An approach to identify gene-environment interactions and reveal new biological insight in complex traits.

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci (6 independent signals) interacted with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrate that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated heritability is significant (P < 0.02) for low-density lipoprotein cholesterol and triglycerides in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.

MRBEE: A bias-corrected multivariable Mendelian randomization method.

Mendelian randomization (MR) is an instrumental variable approach used to infer causal relationships between exposures and outcomes, which is becoming increasingly popular because of its ability to handle summary statistics from genome-wide association studies. However, existing MR approaches often suffer the bias from weak instrumental variables, horizontal pleiotropy and sample overlap. We introduce MRBEE (MR using bias-corrected estimating equation), a multivariable MR method capable of simultaneously removing weak instrument and sample overlap bias and identifying horizontal pleiotropy. Our extensive simulations and real data analyses reveal that MRBEE provides nearly unbiased estimates of causal effects, well-controlled type I error rates and higher power than comparably robust methods and is computationally efficient. Our real data analyses result in consistent causal effect estimates and offer valuable guidance for conducting multivariable MR studies, elucidating the roles of pleiotropy, and identifying total 42 horizontal pleiotropic loci missed previously that are associated with myopia, schizophrenia, and coronary artery disease.

simmrd: An open-source tool to perform simulations in Mendelian randomization.

Mendelian randomization (MR) has become a popular tool for inferring causality of risk factors on disease. There are currently over 45 different methods available to perform MR, reflecting this extremely active research area. It would be desirable to have a standard simulation environment to objectively evaluate the existing and future methods. We present simmrd, an open-source software for performing simulations to evaluate the performance of MR methods in a range of scenarios encountered in practice. Researchers can directly modify the simmrd source code so that the research community may arrive at a widely accepted framework for researchers to evaluate the performance of different MR methods.

A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits.

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the CHARGE Gene-Lifestyle Interactions Working Group has been spearheading efforts to investigate G×E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identified and confirmed 5 loci (6 independent signals) interacting with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrated that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated contribution ranges from 1.76% to 14.05% of SNP heritability of serum lipids in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.

Feasibility of Simultaneous Quantification of Myocardial and Renal Perfusion With Cardiac Positron Emission Tomography.

BACKGROUND: Given the central importance of cardiorenal interactions, mechanistic tools for evaluating cardiorenal physiology are needed. In the heart and kidneys, shared pathways of neurohormonal activation, hypertension, and vascular and interstitial fibrosis implicate the relevance of systemic vascular health. The availability of a long axial field of view positron emission tomography (PET)/computed tomography (CT) system enables simultaneous evaluation of cardiac and renal blood flow. METHODS: This study evaluated the feasibility of quantification of renal blood flow using data acquired during routine, clinically indicated 13N-ammonia myocardial perfusion PET/CT. Dynamic PET image data were used to calculate renal blood flow. Reproducibility was assessed by the intraclass correlation coefficient among 3 independent readers. PET-derived renal blood flow was correlated with imaging and clinical parameters in the overall cohort and with histopathology in a small companion study of patients with a native kidney biopsy. RESULTS: Among 386 consecutive patients with myocardial perfusion PET/CT, 296 (76.7%) had evaluable images to quantify renal perfusion. PET quantification of renal blood flow was highly reproducible (intraclass correlation coefficient 0.98 [95% CI, 0.93-0.99]) and was correlated with the estimated glomerular filtration rate (r=0.64; P<0.001). Compared across vascular beds, resting renal blood flow was correlated with maximal stress myocardial blood flow and myocardial flow reserve (stress/rest myocardial blood flow), an integrated marker of endothelial health. In patients with kidney biopsy (n=12), resting PET renal blood flow was strongly negatively correlated with histological interstitial fibrosis (r=-0.85; P<0.001). CONCLUSIONS: Renal blood flow can be reliably measured from cardiac 13N-ammonia PET/CT and allows for simultaneous assessment of myocardial and renal perfusion, opening a potential novel avenue to interrogate the mechanisms of emerging therapies with overlapping cardiac and renal benefits.

Atypical Anti-Glomerular Basement Membrane Disease.

Atypical anti-glomerular basement membrane (anti-GBM) disease is characterized by linear immunoglobulin G (IgG) deposition along the GBM without circulating IgG anti-GBM antibodies. Compared to classic anti-GBM disease, atypical anti-GBM disease tends to be milder with a more indolent course in certain cases. Moreover, pathologic disease pattern is much more heterogenous in atypical anti-GBM disease than in the classic type, which is uniformly characterized by diffuse crescentic and necrotizing glomerulonephritis. Although there is no single well-established target antigen in atypical anti-GBM disease, the target antigen (within the GBM) and the autoantibody type are hypothesized to be different from the classic type. Some patients have the same antigen as the Goodpasture antigen that are detected only by a highly sensitive technique (biosensor analysis). Some cases of atypical anti-GBM disease have autoantibodies of a different subclass restriction like IgG4, or of monoclonal nature. Antibodies targeting antigen/epitope structure other than the Goodpasture antigen can be detected using modified assays in some cases. Patients with IgA- and IgM-mediated anti-GBM disease are known to have negative circulating antibodies because conventional assays do not detect these classes of antibodies. A significant proportion of cases with atypical anti-GBM disease do not have any identifiable antibodies despite extensive evaluation. Nevertheless, extensive evaluation of atypical autoantibodies using modified assays and sensitive techniques should be attempted, if feasible. This review summarizes the recent literature on atypical anti-GBM disease.

MRBEE: A novel bias-corrected multivariable Mendelian Randomization method.

Mendelian randomization (MR) is an instrumental variable approach used to infer causal relationships between exposures and outcomes and can apply to summary data from genome-wide association studies (GWAS). Since GWAS summary statistics are subject to estimation errors, most existing MR approaches suffer from measurement error bias, whose scale and direction are influenced by weak instrumental variables and GWAS sample overlap, respectively. We introduce MRBEE (MR using Bias-corrected Estimating Equation), a novel multivariable MR method capable of simultaneously removing measurement error bias and identifying horizontal pleiotropy. In simulations, we showed that MRBEE is capable of effectively removing measurement error bias in the presence of weak instrumental variables and sample overlap. In two independent real data analyses, we discovered that the causal effect of BMI on coronary artery disease risk is entirely mediated by blood pressure, and that existing MR methods may underestimate the causal effect of cannabis use disorder on schizophrenia risk compared to MRBEE. MRBEE possesses significant potential for advancing genetic research by providing a valuable tool to study causality between multiple risk factors and disease outcomes, particularly as a large number of GWAS summary statistics become publicly available.

MRBEE: A novel bias-corrected multivariable Mendelian Randomization method.

Mendelian Randomization (MR) has been widely applied to infer causality of exposures on outcomes in the genome wide association (GWAS) era. Existing approaches are often subject to biases from multiple sources including weak instruments, sample overlap, and measurement error. We introduce MRBEE, a computationally efficient multivariable MR method that can correct for all known biases simultaneously, which is demonstrated in theory, simulations, and real data analysis. In comparison, all existing MR methods are biased. In two independent real data analyses, we observed that the causal effect of BMI on coronary artery disease risk is completely mediated by blood pressure, and that existing MR methods drastically underestimate the causal effect of cannabis use disorder on schizophrenia risk compared to MRBEE. We demonstrate that MRBEE can be a useful tool in studying causality between multiple risk factors and a disease outcome, especially as more GWAS summary statistics are being made publicly available.

Oxalate nephropathy: a review.

This review describes the clinical and pathological features of oxalate nephropathy (ON), defined as a syndrome of decreased renal function associated with deposition of calcium oxalate crystals in kidney tubules. We review the different causes of hyperoxaluria, including primary hyperoxaluria, enteric hyperoxaluria and ingestion-related hyperoxaluria. Recent case series of biopsy-proven ON are reviewed in detail, as well as the implications of these series. The possibility of antibiotic use predisposing to ON is discussed. Therapies for hyperoxaluria and ON are reviewed with an emphasis on newer treatments available and in development. Promising research avenues to explore in this area are discussed.

Mesenteric Arteriovenous Dysplasia/Vasculopathy Mimicking Crohn's Disease: A Case Report / Displasia arteriovenosa mesentérica/vasculopatía mimetizante de enfermedad de Crohn: reporte de un caso

Mesenteric arteriovenous vasculopathy (MAVD/V) is an extremely rare and poorly understood disease and its incidence is probably underestimated. It is an uncommon, non-inflammatory and non-atherosclerotic form of mesenteric vascular injury, first reported in 2016, with characteristic histopathologic evidence of fibromuscular dysplasia-like vascular changes. We present the case of a chronically ill 84-year-old female with a 5 year history of recurrent small bowel obstruction, who underwent segmental resection of the small bowel. Intraoperative examination showed bowel stricture with fibrosis, intraluminal pill fragments and creeping mesenteric adipose tissue clinically compatible with Crohn's disease. Histological examination showed acute and chronic mucosal injury characterized by crypt distortion, ulcerations with granulation tissue, pseudo-pyloric metaplasia, areas of fibrosis and serosal adhesions. Multiple blood vessels (including both veins and arteries) demonstrated wall hyalinization, elastic degeneration and non-atherosclerotic luminal occlusion. The pattern of the mucosal injury is, in this case, potentially a consequence of acute and chronic ischemic processes secondary to mesenteric arteriovenous vasculopathy

La vasculopatía arteriovenosa mesentérica (MAVD/V) es una enfermedad extremadamente rara y poco conocida, con una incidencia probablemente subestimada. Se trata de una forma infrecuente, no inflamatoria y no aterosclerótica de lesión vascular mesentérica, reportada por primera vez en 2016, con evidencia histopatológica característica de cambios vasculares de tipo displasia fibromuscular. Presentamos el caso de una paciente crónica de 84 años de edad, con historia de cinco años de obstrucción recurrente de intestino delgado a quien se le practicó resección segmental del mismo. El examen intraoperatorio reveló estenosis intestinal con fibrosis, fragmentos intraluminales de píldoras, y tejido adiposo mesentérico serpiginoso clínicamente compatible con enfermedad de Crohn. El examen histológico reveló lesión mucosa aguda y crónica, evidenciada por distorsión de la cripta, ulceraciones con tejido granuloso, metaplasia pseudopilórica, áreas de fibrosis y adherencias serosas. Los múltiples vasos sanguíneos (incluyendo venas y arterias) reflejaron hialinización de la pared, degeneración elástica y oclusión luminal no aterosclerótica. El patrón de la lesión mucosa es, en este caso, una consecuencia potencial de un proceso isquémico crónico secundario a vasculopatía arteriovenosa mesentérica

Mesenteric Arteriovenous Dysplasia/Vasculopathy Mimicking Crohn's Disease: A Case Report.

Mesenteric arteriovenous vasculopathy (MAVD/V) is an extremely rare and poorly understood disease and its incidence is probably underestimated. It is an uncommon, non-inflammatory and non-atherosclerotic form of mesenteric vascular injury, first reported in 2016, with characteristic histopathologic evidence of fibromuscular dysplasia-like vascular changes. We present the case of a chronically ill 84-year-old female with a 5 year history of recurrent small bowel obstruction, who underwent segmental resection of the small bowel. Intraoperative examination showed bowel stricture with fibrosis, intraluminal pill fragments and creeping mesenteric adipose tissue clinically compatible with Crohn's disease. Histological examination showed acute and chronic mucosal injury characterized by crypt distortion, ulcerations with granulation tissue, pseudo-pyloric metaplasia, areas of fibrosis and serosal adhesions. Multiple blood vessels (including both veins and arteries) demonstrated wall hyalinization, elastic degeneration and non-atherosclerotic luminal occlusion. The pattern of the mucosal injury is, in this case, potentially a consequence of acute and chronic ischemic processes secondary to mesenteric arteriovenous vasculopathy.

Yttrium-90 Radioembolization and Tumor Hypoxia: Gas-challenge BOLD Imaging in the VX2 Rabbit Model of Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: To use a rapid gas-challenge blood oxygen-level dependent magnetic resonance imaging exam to evaluate changes in tumor hypoxia after 90Y radioembolization (Y90) in the VX2 rabbit model. MATERIALS AND METHODS: White New Zealand rabbits (n = 11) provided a Y90 group (n = 6 rabbits) and untreated control group (n = 5 rabbits). R2* maps were generated with gas-challenges (O2/room air) at baseline, 1 week, and 2 weeks post-Y90. Laboratory toxicity was evaluated at baseline, 24 hours, 72 hours, 1 hours, and 2 weeks. Histology was used to evaluate tumor necrosis on hematoxylin and eosin and immunofluorescence imaging was used to assess microvessel density (CD31) and proliferative index (Ki67). RESULTS: At baseline, median tumor volumes and time to imaging were similar between groups (p = 1.000 and p = 0.4512, respectively). The median administered dose was 50.4 Gy (95% confidence interval:44.8-55.9). At week 2, mean tumor volumes were 5769.8 versus 643.7 mm3 for control versus Y90 rabbits, respectively (p = 0.0246). At two weeks, ΔR2* increased for control tumors to 12.37 ± 12.36sec-1 and decreased to 4.48 ± 9.00sec-1 after Y90. The Pearson correlation coefficient for ΔR2* at baseline and percent increase in tumor size by two weeks was 0.798 for the Y90 group (p = 0.002). There was no difference in mean microvessel density for control versus Y90 treated tumors (p = 0.6682). The mean proliferative index was reduced in Y90 treated tumors at 30.5% versus 47.5% for controls (p = 0.0071). CONCLUSION: The baseline ΔR2* of tumors prior to Y90 may be a predictive imaging biomarker of tumor response and treatment of these tumors with Y90 may influence tumor oxygenation over time.

CD4 T Follicular Helper Cells Prevent Depletion of Follicular B Cells in Response to Cecal Ligation and Puncture.

Recent studies have demonstrated that induction of a diverse repertoire of memory T cells ("immune education") affects responses to murine cecal ligation and puncture (CLP), the most widely - used animal model of sepsis. Among the documented effects of immune education on CLP are changes in T cell, macrophage and neutrophil activity, more pronounced organ dysfunction and reduced survival. Little is known, however, about the effects of CLP on B cell responses, and how these responses might be altered by immune education. Importantly, effective B cell responses are modulated by IL21 produced by CD4+/CXCR5+/PD1+ T follicular helper (Tfh) cells. We examined the B cell population in control and immune educated mice 24 h and 60 days after CLP. Education alone increased Tfh cells. Twenty-four hours after CLP, Tfh cells were depleted. However, this reduction was less pronounced in immune educated mice than in controls and the percentage of CD4 T cells expressing a Tfh phenotype increased in the animals. CLP did not alter splenic architecture and decreased numbers of follicular, marginal, and germinal center B cells. CLP induced changes were not, however, noted following CLP in immune educated mice. At 60 days post - CLP, numbers of follicular, germinal center and marginal zone B cells were increased; this increase was more pronounced in immune educated mice. Finally, while CLP reduced the induction of antigen specific B cells in controls, this response was maintained following CLP in immune educated mice. Our data suggest that preexisting Tfh assists in rescuing the B cell response to CLP.

Rapid Emergence of SARS-CoV-2 in the Greater New York Metropolitan Area: Geolocation, Demographics, Positivity Rates, and Hospitalization for 46 793 Persons Tested by Northwell Health.

BACKGROUND: In March 2020, the greater New York metropolitan area became an epicenter for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The initial evolution of case incidence has not been well characterized. METHODS: Northwell Health Laboratories tested 46 793 persons for SARS-CoV-2 from 4 March through 10 April. The primary outcome measure was a positive reverse transcription-polymerase chain reaction test for SARS-CoV-2. The secondary outcomes included patient age, sex, and race, if stated; dates the specimen was obtained and the test result; clinical practice site sources; geolocation of patient residence; and hospitalization. RESULTS: From 8 March through 10 April, a total of 26 735 of 46 793 persons (57.1%) tested positive for SARS-CoV-2. Males of each race were disproportionally more affected than females above age 25, with a progressive male predominance as age increased. Of the positive persons, 7292 were hospitalized directly upon presentation; an additional 882 persons tested positive in an ambulatory setting before subsequent hospitalization, a median of 4.8 days later. Total hospitalization rate was thus 8174 persons (30.6% of positive persons). There was a broad range (>10-fold) in the cumulative number of positive cases across individual zip codes following documented first caseincidence. Test positivity was greater for persons living in zip codes with lower annual household income. CONCLUSIONS: Our data reveal that SARS-CoV-2 incidence emerged rapidly and almost simultaneously across a broad demographic population in the region. These findings support the premise that SARS-CoV-2 infection was widely distributed prior to virus testing availability.

COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings.

BACKGROUND: Reports show that AKI is a common complication of severe coronavirus disease 2019 (COVID-19) in hospitalized patients. Studies have also observed proteinuria and microscopic hematuria in such patients. Although a recent autopsy series of patients who died with severe COVID-19 in China found acute tubular necrosis in the kidney, a few patient reports have also described collapsing glomerulopathy in COVID-19. METHODS: We evaluated biopsied kidney samples from ten patients at our institution who had COVID-19 and clinical features of AKI, including proteinuria with or without hematuria. We documented clinical features, pathologic findings, and outcomes. RESULTS: Our analysis included ten patients who underwent kidney biopsy (mean age: 65 years); five patients were black, three were Hispanic, and two were white. All patients had proteinuria. Eight patients had severe AKI, necessitating RRT. All biopsy samples showed varying degrees of acute tubular necrosis, and one patient had associated widespread myoglobin casts. In addition, two patients had findings of thrombotic microangiopathy, one had pauci-immune crescentic GN, and another had global as well as segmental glomerulosclerosis with features of healed collapsing glomerulopathy. Interestingly, although the patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by RT-PCR, immunohistochemical staining of kidney biopsy samples for SARS-CoV-2 was negative in all ten patients. Also, ultrastructural examination by electron microscopy showed no evidence of viral particles in the biopsy samples. CONCLUSIONS: The most common finding in our kidney biopsy samples from ten hospitalized patients with AKI and COVID-19 was acute tubular necrosis. There was no evidence of SARS-CoV-2 in the biopsied kidney tissue.

Feasibility of Combination Intra-arterial Yttrium-90 and Irinotecan Microspheres in the VX2 Rabbit Model.

PURPOSE: To evaluate the combination of 90Y radioembolization (Y90) and drug-eluting bead irinotecan (DEBIRI) microspheres in the VX2 rabbit model. MATERIALS AND METHODS: An initial dose finding study was performed in 6 White New Zealand rabbits to identify a therapeutic but subcurative dose of Y90. In total, 29 rabbits were used in four groups: Y90 treatment (n = 8), DEBIRI treatment (n = 6), Y90 + DEBIRI treatment (n = 7), and an untreated control group (n = 8). Hepatic toxicity was evaluated at baseline, 24 h, 72 h, 1 week, and 2 weeks. MRI tumor volume (TV) and enhancing tumor volume were assessed baseline and 2 weeks. Tumor area and necrosis were evaluated on H&E for pathology. RESULTS: Infused activities of 84.0-94.4 MBq (corresponding to 55.1-72.7 Gy) were selected based on the initial dose finding study. Infusion of DEBIRI after Y90 was technically feasible in all cases (7/7). Overall, 21/29 animals survived to 2 weeks, and the remaining animals had extrahepatic disease on necropsy. Liver transaminases were elevated with Y90, DEBIRI, and Y90 + DEBIRI compared to control at 24 h, 72 h, and 1 week post-treatment and returned to baseline by 2 weeks. By TV, Y90 + DEBIRI was the only treatment to show statistically significant reduction at 2 weeks compared to the control group (p = 0.012). The change in tumor volume (week 2-baseline) for both Y90 + DEBIRI versus control (p = 0.002) and Y90 versus control (p = 0.014) was significantly decreased. There were no statistically significant differences among groups on pathology. CONCLUSION: Intra-arterial Y90 + DEBIRI was safe and demonstrated enhanced antitumor activity in rabbit VX2 tumors. This combined approach warrants further investigation.

Kidney oxalate crystal deposition in adult patients: A relatively common finding
.

AIMS: We aim to describe the clinical and histological findings in patients with the finding of any tubular oxalate deposits in kidney biopsy specimens. BACKGROUND: The prevalence, manifestation, and outcome of secondary oxalate nephropathy have not been extensively studied. MATERIALS AND METHODS: In this retrospective cohort study, we analyzed the clinical and histological findings in all patients with the finding of any tubular oxalate deposits in kidney biopsy specimens between July 1, 2017, and December 31, 2018, at Northwell Health Pathology Department (Manhasset, NY, USA). RESULTS: The prevalence of oxalate deposition on a kidney biopsy was 4.07% (25/615), and in 88% of cases was a major finding. Prior to biopsy, oxalate was anticipated in only 1 case. The etiology of oxalosis was clarified retrospectively in 14 cases, most commonly due to GI surgery (n = 10) and increased oxalate intake (n = 4). In 11 cases, etiology remained unknown, although at least 3 cases were exposed to antibiotics associated with secondary oxalosis. There was no significant clinical/pathological or survival difference between known vs. unknown cause groups. The overall 3-month renal survival rate was 76.0 ± 8.5%. Multivariate Cox regression showed that creatinine at the time of biopsy (HR: 1.79, 95% CI: 0.71 - 4.51), background histological chronicity change (HR: 1.82, 95% CI: 0.70 - 4.72) and oxalate density (HR: 2.27, 95% CI: 0.49 - 10.55) are associated with end-stage kidney disease. CONCLUSION: Oxalate deposition is common but rarely anticipated biopsy finding. Nephrologists need to consider surgical history and other secondary causes of oxalosis as causes of acute kidney injury and chronic kidney disease.

Correction to: Prognosticating Survival in Hepatocellular Carcinoma with Elevated Baseline Alpha-fetoprotein Treated with Radioembolization Using a Novel Laboratory Scoring System: Initial Development and Validation.

The name of the eleventh author is listed incorrectly in the published article as Nitin Kataraya. The correct name is Nitin Katariya.