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ObjectiveElectronic health record (EHR) systems contain structured data and unstructured documentation. Clinical insights can be derived from analyzing both but optimal methods for this have not been studied extensively. We compared various approaches to analyzing EHR data for non-alcoholic fatty liver disease (NAFLD).Materials and MethodsWe compared analysis of structured and unstructured EHR data using natural language processing (NLP), free-text search, and diagnostic codes against expert adjudication as the reference standard.ResultsOut of 38,575 patients, we identified 2,281 patients with NAFLD. From the remainder, 10,653 patients with similar data density were selected as a control group. NLP was more sensitive than ICD and text search (NLP 0.93 vs. ICD 0.28 vs. text search 0.81) with higher a F2 score (NLP 0.92 vs. ICD 0.34 vs. text search 0.81). 619 patients had suspected NAFLD documented in radiology notes not acknowledged in other forms of clinical documentation. Of these, 232 (37.5%) were found to have more advanced liver disease after a median of 1,057 days.DiscussionNLP-based approaches have superior accuracy in identifying NAFLD within the EHR compared to ICD/text search-based approaches. Suspected NAFLD on imaging is often not acknowledged in subsequent clinical documentation. Many such patients are later found to have more advanced liver disease.ConclusionFor identification of NAFLD, NLP performed better than alternative selection modalities and facilitated follow-on analysis of information flow. If accuracy can be proven to persist across clinical domains, NLP can identify patient phenotypes for biomedical research in an accurate and high-throughput manner.

Item does not contain fulltext BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0.83 (95% CI 0.74-0.94), decreasing to 0.78 (0.66-0.92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction

Background: Primary percutaneous coronary intervention (PCI) is the most frequently used treatment modality for patients presenting with ST elevation myocardial infarction (STEMI). Current professional society guidelines recommend culprit artery only PCI. Recent evidence suggests the potential benefit of multivessel PCI among patients with STEMI that is not complicated by cardiogenic shock. Methods: We systematically searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for clinical studies of patients with STEMI, not complicated by cardiogenic shock, who underwent primary PCI between January 1966 and January 2018. We evaluated all-cause and cardiovascular mortality, reinfarction, and repeat revascularization among patients randomized to a multivessel PCI strategy compared to a culprit artery only PCI strategy. Results: Four randomized clinical trials with a total of 1,044 patients met the inclusion criteria. Five hundred and sixty-six patients underwent multivessel PCI, and 478 patients underwent culprit artery only PCI. Multivessel PCI reduced all the studied endpoints: total death, cardiac death, reinfarction, and repeat revascularization (all P values

APOL1 risk variants have been shown to be associated with kidney disease and hypertension. In this study, Chen and colleagues assess the association of these risk variants with longitudinal blood pressure in young adults. We review the current literature on association of these alleles with blood pressure and propose future directions to resolve the existing controversies.

BACKGROUND: Study findings show that although palliative care decreases symptom burden, it is still underused in patients with ESKD. Little is known about disparity in use of palliative care services in such patients in the inpatient setting. METHODS: To investigate the use of palliative care consultation in patients with ESKD in the inpatient setting, we conducted a retrospective cohort study using the National Inpatient Sample from 2006 to 2014 to identify admitted patients with ESKD requiring maintenance dialysis. We compared palliative care use among minority groups (black, Hispanic, and Asian) and white patients, adjusting for patient and hospital variables. RESULTS: We identified 5,230,865 hospitalizations of such patients from 2006 through 2014, of which 76,659 (1.5%) involved palliative care. The palliative care referral rate increased significantly, from 0.24% in 2006 to 2.70% in 2014 (P

BackgroundIdentification of symptoms is challenging with surveys, which are time-intensive and low-throughput. Natural language processing (NLP) could be utilized to identify symptoms from narrative documentation in the electronic health record (EHR).MethodsWe utilized NLP to parse notes for maintenance hemodialysis (HD) patients from two EHR databases (BioMe and MIMIC-III) to identify fatigue, nausea/vomiting, anxiety, depression, cramping, itching, and pain. We compared NLP performance with International Classification of Diseases (ICD) codes and validated the performance of both NLP and codes against manual chart review in a representative subset.ResultsWe identified 1034 and 929 HD patients from BioMe and MIMIC-III respectively. The most frequently identified symptoms by NLP from both cohorts were fatigue, pain, and nausea and/or vomiting. NLP was significantly more sensitive than ICD codes for nearly all symptoms. In the BioMe dataset, sensitivity for NLP ranged from 0.85-0.99 vs. 0.09-0.59 for ICD codes. In the MIMIC-III dataset, NLP sensitivity was 0.8-0.98 vs. 0.02-0.53 for ICD. ICD codes were significantly more specific for nausea and/or vomiting (NLP 0.57 vs. ICD 0.97, P=0.03) in BioMe and for depression (NLP 0.67 vs. ICD 0.99, P=0.002) in MIMIC-III. A majority of patients in both cohorts had ?4 symptoms. The more encounters available for a patient the more likely NLP was to identify a symptom.ConclusionsNLP out performed ICD codes for identification of symptoms on several tests parameters including sensitivity for a majority of symptoms. NLP may be useful for the high-throughput identification of patient centered outcomes from EHR.Significance StatementPatients on maintenance hemodialysis experience a high frequency of symptoms. However, symptoms have been measured utilizing time-intensive surveys. This paper compares natural language processing (NLP) to administrative codes for the identification of seven key symptoms from two cohorts with electronic health records and validation through manual chart review. NLP identified high rates of symptoms; the most common were fatigue, pain, and nausea and/or vomiting. A majority of patients had ≥4 symptoms. NLP was significantly more sensitive at identifying symptoms compared to administrative codes for nearly all symptoms but specificity was not significantly different compared to codes. This paper demonstrates utility of a high throughput method of identifying symptoms from EHR which may advance the field of patient centered research in nephrology.

We aggregated genome-wide genotyping data from 32 European-descent GWAS (74,124 T2D cases, 824,006 controls) imputed to high-density reference panels of >30,000 sequenced haplotypes. Analysis of ˜27M variants (˜21M with minor allele frequency [MAF]p−8; MAF 0.02%-50%; odds ratio [OR] 1.04-8.05), 135 not previously-implicated in T2D-predisposition. Conditional analyses revealed 160 additional distinct association signals (p−5) within the identified loci. The combined set of 403 T2D-risk signals includes 56 low-frequency (0.5%≤MAF2. Forty-one of the signals displayed effect-size heterogeneity between BMI-unadjusted and adjusted analyses. Increased sample size and improved imputation led to substantially more precise localisation of causal variants than previously attained: at 51 signals, the lead variant after fine-mapping accounted for >80% posterior probability of association (PPA) and at 18 of these, PPA exceeded 99%. Integration with islet regulatory annotations enriched for T2D association further reduced median credible set size (from 42 variants to 32) and extended the number of index variants with PPA>80% to 73. Although most signals mapped to regulatory sequence, we identified 18 genes as human validated therapeutic targets through coding variants that are causal for disease. Genome wide chip heritability accounted for 18% of T2D-risk, and individuals in the 2.5% extremes of a polygenic risk score generated from the GWAS data differed >9-fold in risk. Our observations highlight how increases in sample size and variant diversity deliver enhanced discovery and single-variant resolution of causal T2D-risk alleles, and the consequent impact on mechanistic insights and clinical translation.

Background Critical limb ischemia (CLI) is the most serious complication of peripheral artery disease (PAD). Objectives The purpose of this study was to characterize pathology of PAD in below- and above-knee amputation specimens in patients presenting with CLI. Methods Peripheral arteries from 95 patients (121 amputation specimens) were examined; 75 patients had presented with CLI, and the remaining 20 had amputations performed for other reasons. The pathological characteristics were separately recorded for femoral and popliteal arteries (FEM-POP), and infrapopliteal arteries (INFRA-POP). Results A total of 299 arteries were examined. In the 239 arteries from CLI patients, atherosclerotic plaques were more frequent in FEM-POP (23 of 34, 67.6%) compared with INFRA-POP (79 of 205, 38.5%) arteries. Of these 239 arteries, 165 (69%) showed ≥70% stenosis, which was due to significant pathological intimal thickening, fibroatheroma, fibrocalcific lesions, or restenosis in 45 of 165 (27.3%), or was due to luminal thrombi with (39 of 165, 23.6%) or without (81 of 165, 49.1%) significant atherosclerotic lesions. Presence of chronic luminal thrombi was more frequently observed in arteries with insignificant atherosclerosis (OR: 16.7; p = 0.0002), more so in INFRA-POP compared with FEM-POP (OR: 2.14; p = 0.0041) arteries. Acute thrombotic occlusion was less frequently encountered in INFRA-POP than FEM-POP arteries (OR: 0.27; p = 0.0067). Medial calcification was present in 170 of 239 (71.1%) large arteries. Conclusions Thrombotic luminal occlusion associated with insignificant atherosclerosis is commonly observed in CLI and suggests the possibility of atherothromboembolic disease. The pathological characteristics of arteries in CLI suggest possible mechanisms of progression of PAD to CLI, especially in INFRA-POP arteries, and may support the preventive role of antithrombotic agents.

ObjectiveAcute kidney injury (AKI) is highly prevalent in critically ill patients with sepsis. Sepsis-associated AKI is a heterogeneous clinical entity, and, like many complex syndromes, is composed of distinct subtypes. We aimed to agnostically identify AKI subphenotypes using machine learning techniques and routinely collected data in electronic health records (EHRs).DesignCohort study utilizing the MIMIC-III Database.SettingICUs from tertiary care hospital in the U.S.PatientsPatients older than 18 years with sepsis and who developed AKI within 48 hours of ICU admission.InterventionsUnsupervised machine learning utilizing all available vital signs and laboratory measurements.Measurements and Main ResultsWe identified 1,865 patients with sepsis-associated AKI. Ten vital signs and 691 unique laboratory results were identified. After data processing and feature selection, 59 features, of which 28 were measures of intra-patient variability, remained for inclusion into an unsupervised machine-learning algorithm. We utilized k-means clustering with k ranging from 2 – 10; k=2 had the highest silhouette score (0.62). Cluster 1 had 1,358 patients while Cluster 2 had 507 patients. There were no significant differences between clusters on age, race or gender. We found significant differences in comorbidities and small but significant differences in several laboratory variables (hematocrit, bicarbonate, albumin) and vital signs (systolic blood pressure and heart rate). In-hospital mortality was higher in cluster 2 patients, 25% vs. 20%, p=0.008. Features with the largest differences between clusters included variability in basophil and eosinophil counts, alanine aminotransferase levels and creatine kinase values.ConclusionsUtilizing routinely collected laboratory variables and vital signs in the EHR, we were able to identify two distinct subphenotypes of sepsis-associated AKI with different outcomes. Variability in laboratory variables, as opposed to their actual value, was more important for determination of subphenotypes. Our findings show the potential utility of unsupervised machine learning to better subtype AKI.

E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine whole genome sequencing data in 2249 African Americans (AAs) from the Jackson Heart Study, we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in Fucosyltransferase 6 (FUT6; rs17855739,p.Glu274Lys, P = 9.02 × 10(−24)) with higher soluble E-selectin levels. This variant is considerably more common in populations of African ancestry compared to non-African ancestry populations. We replicated the association of FUT6 p.Glu274Lys with higher soluble E-selectin in an independent population of 748 AAs from the Women’s Health Initiative and identified an additional pleiotropic association with vitamin B12 levels. Despite the broad role of both selectins and fucosyltransferases in various inflammatory, immune and cancer-related processes, we were unable to identify any additional disease associations of the FUT6 p.Glu274Lys variant in an electronic medical record-based phenome-wide association scan of over 9000 AAs.

Rationale & objectiveRandom assignment to intensive blood pressure (BP) lowering (systolic BP

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated Coronavirus Disease 2019 (COVID-19) is a public health emergency. Acute kidney injury (AKI) is a common complication in hospitalized patients with COVID-19 although mechanisms underlying AKI are yet unclear. There may be a direct effect of SARS-CoV-2 virus on the kidney; however, there is currently no data linking SARS-CoV-2 viral load (VL) to AKI. We explored the association of SARS-CoV-2 VL at admission to AKI in a large diverse cohort of hospitalized patients with COVID-19. Methods and findings We included patients hospitalized between March 13th and May 19th, 2020 with SARS-CoV-2 in a large academic healthcare system in New York City (N = 1,049) with available VL at admission quantified by real-time RT-PCR. We extracted clinical and outcome data from our institutional electronic health records (EHRs). AKI was defined by KDIGO guidelines. We fit a Fine-Gray competing risks model (with death as a competing risk) using demographics, comorbidities, admission severity scores, and log10 transformed VL as covariates and generated adjusted hazard ratios (aHR) and 95% Confidence Intervals (CIs). VL was associated with an increased risk of AKI (aHR = 1.04, 95% CI: 1.01–1.08, p = 0.02) with a 4% increased hazard for each log10 VL change. Patients with a viral load in the top 50th percentile had an increased adjusted hazard of 1.27 (95% CI: 1.02–1.58, p = 0.03) for AKI as compared to those in the bottom 50th percentile. Conclusions VL is weakly but significantly associated with in-hospital AKI after adjusting for confounders. This may indicate the role of VL in COVID-19 associated AKI. This data may inform future studies to discover the mechanistic basis of COVID-19 associated AKI.

ObjectiveMultiple clinical trials fail to identify clinically measurable health benefits of daily multivitamin and multimineral (MVM) consumption in the general adult population. Understanding the determinants of widespread use of MVMs may guide efforts to better educate the public about effective nutritional practices. The objective of this study was to compare self-reported and clinically measurable health outcomes among MVM users and non-users in a large, nationally representative adult civilian non-institutionalised population in the USA surveyed on the use of complementary health practices.DesignCross-sectional analysis of the effect of MVM consumption on self-reported overall health and clinically measurable health outcomes.ParticipantsAdult MVM users and non-users from the 2012 National Health Interview Survey (n=21 603).Primary and secondary outcome measuresFive psychological, physical, and functional health outcomes: (1) self-rated health status, (2) needing help with routine needs, (3) history of 10 chronic diseases, (4) presence of 19 health conditions in the past 12 months, and (5) Kessler 6-Item (K6) Psychological Distress Scale to measure non-specific psychological distress in the past month.ResultsAmong 4933 adult MVM users and 16 670 adult non-users, MVM users self-reported 30% better overall health than non-users (adjusted OR 1.31; 95% CI 1.17 to 1.46; false discovery rate adjusted pConclusionsMVM users self-reported better overall health despite no apparent differences in clinically measurable health outcomes. These results suggest that widespread use of multivitamins in adults may be a result of individuals’ positive expectation that multivitamin use leads to better health outcomes or a self-selection bias in which MVM users intrinsically harbour more positive views regarding their health.

The total number of people living with Parkinson’s disease (PD) worldwide is expected to double by 2030. The risk factors for emergency department visits in PD patients have been described before, however, there is limited data on inpatient hospitalizations of PD patients. We derived our study cohort from the Nationwide Inpatient Sample (NIS) database from 2002–2011. The NIS is a stratified 20% sample of discharges from all U.S. hospitals. We extracted causes of hospitalization using International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes and calculated inpatient mortality, length of stay and cost. Further, the significance of trends over 10 years was assessed. A total of 3,015,645 (weighted) admissions of PD patients were documented from 2002–2011. Pneumonia, urinary tract infection (UTI), septicemia and aspiration pneumonitis were the most common causes of admission, of which incidence of sepsis and UTI was trending up. Of all causes, 3.9% of the admissions resulted in inpatient mortality. Inpatient mortality for PD patients decreased from 4.9% in 2002 to 3.3% in 2011 (p < 0.001). The median length of stay has also steadily declined from 3.6 days in 2002 to 2.3 days in 2011. However, the inflation-adjusted cost of care has been steadily rising, from $22,250 per hospitalization in 2002 to $37,942 in 2011. We conclude that the epidemiology of inpatient admissions in PD has changed significantly over the last decade. Our study underscores the need for future, in-depth prospective studies to explore this changing disease spectrum to design preventive measures and targeted interventions.

We previously reported that obese individuals with the metabolic syndrome (at risk), compared with obese individuals without the metabolic syndrome (healthy obese), have elevated serum AGEs that strongly correlate with insulin resistance, oxidative stress and inflammation. We hypothesised that a diet low in AGEs (L-AGE) would improve components of the metabolic syndrome in obese individuals, confirming high AGEs as a new risk factor for the metabolic syndrome.A randomised 1 year trial was conducted in obese individuals with the metabolic syndrome in two parallel groups: L-AGE diet vs a regular diet, habitually high in AGEs (Reg-AGE). Participants were allocated to each group by randomisation using random permuted blocks. At baseline and at the end of the trial, we obtained anthropometric variables, blood and urine samples, and performed OGTTs and MRI measurements of visceral and subcutaneous abdominal tissue and carotid artery. Only investigators involved in laboratory determinations were blinded to dietary assignment. Effects on insulin resistance (HOMA-IR) were the primary outcome.Sixty-one individuals were randomised to a Reg-AGE diet and 77 to an L-AGE diet; the data of 49 and 51, respectively, were analysed at the study end in 2014. The L-AGE diet markedly improved insulin resistance; modestly decreased body weight; lowered AGEs, oxidative stress and inflammation; and enhanced the protective factors sirtuin 1, AGE receptor 1 and glyoxalase I. The Reg-AGE diet raised AGEs and markers of insulin resistance, oxidative stress and inflammation. There were no effects on MRI-assessed measurements. No side effects from the intervention were identified. HOMA-IR came down from 3.1 ± 1.8 to 1.9 ± 1.3 (p 0.001) in the L-AGE group, while it increased from 2.9 ± 1.2 to 3.6 ± 1.7 (p 0.002) in the Reg-AGE group.L-AGE ameliorates insulin resistance in obese people with the metabolic syndrome, and may reduce the risk of type 2 diabetes, without necessitating a major reduction in adiposity. Elevated serum AGEs may be used to diagnose and treat 'at-risk' obesity.ClinicalTrials.gov NCT01363141 FUNDING: The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (DK091231).

Adults with metabolic syndrome from different race/ethnicities are often predisposed to developing type 2 diabetes (T2D); however, growing evidence suggests that healthy diets and lifestyle choices can significantly slow or prevent progression to T2D. This poorly understood relationship to healthy dietary patterns and prevention of T2D motivated us to conduct a retrospective analysis to determine the potential impact of a minor dietary lifestyle change (daily mushroom consumption) on known T2D risk factors in racially diverse adults with confirmed features of the metabolic syndrome. Retrospectively, we studied 37 subjects who had participated in a dietary intervention focused on vitamin D bioavailability from white button mushrooms (WBM). All 37 had previously completed a 16-week study where they consumed 100 g of WBM daily and were then followed-up for one month during which no mushrooms were consumed. We analyzed differences in serum risk factors from baseline to 16-week, and from baseline to one-month follow-up. Measurement of serum diabetic risk factors included inflammatory and oxidative stress markers and the antioxidant component naturally rich in mushrooms, ergothioneine. Significant beneficial health effects were observed at 16-week with the doubling of ergothioneine from baseline, increases in the antioxidant marker ORAC (oxygen radical absorption capacity) and anti-inflammatory hormone, adiponectin and significant decreases in serum oxidative stress inducing factors, carboxymethyllysine (CML) and methylglyoxal (MG), but no change in the lipid oxidative stress marker 8-isoprostane, leptin or measures of insulin resistance or glucose metabolism. We conclude that WBM contain a variety of compounds with potential anti-inflammatory and antioxidant health benefits that can occur with frequent consumption over time in adults predisposed to T2D. Well-controlled studies are needed to confirm these findings and identify the specific mushroom components beneficial to health.

Background and objectives Current measures for predicting renal functional decline in patients with type 2 diabetes with preserved renal function are unsatisfactory, and multiple markers assessing various biologic axes may improve prediction. We examined the association of four biomarker-to-creatinine ratio levels (monocyte chemotactic protein-1, IL-18, kidney injury molecule-1, and YKL-40) with renal outcome. Design, setting, participants, & measurements We used a nested case-control design in the Action to Control Cardiovascular Disease Trial by matching 190 participants with ≥40% sustained eGFR decline over the 5-year follow-up period to 190 participants with ≤10% eGFR decline in a 1:1 fashion on key characteristics (age within 5 years, sex, race, baseline albumin-to-creatinine ratio within 20 μ g/mg, and baseline eGFR within 10 ml/min per 1.73 m 2 ), with ≤10% decline. We used a Mesoscale Multiplex Platform and measured biomarkers in baseline and 24-month specimens, and we examined biomarker associations with outcome using conditional logistic regression. Results Baseline and 24-month levels of monocyte chemotactic protein-1-to-creatinine ratio levels were higher for cases versus controls. The highest quartile of baseline monocyte chemotactic protein-1-to-creatinine ratio had fivefold greater odds, and each log increment had 2.27-fold higher odds for outcome (odds ratio, 5.27; 95% confidence interval, 2.19 to 12.71 and odds ratio, 2.27; 95% confidence interval, 1.44 to 3.58, respectively). IL-18-to-creatinine ratio, kidney injury molecule-1-to-creatinine ratio, and YKL-40-to-creatinine ratio were not consistently associated with outcome. C statistic for traditional predictors of eGFR decline was 0.70, which improved significantly to 0.74 with monocyte chemotactic protein-1-to-creatinine ratio. Conclusions Urinary monocyte chemotactic protein-1-to-creatinine ratio concentrations were strongly associated with sustained renal decline in patients with type 2 diabetes with preserved renal function.

Recent advances in genomics and sequencing technology have led to a better understanding of genetic risk in CKD. Genetics could account in part for racial differences in treatment response for medications including antihypertensives and immunosuppressive medications due to its correlation with ancestry. However, there is still a substantial lag between generation of this knowledge and its adoption in routine clinical care. This review summarizes the recent advances in genomics and CKD, discusses potential reasons for its underutilization, and highlights potential avenues for application of genomic information to improve clinical care and outcomes in this particularly vulnerable population.

Background In the last few years, peritoneal dialysis (PD) catheter placement techniques and outcomes have become important because of the growing population of PD patients. Although there are a growing number of catheters placed by the minimally invasive Y-TEC peritoneoscopic technique, there are still limited data on outcomes for these catheters, especially those placed by a surgeon. We aimed to conduct a retrospective study of our experience with PD catheters placed by the Y-TEC peritoneoscopic technique in our institution. Methods We reviewed patients with peritoneoscopic PD catheter insertion over the last decade and described their complications and outcomes. In a secondary analysis, we compared the outcomes and complications of these catheters with those with open placement placed by the same surgeon. Results We had complete data on 62 patients with peritoneoscopic catheter placement during the study period. The mean age was 55 years, 48.4% were females and the most common cause of end-stage renal disease was diabetes mellitus (33%). Surgical complications were seen in only 6/62 (9.6%) and peritonitis in 16/62 (26%) of peritoneoscopic catheters. Most catheters were used after 2 months of placement, while 12.3% were used within 2 months. When compared with 93 patients with open placement of catheters as a secondary analysis, peritoneoscopic catheters were found to have a higher 2-year survival. Conclusion Our large series of peritoneoscopically placed catheters by a surgeon demonstrate low surgical complications and peritonitis rates as well as superior 2-year survival compared with open placement of catheters.

Background and Purpose— The epidemiology of dialysis requiring acute kidney injury (AKI-D) in acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH) admissions is poorly understood with previous studies being from a single center or year. Methods— We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends of AKI-D in hospitalizations with AIS and ICH from 2002 to 2011. We also evaluated the trend of impact of AKI-D on in-hospital mortality and adverse discharge using adjusted odds ratios (aOR) after adjusting for demographics and comorbidity indices. Results— We extracted a total of 3 937 928 and 696 754 hospitalizations with AIS and ICH, respectively. AKI-D occurred in 1.5 and 3.5 per 1000 in AIS and ICH admissions, respectively. Incidence of admissions complicated by AKI-D doubled from 0.9/1000 to 1.7/1000 in AIS and from 2.1/1000 to 4.3/1000 in ICH admissions. In AIS admissions, AKI-D was associated with 30% higher odds of mortality (aOR, 1.30; 95% confidence interval, 1.12–1.48; P P P P Conclusions— Incidence of AKI-D complicating hospitalizations with cerebrovascular accident continues to grow and is associated with increased mortality and adverse discharge. This highlights the need for early diagnosis, better risk stratification, and preparedness for need for complex long-term care in this vulnerable population.

Renal allografts from deceased African Americans with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10,000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with 0/1 variant and 1.8527 for 93 donors with 2 variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence/absence of 2 APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need.

The need for reliable and widely available SARS-CoV-2 testing is well recognized, but it will be equally necessary to develop quantitative methods that determine viral load in order to guide patient triage and medical decision making. We are the first to report that SARS-CoV-2 viral load at the time of presentation is an independent predictor of COVID-19 mortality in a large patient cohort (n=1,145). Viral loads should be used to identify higher-risk patients that may require more aggressive care and should be included as a key biomarker in the development of predictive algorithms.

Background Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS. Methods and findings Using biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range [IQR]: age = 28 [25–32], body mass index [BMI] = 35.4 [28.2–41.5]). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 [24–33], BMI = 35.7 [28.4–42.3]). The clustering revealed 2 distinct PCOS subtypes: a “reproductive” group (21%–23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels, and a “metabolic” group (37%–39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in 4 loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN, P = 2.2 × 10−10; IQCA1, P = 2.8 × 10−9; BMPR1B/UNC5C, P = 9.7 × 10−9; CDH10, P = 1.2 × 10−8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P = 1.0 × 10−8). We developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS (median and IQR: age = 28 [25–33], BMI = 34.3 [27.8–42.3]) and found that the subtypes tended to cluster in families and that carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by National Institutes of Health (NIH) criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated. Conclusions In conclusion, we have found reproducible reproductive and metabolic subtypes of PCOS. Furthermore, these subtypes were associated with novel, to our knowledge, susceptibility loci. Our results suggest that these subtypes are biologically relevant because they appear to have distinct genetic architecture. This study demonstrates how phenotypic subtyping can be used to gain additional insights from GWAS data., In a clustering analysis, Matthew Dapas and colleagues investigate the genetic traits associated with phenotypic subtypes of polycystic ovary syndrome in women., Author summary Why was this study done? Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. The signs and symptoms of PCOS are heterogeneous, which suggests that the etiology may differ among subsets of women with PCOS. Elucidating the genetic mechanisms of PCOS could result in improved diagnosis and treatment. What did the researchers do and find? A clustering analysis of 893 women with PCOS, using reproductive and metabolic quantitative traits, was performed to identify subsets of affected women with similar hormonal profiles. There were distinct reproductive and metabolic “subtypes” of women with PCOS. Novel genetic variants were uniquely associated with each of the PCOS subtypes. What do these findings mean? Our results suggest that there are distinct forms of PCOS that are associated with different underlying biological mechanisms. Women with PCOS may be poorly served by being grouped under a single diagnosis because PCOS subtypes may differ in responses to therapy and in long-term outcomes.

Despite known pathogenesis of coronary artery disease (CAD), the pathogenesis of peripheral and carotid artery disease (PAD, CAS) are poorly understood. Genome-wide association studies (GWAS) offer an unbiased assessment of specific genetic variations, and can provide insight into the etiology of

Chronic kidney disease (CKD) affects ∼10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

Rationale & Objective Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. Study Design Cross-sectional individual participant-level analyses in a global consortium. Setting & Study Populations 17 CKD and 38 general population and high-risk cohorts. Selection Criteria for Studies Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. Data Extraction Data were obtained and analyzed between July 2015 and January 2018. Analytical Approach We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. Results The CKD cohorts (n = 254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n = 1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59 mL/min/1.73 m 2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30 mg/g). Limitations Variations in study era, health care delivery system, typical diet, and laboratory assays. Conclusions Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD. © 2018. This is the authors’ accepted and refereed manuscript to the article. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ "

Background and objectives Hypernatremia is common in hospitalized, critically ill patients. Although there are no clear guidelines on sodium correction rate for hypernatremia, some studies suggest a reduction rate not to exceed 0.5 mmol/L per hour. However, the data supporting this recommendation and the optimal rate of hypernatremia correction in hospitalized adults are unclear. Design, setting, participants, & measurements We assessed the association of hypernatremia correction rates with neurologic outcomes and mortality in critically ill patients with hypernatremia at admission and those that developed hypernatremia during hospitalization. We used data from the Medical Information Mart for Intensive Care-III and identified patients with hypernatremia (serum sodium level >155 mmol/L) on admission (n=122) and hospital-acquired (n=327). We calculated different ranges of rapid correction rates (>0.5 mmol/L per hour overall and >8, >10, and >12 mmol/L per 24 hours) and utilized logistic regression to generate adjusted odds ratios (aOR) with 95% confidence intervals (95% CIs) to examine association with outcomes. Results We had complete data on 122 patients with severe hypernatremia on admission and 327 patients who developed hospital-acquired hypernatremia. The difference in in-hospital 30-day mortality proportion between rapid (>0.5 mmol/L per hour) and slower (≤0.5 mmol/L per hour) correction rates were not significant either in patients with hypernatremia at admission with rapid versus slow correction (25% versus 28%; P=0.80) or in patients with hospital-acquired hypernatremia with rapid versus slow correction (44% versus 40%; P=0.50). There was no difference in aOR of mortality for rapid versus slow correction in either admission (aOR, 1.3; 95% CI, 0.5 to 3.7) or hospital-acquired hypernatremia (aOR, 1.3; 95% CI, 0.8 to 2.3). Manual chart review of all suspected chronic hypernatremia patients, which included all 122 with hypernatremia at admission, 128 of the 327 hospital-acquired hypernatremia, and an additional 28 patients with ICD-9 codes for cerebral edema, seizures and/or alteration of consciousness, did not reveal a single case of cerebral edema attributable to rapid hyprnatremia correction. Conclusions We did not find any evidence that rapid correction of hypernatremia is associated with a higher risk for mortality, seizure, alteration of consciousness, and/or cerebral edema in critically ill adult patients with either admission or hospital-acquired hypernatremia.

IMPORTANCE: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. OBJECTIVE: To assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. EXPOSURES: TTR V122I carrier status. MAIN OUTCOMES AND MEASURES: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured. RESULTS: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. CONCLUSIONS AND RELEVANCE: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center–based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.

Background Community-acquired pneumonia (CAP) is a common cause of hospitalization. While there are single-center studies on acute kidney injury requiring dialysis (AKI-D) and CAP, data on national trends and outcomes regarding AKI-D in CAP hospitalizations is lacking. Methods We utilized the Nationwide Inpatient Sample to analyze trends overall and within subgroups. We also utilized multivariate regression to adjust for potential confounders of annual trends and to generate adjusted odds ratios (aOR) for predictors and outcomes, including mortality and adverse discharge. Results There were 11,500,456 pneumonia hospitalizations between 2002 and 2013, of which 3675 (0.3%) were complicated by AKI-D. The AKI-D rate increased from 2.7/1000 hospitalizations in 2002 to 4.3/1000 hospitalizations in 2013. The rate of increase was higher in males and African Americans. Although temporal changes in demographics and comorbidities explained a substantial proportion, they could not explain the entire trend. The predictor with the highest odds of AKI-D required mechanical ventilation during hospitalization (aOR 12.47; 95% CI 11.66-13.34). Other significant predictors included sepsis (aOR 4.37; 95% CI 4.09-4.66), heart failure (aOR 2.40; 95% CI 2.25-2.55), and chronic kidney disease (CKD) (aOR 2.00; 95% CI 1.86-2.16). AKI-D was associated with increased in-hospital mortality (aOR 3.08; 95% CI 2.88-3.30) and adverse discharge (aOR 2.09; 95% CI 1.92-2.26). Although adjusted mortality decreased per year, attributable mortality remained stable. Conclusion Pneumonia hospitalizations complicated by AKI-D have increased with a differential increase by demographic groups. AKI-D is associated with significant morbidity and mortality. In the absence of effective AKI-D therapies, the focus should be on early risk stratification and prevention to avoid this devastating complication.

Novel biomarkers are needed to predict kidney function decline in patients with type 2 diabetes, especially those with preserved glomerular filtration rate (GFR). There are limited data on the association of markers of endothelial dysfunction with longitudinal GFR decline. We used banked specimens from a nested case-control study in the Action to Control Cardiovascular Disease (ACCORD) trial (n=187 cases: 187 controls) and from a diverse contemporary cohort of type 2 diabetic patients from the Mount Sinai BioMe Biobank (n=871) to assess the association of plasma endostatin and kidney outcomes. We measured plasma endostatin at enrollment and examined its association with a composite kidney outcome of sustained 40% decline in estimated GFR or end-stage renal disease. Baseline plasma endostatin levels were higher in participants with the composite outcome. Each log2 increment in plasma endostatin was associated with approximately 2.5-fold higher risk of the kidney outcome (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5-4.3 in ACCORD and adjusted hazard ratio [HR] 2.6; 95% CI 1.8-3.8 in BioMe). Participants in the highest vs. lowest quartile of plasma endostatin had approximately four-fold higher risk for the kidney outcome (adjusted OR 3.6; 95% CI 1.8-7.3 in ACCORD and adjusted HR 4.4; 95% CI 2.3-8.5 in BioMe). The AUC for the kidney outcome improved from 0.74 to 0.77 in BioMe with the addition of endostatin to a base clinical model. Plasma endostatin was strongly associated with kidney outcomes in type 2 diabetics with preserved eGFR and improved risk discrimination over traditional predictors.

Background The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS2°P), a 0‐to‐9‐point system based on the presence/absence of 9 clinical factors, was developed to classify the risk of major adverse cardiovascular events ( MACE ) (a composite of cardiovascular death, recurrent myocardial infarction, or ischemic stroke) among patients with a recent myocardial infarction. Its performance has not been examined internationally outside of a clinical trial setting. Methods and Results We evaluated the performance of TRS2°P for predicting MACE in 53 599 patients with recent myocardial infarction in 5 international cohorts from New Zealand, South Korea, Sweden, and the United States participating in the Chronic Kidney Disease Prognosis Consortium. Overall, there were 19 444 cases of MACE across 5 cohorts over a mean follow‐up of 5 years, and the overall MACE rate ranged from 5.0 to 18.4 (per 100 person‐years). The TRS2°P showed modest calibration (Brier score ranged from 0.144 to 0.173) and discrimination (C‐statistics >0.61 in all studies except 1 from Korea with 0.55) across cohorts relative to its original Brier score of 0.098 and C‐statistic of 0.67 in the derived data set. Although there was some heterogeneity across cohorts, the 9 predictors in the TRS2°P were generally associated with higher MACE risk, with strongest associations observed (meta‐analyzed adjusted hazard ratio 1.6–1.7) for history of heart failure, age ≥75 years, and prior stroke, followed by peripheral artery disease, kidney dysfunction, diabetes mellitus, and hypertension (hazard ratio 1.3–1.4). Prior coronary bypass graft surgery and smoking did not reach statistical significance (hazard ratio ≈1.1). Conclusions TRS2°P, a simple scoring system with 9 routine clinical factors, was modestly predictive of secondary events when applied in patients with recent myocardial infarction from diverse clinical and geographic settings.

BACKGROUND: Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-β/activin receptor-like kinase 1 (ALK1) signaling. However, LRG1’s role in the kidney, particularly in the setting of DKD, has been unclear. METHODS: We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes. RESULTS: LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes. CONCLUSIONS: These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

Simultaneous liver-kidney allocation protocols allocate dual organs based on a sustained eGFR of 30 mL/min or less. A 2017-UNOS update includes CKD3 as dual organ candidates but only when the listing eGFR is30 mL/min while recommending a "safety net" for prioritized kidney listing post-LT. We retrospectively reviewed adult LTs examine whether the UNOS proposal captured the LT population at highest risk for developing post-LT ESRD. Among 290 LT recipients, 67 had pre-LT CKD3, 141 had AKI, of whom 47 required dialysis (4 weeks). During follow-up, 25 (8.62%) developed ESRD, while 70 (24.1%) died. In adjusted Cox models, CKD3 had an independent association with post-LT ESRD (adjusted HR 4.8; P = 0.001), independent of AKI. Interestingly, CKD3 with listing GFR 30 mL/min was still significantly associated with post-LT ESRD. AKI was associated with reduced post-LT survival (adjusted HR 1.9; P = 0.02), albeit only in the first-year post-LT. Severe AKI-D was associated with post-LT ESRD and mortality. The safety net would have captured only 60% of all post-LT ESRD cases in our cohort. Pre-LT CKD3 was associated with increased risk of post-LT ESRD above the recommended cutoff for listing GFR. These findings, if generalizable in larger cohorts have important implications for dual organ allocation.

Identification of coding variant associations for complex diseases offers a direct route to biological insight, but is dependent on appropriate inference concerning the causal impact of those variants on disease risk. We aggregated coding variant data for 81,412 type 2 diabetes (T2D) cases and 370,832 controls of diverse ancestry, identifying 40 distinct coding variant association signals (at 38 loci) reaching significance (p−7). Of these, 16 represent novel associations mapping outside known genome-wide association study (GWAS) signals. We make two important observations. First, despite a threefold increase in sample size over previous efforts, only five of the 40 signals are driven by variants with minor allele frequency 1.29. Second, we used GWAS data from 50,160 T2D cases and 465,272 controls of European ancestry to fine-map these associated coding variants in their regional context, with and without additional weighting to account for the global enrichment of complex trait association signals in coding exons. At the 37 signals for which we attempted fine-mapping, we demonstrate convincing support (posterior probability >80% under the “annotation-weighted” model) that coding variants are causal for the association at 16 (including novel signals involving POC5 p.His36Arg, ANKH p.Arg187Gln, WSCD2 p.Thr113Ile, PLCB3 p.Ser778Leu, and PNPLA3 p.Ile148Met). However, at 13 of the 37 loci, the associated coding variants represent “false leads” and naïve analysis could have led to an erroneous inference regarding the effector transcript mediating the signal. Accurate identification of validated targets is dependent on correct specification of the contribution of coding and non-coding mediated mechanisms at associated loci.

Introduction: Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists have been introduced as novel antidiabetic agents, but their potential health impact in the US is unknown. We assessed the number of potentially eligible type 2 diabetes (T2D) patients, as well as projected changes in death and complication rates for nationwide use. Methods: Based on inclusion criteria of SGLT2i and GLP-1 receptor agonist RCTs, we determined eligibility in a weighted sample of 69.2M T2D patients from 2007-2014 National Health and Nutrition Examination Survey (NHANES) data. We employed a validated microsimulation model based on the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to simulate virtual life courses of eligible US patients. Pooled hazard ratios from meta-analyses of published RCTs were applied to model death and non-fatal adverse event rates with SGLT2i and GLP-1 receptor agonist use. Results: The proportion eligible in NHANES was 9.2% (95% CI 7.3-11.1), which translates into ~6.4M US adults. Simulated 10-year mortality (32.5%) decreased by 4.6% (95% CI 2.7-7.3) with SGLT2i and by 2.9% (95% CI 1.6-4.8) with GLP-1 receptor agonists. Mean life expectancy was 16.5 y, and increased by 1.3 y (95% CI 0.6-2.2) with SGLT2i and by 0.8 y (95% CI 0.4-1.5) with GLP-1 receptor agonists. With SGLT2i, lifetime heart failure risk decreased by 7.4% (95% CI 4.1-12.3) and end-stage renal disease (ESRD) risk decreased by 0.4% (95% CI -0.1-0.9). Improvements in these event risks were uncertain with GLP-1 receptor agonist use (Figure). With lifetime SGLT2i use, fracture risk increased from 16.9 to 22.4% (95% CI of Δ 2.5-9.6) and amputation risk rose from 5.7 to 11.2% (95% CI of Δ 2.3-9.5). Conclusions: Nationwide use of SGLT2i or GLP-1 receptor agonists may save over 8 or 5M life years, respectively. Moreover, SGLT2i may avoid over 470K new cases of heart failure and over 28K ESRD cases. Further research should illuminate whether these benefits outweigh additional costs and harms.

The number of patients with advanced heart failure receiving left ventricular assist device (LVAD) implantation has increased dramatically over the last decade. There are limited data available about the nationwide trends of complications leading to readmissions following implantation of contemporary devices. Patients undergoing LVAD implantation from January 2013 to December 2013 were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 37.66 from the healthcare cost and utilization project’s (HCUP) National Readmission Database (NRD). The top causes of unplanned 30-day readmission after LVAD implantation were determined. Survey logistic regression was used to analyze the significant predictors of readmission. In 2013, there were 2,235 patients with an LVAD implantation. Of them, 665 (29.7%) had at least one unplanned readmission within 30 days, out of which 289 (43.4%) occurred within 10 days post discharge. Implant complications (14.9%), congestive heart failure (11.7%) and gastrointestinal bleeding (8.4%) were the top 3 diagnoses for the first readmission and accounted for more than a third of all readmissions. Significant predictors of readmissions included a prolonged LOS during the index admission, Medicare insurance, and discharge to short term facility. In conclusion, despite increased experience with LVADs, unplanned readmissions within 30 days of implantation remain significantly high.

Background: Chronic kidney disease (CKD) patients who live far (>30 miles) from their nephrologist experience lower rates of clinic visit adherence, limited access to treatment, and higher rates of hospitalization and mortality than patients who live in close proximity to their nephrologist. Strategies to minimize disparities between urban and remotely located CKD patients are needed. The purpose of this study was to determine whether adherence to clinic visits and clinical outcomes in the remote management of CKD via telenephrology is comparable to in-person conventional care. Methods: Renal clinic adherence and composite outcomes of death, end-stage renal disease (ESRD), or doubling of serum creatinine (Cr) were measured in geographically remote Hudson Valley VA Medical Center (HVVAMC) CKD patients enrolled in telenephrology (n = 112) and CKD patients enrolled in the Bronx VAMC renal clinic (n = 116). Results: Prior to implementing the telenephrology service, 53.1% of scheduled visits of rural HVVAMC patients to the Bronx VAMC renal clinic were either cancelled or were “no-shows.” This was reduced by nearly half (28.5%) after instituting telenephrology (p < 0.001). Moreover, the frequency of attending appointments was greater in the telenephrology (71.9%) vs. in-person Bronx VA cohort (61.0%). The incidence of the composite outcome of death, ESRD, or doubling of Cr was similar between both groups (p = 0.96) over 2 years of follow-up. Conclusions: Remote CKD care delivered through telenephrology improves renal clinic visit adherence while delivering comparable renal outcomes. Application of this technology is a promising method to provide access to care to rural CKD patients and to minimize the disparity between urban/rural patients.

Background: Various medications are cleared by the kidneys, therefore patients with impaired renal function, especially dialysis patients are at risk for adverse drug events (ADEs). There are limited studies on ADEs in maintenance dialysis patients. Methods: We utilized a nationally representative database, the Nationwide Emergency Department Sample, from 2008 to 2013, to compare emergency department (ED) visits for dialysis and propensity matched non-dialysis patients. Log binomial regression was used to calculate relative risk of hospital admission and logistic regression to calculate ORs for in-hospital mortality while adjusting for patient and hospital characteristics. Results: While ED visits for ADEs decreased in both groups, they were over 10-fold higher in dialysis patients than non-dialysis patients (65.8–88.5 per 1,000 patients vs. 4.6–5.4 per 1,000 patients respectively, p < 0.001). The top medication category associated with ED visits for ADEs in dialysis patients is agents primarily affecting blood constituents, which has increased. After propensity matching, patient admission was higher in dialysis patients than non-dialysis patients, (88 vs. 76%, p < 0.001). Dialysis was associated with a 3% increase in risk of admission and 3 times the odds of in-hospital mortality (adjusted OR 3, 95% CI 2.7–2.3.3). Conclusions: ED visits for ADEs are substantially higher in dialysis patients than non-dialysis patients. In dialysis patients, ADEs associated with agents primarily affecting blood constituents are on the rise. ED visits for ADEs in dialysis patients have higher inpatient admissions and in-hospital mortality. Further studies are needed to identify and implement measures aimed at reducing ADEs in dialysis patients.

Background Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with APOL1 risk alleles—genetic variants associated with CKD risk commonly present in persons of African descent—may reveal novel markers of CKD progression relevant to other populations. Methods We evaluated associations between the number of APOL1 risk alleles and 760 serum metabolites identified via untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) ( n =588; Bonferroni significance threshold P −5 ) and replicated findings in 678 black participants with CKD in Bio Me , an electronic medical record–linked biobank. We tested the metabolite association with CKD progression in AASK, Bio Me , and the Modification of Diet in Renal Disease (MDRD) Study. Results One metabolite, 6-bromotryptophan, was significant in AASK ( P =4.7×10 −5 ) and replicated in Bio Me ( P =5.7×10 −3 ) participants, with lower levels associated with more APOL1 risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and Bio Me participants and in white participants in the MDRD Study, independent of demographics and clinical characteristics, including baseline GFR (adjusted hazard ratio per two-fold higher 6-bromotryptophan level, AASK, 0.76; 95% confidence interval [95% CI], 0.64 to 0.91; Bio Me , 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the APOL1 risk alleles and 6-bromotryptophan was not significant. The identity of 6-bromotryptophan was confirmed in experiments comparing its molecular signature with that of authentic standards of other bromotryptophan isomers. Conclusions Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression.

Background and Purpose: With the “weekend effect” being well described, the Brain Attack Coalition released a set of “best practice” guidelines in 2005, with the goal to uniformly provide standard of care to patients with stroke. We attempted to define a “weekend effect” in outcomes among patients with intracranial hemorrhage (ICH) over the last decade, utilizing the Nationwide Inpatient Sample (NIS) data. We also attempted to analyze the trend of such an effect. Materials and Methods: We determined the association of ICH weekend admissions with hospital outcomes including mortality, adverse discharge, length of stay, and cost compared to weekday admissions using multivariable logistic regression. We extracted our study cohort from the NIS, the largest all-payer data set in the United States. Results: Of 485 329 ICH admissions from 2002 to 2011, 27.5% were weekend admissions. Overall, weekend admissions were associated with 11% higher odds of in-hospital mortality. When analyzed in 3-year groups, excess mortality of weekend admissions showed temporal decline. There was higher mortality with weekend admissions in nonteaching hospitals persisted (odds ratios 1.16, 1.13, and 1.09, respectively, for 3-year subgroups). Patients admitted during weekends were also 9% more likely to have an adverse discharge (odds ratio 1.09; 95% confidence interval: 1.07-1.11; P < .001) with no variation by hospital status. There was no effect of a weekend admission on either length of stay or cost of care. Conclusion: Nontraumatic ICH admissions on weekends have higher in-hospital mortality and adverse discharge. This demonstrates need for in-depth review for elucidating this discrepancy and stricter adherence to standard-of-care guidelines to ensure uniform care.

Nontraumatic intracerebral hemorrhage (ICH) is associated with substantial morbidity and mortality. Do-not-resuscitate (DNR) orders are linked to poorer outcomes in patients with ICH, possibly due to less active management. Demographic, regional, and social factors, not related to ICH severity, have not been adequately looked at as significant predictors of DNR utilization. We reviewed the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample (NIS) database in 2011 for adult ICH admissions and DNR status. We generated hierarchical 2-level multivariate regression models to estimate adjusted odds ratios. We analyzed 25 768 ICH hospitalizations, 18% of which (4620 hospitalizations) had DNR orders, corresponding to national estimates of 126 254 and 22 668, respectively. In multivariable regression, female gender, white or Hispanic/Latino ethnicity, no insurance coverage, and teaching hospitals were significantly associated with increased DNR utilization after adjusting for confounders. There was also significantly more interhospital variability in the lowest quartile of hospital volume. In conclusion, demographic factors and insurance status are significantly associated with increased DNR utilization, with more individual hospital variability in low-volume hospitals. The reasons for this are likely qualitative and linked to patient, provider, and hospital practices.

Chronic hepatitis C virus (HCV) infection may cause kidney injury, particularly in the setting of cryoglobulinemia or cirrhosis; however, few studies have evaluated the epidemiology of acute kidney injury in patients with HCV. We aimed to describe national temporal trends of incidence and impact of severe acute kidney injury (AKI) requiring renal replacement 'dialysis-requiring AKI' in hospitalized adults with HCV. We extracted our study cohort from the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project using data from 2004 to 2012. We defined HCV and dialysis-requiring acute kidney injury based on previously validated ICD-9-CM codes. We analysed temporal changes in the proportion of hospitalizations complicated by dialysis-requiring AKI and utilized survey multivariable logistic regression models to estimate its impact on in-hospital mortality. We identified a total of 4,603,718 adult hospitalizations with an associated diagnosis of HCV from 2004 to 2012, of which 51,434 (1.12%) were complicated by dialysis-requiring acute kidney injury. The proportion of hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly from 0.86% in 2004 to 1.28% in 2012. In-hospital mortality was significantly higher in hospitalizations complicated by dialysis-requiring acute kidney injury vs those without (27.38% vs 2.95%; adjusted odds ratio: 2.09; 95% confidence interval: 1.74-2.51). The proportion of HCV hospitalizations complicated by dialysis-requiring acute kidney injury increased significantly between 2004 and 2012. Similar to observations in the general population, dialysis-requiring acute kidney injury was associated with a twofold increase in odds of in-hospital mortality in adults with HCV. These results highlight the burden of acute kidney injury in hospitalized adults with HCV infection.

Self-reported ancestry, genetically determined ancestry, and APOL1 polymorphisms are associated with variation in kidney function and related disease risk, but the relative importance of these factors remains unclear. We estimated the global proportion of African ancestry for 9048 individuals at Mount Sinai Medical Center in Manhattan (3189 African Americans, 1721 European Americans, and 4138 Hispanic/Latino Americans by self-report) using genome-wide genotype data. CKD-EPI eGFR and genotypes of three APOL1 coding variants were available. In admixed African Americans and Hispanic/Latino Americans, serum creatinine values increased as African ancestry increased (per 10% increase in African ancestry, creatinine values increased 1% in African Americans and 0.9% in Hispanic/Latino Americans; P≤1x10(-7)). eGFR was likewise significantly associated with African genetic ancestry in both populations. In contrast, APOL1 risk haplotypes were significantly associated with CKD, eGFR

Objective: The objective of this study was to describe the incidence of acute kidney injury (AKI) requiring renal replacement therapy (’dialysis-requiring AKI’) and the impact on in-hospital mortality among hospitalized adults with HIV infection. Design: A longitudinal analysis of a nationally representative administrative database. Methods: We reviewed the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample Database, a large, nationally representative sample of inpatient hospital admissions, to identify all adult hospitalizations with an associated diagnosis of HIV infection from 2002 to 2010. We analysed temporal trends in the incidence of dialysis-requiring AKI and the associated odds of in-hospital mortality. We also explored potential reasons behind temporal changes. Results: Among 183 0041 hospitalizations with an associated diagnosis of HIV infection, the proportion complicated by dialysis-requiring AKI increased from 0.7% in 2002 to 1.35% in 2010. This temporal rise was completely explained by changes in demographics and an increase in concurrent comorbidities and procedure utilization. The adjusted odds of in-hospital mortality associated with dialysis-requiring AKI also increased over the study period, from 1.45 [95% confidence interval (95% CI) 0.97–2.12] in 2002 to 2.64 (95% CI 2.04–3.42) in 2010. Conclusion: These data suggest that the incidence of dialysis-requiring AKI among hospitalized adults with HIV infection continues to increase, and that severe AKI remains a significant predictor of in-hospital mortality in this population. The increased incidence of dialysis-requiring AKI was largely explained by ageing of the HIV population and increasing prevalence of chronic non-AIDS comorbidities, suggesting that these trends will continue.

Background Hemodialysis (HD) access failure is a common cause of increased morbidity and healthcare cost in patients with end stage renal disease (ESRD). Percutaneous balloon angioplasty has been used to treat hemodialysis access stenosis but is complicated by a high rate of restenosis. Percutaneous cutting balloon (PCB) angioplasty is an alternative approach that has shown to reduce restenosis. Objectives The aim of the study is to assess the safety and efficacy of PCB angioplasty in comparison with conventional and high-pressure balloon angioplasty in the treatment of hemodialysis access site stenosis. Methods We searched PubMed, EMBASE and the Cochrane Central register of controlled trials (CENTRAL) databases through August 2014 and selected studies using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. We included all randomized clinical trials with a head-to-head comparison between PCB and conventional or high-pressure balloon angioplasty Results Three studies with 1034 participants (age 60.7 (±12.9) years and 50.1% males) with 525 in PCB and 509 in control arm were included in the analysis. The immediate procedural success rate was not significantly different in the PCB angioplasty and control arm respectively, (87.2% vs. 83.7% RD −0.02; 95%CI −0.06 to 0.01; P = 0.38). The six-month target lesion patency was significantly higher in the PCB angioplasty arm (67.2% vs. 55.6% RD 0.12; 95%CI 0.05–0.19; P

Introduction Clinical trials have shown a short-term benefit of drug-eluting stents (DES) compared to vascular brachytherapy (VBT) for treatment of in-stent restenosis (ISR). The long-term benefits of DES vs. VBT are conflicting in the literature. This study aimed to do a meta-analysis of long-term outcomes of DES compared to VBT for treatment of ISR. Methods PubMed, EMBASE, Cochrane Central and unpublished data were searched for cohort studies and randomized controlled trials (RCTs) that directly compared VBT to DES for the treatment of ISR. We evaluated the following outcomes at 2–5 years of follow-up: target lesion revascularization (TLR), target vessel revascularization (TVR), myocardial infarction (MI), stent thrombosis, cardiovascular (CV) mortality, and overall mortality. Heterogeneity was defined as I2 values > 25%. Review Manager 5.1 was used for statistical analysis. Results We included 1,375 patients from five studies, of which three were RCTs. VBT was used to treat ISR in 685 (49.8%) patients. After a 2–5 year follow-up, no significant differences were found between treatment groups regarding MI (P = 0.49), stent thrombosis (P = 0.86), CV mortality (P = 0.35), and overall mortality (P = 0.71). TLR (OR 2.37; CI 1.55–3.63; P