidney function decline using a machine
learning model, electronic phenotyping technique for diagnosing
chronic kidney disease, deep learning to identify biventricular
structure and function, fusion models for identification of pulmonary
embolism, and SparTeN: a novel spatio-temporal deep learning
model; has served on a Data Safety and Monitoring Board for CRIC
OSMB; has leadership roles for Renalytix scientific advisory board,
Pensive Health scientific advisory board, and ASN Augmented Intelligence and Digital Health Committee; has ownership interests in
Renalytix, Data2Wisdom LLC, Verici Dx, Nexus I Connect, and Pensieve Health; and his institution receives royalties from Renalytix. Dr
Goday has received the Frederick Banting and Charles Best Canada
Graduate Scholarship (Doctoral Research Award) from the Canadian
Institutes of Health Research. Dr Furtado has received institutional
research grants from AstraZeneca, CytoDin, Pfizer, Servier, Amgen,
Alliar Diagnostics, and the Brazilian Ministry of Health; has received
consulting fees from Biomm and Bayer; has received honoraria from
AstraZeneca, Bayer, Servier, and Pfizer; and has received travel support from Servier, AstraZeneca, and Bayer. Dr Granada has received
consulting fees, travel support, and stock from Cogent Technologies
Corp; and has received stock from Kutai. Dr Contreras has served as a
consultant for Merck, CVRx, Novodisk, and Boehringer Ingelheim;
and has received educational grants from Alnylam Pharmaceuticals
and AstraZeneca. Dr Bhatt has received research funding from Abbott,
Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen,
AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific,
Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi,
Cincor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring
Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly,
Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo
Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The
Medicines Company, Youngene, and 89bio; has received royalties
from Elsevier; has received consultant fees from Broadview Ventures
and McKinsey; has received honoraria from the American College of
Cardiology, Baim Institute for Clinical Research, Belvoir Publications,
Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute,
Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population
Health Research Institute, Rutgers University, Canadian Medical and
Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P,
Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME,
Piper Sandler, Population Health Research Institute, Slack Publications, WebMD, Wiley, Society of Cardiovascular Patient Care; has
received fees from expert testimony from the Arnold and Porter law
firm; has received travel support from the American College of Cardiology, Society of Cardiovascular Patient Care, American Heart Association; has a patent for otagliflozin assigned to Brigham and
Women’s Hospital who assigned to Lexicon; has participated on a
data safety monitoring board or advisory board for Acesion Pharma,
Assistance Publique-Hôpitaux de Paris, AngioWave, Baim Institute,
Bayer, Boehringer Ingelheim, Boston Scientific, Cardax, CellProthera,
Cereno Scientific, Cleveland Clinic, Contego Medical, Duke Clinical
Research Institute, Elsevier Practice Update Cardiology, Janssen,
Level Ex, Mayo Clinic, Medscape Cardiology, Merck, Mount Sinai
School of Medicine, MyoKardia, NirvaMed, Novartis, Novo Nordisk,
PhaseBio, PLx Pharma, Regado Biosciences, Population Health
Research Institute, and Stasys; serves as a trustee or director for
American College of Cardiology, AngioWave, Boston VA Research
Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of
Cardiovascular Patient Care, and TobeSoft; has ownership interests in
AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; has
other interests in Clinical Cardiology, the NCDR-ACTION Registry
Steering Committee; has conducted unfunded research with FlowCo
and Takeda, Contego Medical, American Heart Association Quality
Oversight Committee, Inaugural Chair, VA CART Research and Publications Committee; and has been a site co-investigator for Abbott,
Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott),
Phillips SpectraWAVE, Svelte, and Vascular Solutions. Dr Fuster declares that he raised $7 million from patients for this study granted to
Mount Sinai Heart, unrelated to industry. All other authors have reported that they have no relationships relevant to the contents of this
paper to disclose.S
Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility
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