In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We ...discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
Abstract
Objective
Predictive analytics create opportunities to incorporate personalized risk estimates into clinical decision support. Models must be well calibrated to support decision-making, yet ...calibration deteriorates over time. This study explored the influence of modeling methods on performance drift and connected observed drift with data shifts in the patient population.
Materials and Methods
Using 2003 admissions to Department of Veterans Affairs hospitals nationwide, we developed 7 parallel models for hospital-acquired acute kidney injury using common regression and machine learning methods, validating each over 9 subsequent years.
Results
Discrimination was maintained for all models. Calibration declined as all models increasingly overpredicted risk. However, the random forest and neural network models maintained calibration across ranges of probability, capturing more admissions than did the regression models. The magnitude of overprediction increased over time for the regression models while remaining stable and small for the machine learning models. Changes in the rate of acute kidney injury were strongly linked to increasing overprediction, while changes in predictor-outcome associations corresponded with diverging patterns of calibration drift across methods.
Conclusions
Efficient and effective updating protocols will be essential for maintaining accuracy of, user confidence in, and safety of personalized risk predictions to support decision-making. Model updating protocols should be tailored to account for variations in calibration drift across methods and respond to periods of rapid performance drift rather than be limited to regularly scheduled annual or biannual intervals.
The study of acute kidney injury (AKI) has expanded with the increasing availability of electronic health records and the use of standardized definitions. Understanding the impact of AKI between ...settings is limited by heterogeneity in the selection of reference creatinine to anchor the definition of AKI. In this mini-review, we discuss different approaches used to select reference creatinine and their relative merits and limitations.
We reviewed the literature to obtain representative examples of published baseline creatinine definitions when pre-hospital data were not available, as well as literature evaluating the estimation of baseline renal function, using PubMed and reference back-tracing within known works.
(1) Pre-hospital creatinine values are useful in determining reference creatinine, and in high-risk populations, the mean outpatient serum creatinine value 7-365 days before hospitalization closely approximates nephrology adjudication, (2) in patients without pre-hospital data, the eGFR 75 approach does not reliably estimate true AKI incidence in most at-risk populations, (3) using the lowest inpatient serum creatinine may be reasonable, especially in those with preserved kidney function, but may generously estimate AKI incidence and severity and miss community-acquired AKI that does not fully resolve, (4) using more specific definitions of AKI (e.g., KIDGO stages 2 and 3) may help to reduce the effects of misclassification when using surrogate values and (5) leveraging available clinical data may help refine the estimate of reference creatinine.
Choosing reference creatinine for AKI calculation is important for AKI classification and study interpretation. We recommend obtaining data on pre-hospital kidney function, wherever possible. In studies where surrogate estimates are used, transparency in how they are applied and discussion that informs the reader of potential biases should be provided. Further work to refine the estimation of reference creatinine is needed.
Although the incidence of inflammatory bowel diseases (IBDs) varies with age, few studies have examined variations between the sexes. We therefore used population data from established cohorts to ...analyze sex differences in IBD incidence according to age at diagnosis.
We identified population-based cohorts of patients with IBD for which incidence and age data were available (17 distinct cohorts from 16 regions of Europe, North America, Australia, and New Zealand). We collected data through December 2016 on 95,605 incident cases of Crohn’s disease (CD) (42,831 male and 52,774 female) and 112,004 incident cases of ulcerative colitis (UC) (61,672 male and 50,332 female). We pooled incidence rate ratios of CD and UC for the combined cohort and compared differences according to sex using random effects meta-analysis.
Female patients had a lower risk of CD during childhood, until the age range of 10–14 years (incidence rate ratio, 0.70; 95% CI, 0.53–0.93), but they had a higher risk of CD thereafter, which was statistically significant for the age groups of 25–29 years and older than 35 years. The incidence of UC did not differ significantly for female vs male patients (except for the age group of 5–9 years) until age 45 years; thereafter, men had a significantly higher incidence of ulcerative colitis than women.
In a pooled analysis of population-based studies, we found age at IBD onset to vary with sex. Further studies are needed to investigate mechanisms of sex differences in IBD incidence.
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In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). The guideline was derived from evidence available ...through February 2011. Since then, new evidence has emerged that has important implications for clinical practice in diagnosing and managing AKI. In April of 2019, KDIGO held a controversies conference entitled Acute Kidney Injury with the following goals: determine best practices and areas of uncertainty in treating AKI; review key relevant literature published since the 2012 KDIGO AKI guideline; address ongoing controversial issues; identify new topics or issues to be revisited for the next iteration of the KDIGO AKI guideline; and outline research needed to improve AKI management. Here, we present the findings of this conference and describe key areas that future guidelines may address.
Inaccurate determination of baseline kidney function can misclassify acute kidney injury (AKI) and affect the study of AKI-related outcomes. No consensus exists on how to optimally determine baseline ...kidney function when multiple preadmission creatinine measurements are available.
The accuracy of commonly used methods for estimating baseline serum creatinine was compared with that of a reference standard adjudicated by a panel of board-certified nephrologists in 379 patients with AKI or CKD admitted to a tertiary referral center.
Agreement between estimating methods and the reference standard was highest when using creatinine values measured 7-365 days before admission. During this interval, the intraclass correlation coefficient (ICC) for the mean outpatient serum creatinine level (0.91 95% confidence interval (CI), 0.88-0.92) was higher than the most recent outpatient (ICC, 0.84 95% CI, 0.80-0.88; P<0.001) and the nadir outpatient (ICC, 0.83 95% CI, 0.76-0.87; P<0.001) serum creatinine. Using the final creatinine value from a prior inpatient admission increased the ICC of the most recent outpatient creatinine method (0.88 95% CI, 0.85-0.91). Performance of all methods declined or was unchanged when the time interval was broadened to 2 years or included serum creatinine measured within a week of admission.
The mean outpatient serum creatinine measured within a year of hospitalization most closely approximates nephrologist-adjudicated serum creatinine values.
Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in ...patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood.
We used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities.
PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4(th) ventricle volume but did not disrupt sensorimotor gating.
Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.
Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute ...kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial.
To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction.
The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022.
Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam.
The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days.
There were 2511 patients included in the primary analysis (median age, 58 years IQR, 43-69 years; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 95% CI, 0.80 to 1.13, P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients 10.2% in the cefepime group vs 114 patients 8.8% in the piperacillin-tazobactam group; absolute difference, 1.4% 95% CI, -1.0% to 3.8%). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean SD, 11.9 4.6 days vs 12.2 4.3 days in the piperacillin-tazobactam group; odds ratio, 0.79 95% CI, 0.65 to 0.95).
Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction.
ClinicalTrials.gov Identifier: NCT05094154.
Studies of acute kidney injury usually lack data on pre-admission kidney function and often substitute an inpatient or imputed serum creatinine as an estimate for baseline renal function. In this ...study, we compared the potential error introduced by using surrogates such as (1) an estimated glomerular filtration rate of 75 ml/min per 1.73 m2 (suggested by the Acute Dialysis Quality Initiative), (2) a minimum inpatient serum creatinine value, and (3) the first admission serum creatinine value, with values computed using pre-admission renal function. The study covered a 12-month period and included a cohort of 4863 adults admitted to the Vanderbilt University Hospital. Use of both imputed and minimum baseline serum creatinine values significantly inflated the incidence of acute kidney injury by about half, producing low specificities of 77–80%. In contrast, use of the admission serum creatinine value as baseline significantly underestimated the incidence by about a third, yielding a low sensitivity of 39%. Application of any surrogate marker led to frequent misclassification of patient deaths after acute kidney injury and differences in both in-hospital and 60-day mortality rates. Our study found that commonly used surrogates for baseline serum creatinine result in bi-directional misclassification of the incidence and prognosis of acute kidney injury in a hospital setting.
Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the ...attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC.
Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute.
For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities.
Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.
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