Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest Trial (GOT ICE): A Randomized Clinical Trial Comparing Outcomes After Aortic Arch Surgery.

BACKGROUND: Deep hypothermia has been the standard for hypothermic circulatory arrest (HCA) during aortic arch surgery. However, centers worldwide have shifted toward lesser hypothermia with antegrade cerebral perfusion. This has been supported by retrospective data, but there has yet to be a multicenter, prospective randomized study comparing deep versus moderate hypothermia during HCA. METHODS: This was a randomized single-blind trial (GOT ICE [Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest]) of patients undergoing arch surgery with HCA plus antegrade cerebral perfusion at 4 US referral aortic centers (August 2016-December 2021). Patients were randomized to 1 of 3 hypothermia groups: DP, deep (≤20.0 °C); LM, low-moderate (20.1-24.0 °C); and HM, high-moderate (24.1-28.0 °C). The primary outcome was composite global cognitive change score between baseline and 4 weeks postoperatively. Analysis followed the intention-to-treat principle to evaluate if: (1) LM noninferior to DP on global cognitive change score; (2) DP superior to HM. The secondary outcomes were domain-specific cognitive change scores, neuroimaging findings, quality of life, and adverse events. RESULTS: A total of 308 patients consented; 282 met inclusion and were randomized. A total of 273 completed surgery, and 251 completed the 4-week follow-up (DP, 85 [34%]; LM, 80 [34%]; HM, 86 [34%]). Mean global cognitive change score from baseline to 4 weeks in the LM group was noninferior to the DP group; likewise, no significant difference was observed between DP and HM. Noninferiority of LM versus DP, and lack of difference between DP and HM, remained for domain-specific cognitive change scores, except structured verbal memory, with noninferiority of LM versus DP not established and structured verbal memory better preserved in DP versus HM (P = 0.036). There were no significant differences in structural or functional magnetic resonance imaging brain imaging between groups postoperatively. Regardless of temperature, patients who underwent HCA demonstrated significant reductions in cerebral gray matter volume, cortical thickness, and regional brain functional connectivity. Thirty-day in-hospital mortality, major morbidity, and quality of life were not different between groups. CONCLUSIONS: This randomized multicenter study evaluating arch surgery HCA temperature strategies found low-moderate hypothermia noninferior to traditional deep hypothermia on global cognitive change 4 weeks after surgery, although in secondary analysis, structured verbal memory was better preserved in the deep group. The verbal memory differences in the low- and high-moderate groups and structural and functional connectivity reductions from baseline merit further investigation and suggest opportunities to further optimize brain perfusion during HCA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02834065.

Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS). METHODS: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases. RESULTS: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model. CONCLUSIONS: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.

HLA-B*53:01 Is a Significant Risk Factor of Liver Injury due to Phenytoin and Other Antiepileptic Drugs in African Americans.

INTRODUCTION: To investigate human leukocyte antigen alleles associated with liver injury due to antiepileptic drugs (AEDs) in African Americans (AA). METHODS: In this study, 21 AA with AED drug-induced liver injury (DILI), 176 AA with DILI due to non-AEDs, and 5816 AA population controls were included. RESULTS: HLA-B*53:01 was significantly associated with aromatic AED-DILI (odds ratio: 4.52, 95% confidence interval: 2.42-8.44, P = 1.46 × 10 -5 ). Phenytoin DILI showed the strongest association with HLA-B*53:01 (odds ratio: 9.17; 95% confidence interval: 3.61-23.28, P = 1.1 × 10 -5 ). The HLA-B*53:01 allele was carried by 8 of 9 AA phenytoin DILI cases. DISCUSSION: HLA-B*53:01 is a significant risk factor of liver injury due to antiepileptics, particularly phenytoin, in AA.

ERAP-1 and ERAP-2 Variants in Liver Injury After COVID-19 mRNA Vaccination: A US Multicenter Study.

INTRODUCTION: The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination. METHODS: Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform. RESULTS: Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively). DISCUSSION: Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

Serum proteomic biomarkers diagnostic of knee osteoarthritis.

OBJECTIVE: To better understand the pathogenesis of knee osteoarthritis (OA) through identification of serum diagnostics. DESIGN: We conducted multiple reaction monitoring mass spectrometry analysis of 107 peptides in baseline sera of two cohorts: the Foundation for National Institutes of Health (NIH) (n = 596 Kellgren-Lawrence (KL) grade 1-3 knee OA participants); and the Johnston County Osteoarthritis Project (n = 127 multi-joint controls free of radiographic OA of the hands, hips, knees (bilateral KL=0), and spine). Data were split into (70%) training and (30%) testing sets. Diagnostic peptide and clinical data predictors were selected by random forest (RF); selection was based on association (p < 0.05) with OA status in multivariable logistic regression models. Model performance was based on area under the curve (AUC) of receiver operating characteristic (ROC) and precision-recall (PR) curves. RESULTS: RF selected 23 peptides (19 proteins) and body mass index (BMI) as diagnostic of OA. BMI weakly diagnosed OA (ROC-AUC 0.57, PR-AUC 0.812) and only symptomatic OA cases. ACTG was the strongest univariable predictor (ROC-AUC 0.705, PR-AUC 0.897). The final model (8 serum peptides) was highly diagnostic (ROC-AUC 0.833, 95% confidence interval [CI] 0.751, 0.905; PR-AUC 0.929, 95% CI 0.876, 0.973) in the testing set and equally diagnostic of non-symptomatic and symptomatic cases (AUCs 0.830-0.835), and not significantly improved with addition of BMI. The STRING database predicted multiple high confidence interactions of the 19 diagnostic OA proteins. CONCLUSIONS: No more than 8 serum protein biomarkers were required to discriminate knee OA from non-OA. These biomarkers lend strong support to the involvement and cross-talk of complement and coagulation pathways in the development of OA.

Precisely modeling zero-inflated count phenotype for rare variants.

Count data with excessive zeros are increasingly ubiquitous in genetic association studies, such as neuritic plaques in brain pathology for Alzheimer's disease. Here, we developed gene-based association tests to model such data by a mixture of two distributions, one for the structural zeros contributed by the Binomial distribution, and the other for the counts from the Poisson distribution. We derived the score statistics of the corresponding parameter of the rare variants in the zero-inflated Poisson regression model, and then constructed burden (ZIP-b) and kernel (ZIP-k) tests for the association tests. We evaluated omnibus tests that combined both ZIP-b and ZIP-k tests. Through simulated sequence data, we illustrated the potential power gain of our proposed method over a two-stage method that analyzes binary and non-zero continuous data separately for both burden and kernel tests. The ZIP burden test outperformed the kernel test as expected in all scenarios except for the scenario of variants with a mixture of directions in the genetic effects. We further demonstrated its applications to analyses of the neuritic plaque data in the ROSMAP cohort. We expect our proposed test to be useful in practice as more powerful than or complementary to the two-stage method.

Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.

BACKGROUND & AIMS: Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN). METHODS: Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661). RESULTS: Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10-4), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10-5), and non-NTF DILI (OR 3.34, p = 0.003). CONCLUSION: NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies. IMPACT AND IMPLICATIONS: Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.

The Impact of Patient Age and Corticosteroids in Patients With Sulfonamide Hepatotoxicity.

INTRODUCTION: Sulfonamides are widely used to treat and prevent various bacterial and opportunistic infections. The aim of this study was to describe the clinical presentation and outcomes of a large cohort of patients with sulfonamide hepatotoxicity. METHODS: Between 2004 and 2020, 105 patients with hepatotoxicity attributed to trimethoprim/sulfamethoxazole (TMP-SMZ) (n = 93) or other sulfonamides (n = 12) were enrolled. Available liver biopsies were reviewed by a single hepatopathologist. RESULTS: Among the 93 TMP-SMZ cases, 52% were female, 7.5% younger than 20 years, and the median time to drug-induced liver injury (DILI) onset was 22 days (range: 3-157). Younger patients were significantly more likely to have rash, fever, eosinophilia, and a hepatocellular injury pattern at onset that persisted at the peak of liver injury compared with older patients ( P < 0.05). The 18 (19%) TMP-SMZ patients treated with corticosteroids had more severe liver injury and a higher mortality but a trend toward more rapid normalization of their laboratory abnormalities compared with untreated patients. During follow-up, 6.2% of the TMP-SMZ patients died or underwent liver transplantation. Chronic DILI developed in 20% and was associated with cholestatic injury at onset and higher peak total bilirubin levels. DISCUSSION: Sulfonamide hepatotoxicity is characterized by a short drug latency with frequent hypersensitivity features at onset. Subject age is an important determinant of the laboratory profile at presentation, and patients with cholestasis and higher total bilirubin levels were at increased risk of developing chronic DILI. Corticosteroids may benefit a subgroup of patients with severe injury, but further studies are needed.

Maternal Cardiovascular Morbidity Events Following Preeclampsia: A Retrospective Cohort Study.

BACKGROUND: Patients with preeclampsia are at high risk for long-term cardiovascular events, yet the short-term, acute cardiovascular complications that follow preeclampsia are understudied. The objective of this study was to compare the short-term, acute maternal cardiovascular morbidity events after delivery among patients with a diagnosis of preeclampsia versus those without this diagnosis. METHODS: In this retrospective cohort study, the Premier inpatient database was used to examine a cohort of obstetric patients older than 18 years, who delivered from January 1, 2016, to September 30, 2020. A diagnosis of preeclampsia and preeclampsia with severe features during delivery hospitalization were the exposures of interest. The primary outcome was a composite of maternal cardiovascular morbidity events during delivery hospital admission. The secondary outcome was the occurrence of maternal cardiovascular morbidity events during a readmission within 90 days of delivery hospitalization. RESULTS: In total, 4,488,759 patients met inclusion criteria, of which 158,114 (3.5%) were diagnosed with preeclampsia without severe features, and 117,940 (2.6%) with preeclampsia with severe features. Adjusted odds of maternal cardiovascular morbidity events were higher in patients with preeclampsia and in those with preeclampsia with severe features compared with those without preeclampsia during delivery hospitalization (adjusted odds ratio [OR] [95% confidence interval {CI}] 1.87 [1.78-1.97] and 4.74 [4.44-5.05], respectively) and within 90 days (adjusted OR [95% CI] 2.01 [1.83-2.21] and 2.32 [2.10-2.57], respectively). CONCLUSIONS: Patients with both preeclampsia and preeclampsia with severe features have higher rates of maternal cardiovascular morbidity events than those without preeclampsia. Future studies are necessary to examine which patients with preeclampsia are at highest risk for cardiovascular complications.

Identification of novel genes for age-at-onset of Alzheimer's disease by combining quantitative and survival trait analyses.

INTRODUCTION: Our understanding of the genetic predisposition for age-at-onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any have sex-specific effects. METHODS: Genome-wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome. RESULTS: We identified 11 genome-wide significant loci (P < 5 × 10-8 ), including six known AD-risk genes and five novel loci, UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25, affecting AAO of AD. Additionally, 39 suggestive loci showed strong association. Twelve loci showed sex-specific effects on AAO including CD300LG and MLX/TUBG2 for females and MIR4445 for males. DISCUSSION: Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD.

An exploration of genetic association tests for disease risk and age at onset.

Risk genes influence the chance of an individual developing disease over their lifetime, although the age at onset (AAO) genes influence disease timing. These two categories are not disjoint; a gene that influences AAO might also appear to influence the risk. When an allele influences both AAO and risk, a reasonable question is whether we would have more power to detect association using a statistical test based on risk or AAO. To address this question, we compared power analytically for the Cochran-Armitage trend case-control test for risk and a linear regression case-only test for AAO. We also used simulations to compare the power of these tests with a 2-degree of freedom joint test (which combines the risk and AAO statistics) and the Cox proportional hazards survival model testing AAO (with censored data in controls). We found that when there is little heterogeneity, the case-control risk test has more power than the case-only AAO test (with equivalent sample sizes), but when the model is complex (e.g., with heterogeneity or reduced penetrance), the relationship reverses. The joint test generally outperforms the risk or AAO test alone and ultimately is our recommendation as a powerful alternative in many scenarios.

Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury.

BACKGROUND & AIMS: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS. RESULTS: Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13-223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10-6). CONCLUSIONS: The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. CLINICAL TRIALS: gov number: NCT00345930.

Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With Trimethoprim-Sulfamethoxazole Induced Liver Injury.

BACKGROUND AND AIMS: Trimethoprim (TMP)-sulfamethoxazole (SMX) is an important cause of idiosyncratic drug-induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well-characterized cases of TMP-SMX DILI. APPROACH AND RESULTS: European American and African American persons with TMP-SMX DILI were compared with respective population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, San Diego, CA) for cases. The HLA genotype imputation with attribute bagging program was used to impute HLA alleles for controls. The allele frequency difference between case patients and controls was tested by Fisher's exact tests for each ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test the HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess HLA binding with TMP and SMX. The European American subset had 51 case patients and 12,156 controls, whereas the African American subset had 10 case patients and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA-B*14:01 ranking at the top (odds ratio, 9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate adjustment. All carriers of HLA-B*14:01 with TMP-SMX DILI possessed HLA-C*08:02, another significant allele (P = 0.0026). This pattern was supported by HLA-B*14:01-HLA-C*08:02 haplotype association (P = 1.33 × 10-5 ). For the African American patients, HLA-B*35:01 had 2.8-fold higher frequency in case patients than in controls, with 5 of 10 patients carrying this allele. Molecular docking showed cysteine at position 67 in HLA-B*14:01 and phenylalanine at position 67 in HLA-B*35:01 to be the predictive binding sites for SMX metabolites. CONCLUSIONS: HLA-B*14:01 is associated with TMP-SMX DILI in European Americans, and HLA-B*35:01 may be a potential genetic risk factor for African Americans.

HLA-B*35:01 and Green Tea-Induced Liver Injury.

BACKGROUND AND AIMS: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

Allopurinol hepatotoxicity is associated with human leukocyte antigen Class I alleles.

BACKGROUND/AIMS: Allopurinol can cause HLA class I-associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinol hepatotoxicity are unknown. METHODS: Eleven of 17 patients with suspected allopurinol hepatotoxicity enrolled into the Drug-Induced Liver Injury Network were adjudicated as definite, highly likely, or probable. High-resolution HLA sequencing was undertaken in cases and compared with population and other DILI controls. RESULT: Median age was 60 years, 54% were male, and 63% African- American, 27% Caucasian, and 9% Hispanic. Patients presented at a median of 52 days after starting allopurinol, all were hospitalized and six were jaundiced. The median peak ALT, alkaline phosphatase, and total bilirubin were 525 U/L, 521 U/L, and 7.8 mg/dl, respectively, with a median R ratio of 2.7 at onset. During follow-up, nine patients were treated with corticosteroids including five of the six with suspected DRESS. Three patients died including two from liver failure at 38 and 45 days after onset, and the remaining eight recovered. Three HLA alleles were found to be overrepresented in allopurinol cases, particularly in African Americans: HLA-B*58:01, which has been previously linked to severe skin reactions, and HLA-B*53:01 and HLA-A*34:02, all of which are more frequently found in African Americans than European Americans or Latinos. CONCLUSIONS: Allopurinol hepatotoxicity is associated with systemic hypersensitivity, a short latency to onset, African-American race and three HLA risk alleles, HLA-B*58:01, HLA-B*53:01, and HLA-A*34:02-58:01 testing may help confirm a diagnosis of hepatotoxicity in allopurinol-treated patients.

Unplanned hospital admission after ambulatory surgery: a retrospective, single cohort study.

PURPOSE: We estimated the rate of unplanned hospital and intensive care unit (ICU) admissions following ambulatory surgery centre (ASC) procedures, and identified factors associated with their occurrence. METHODS: This retrospective cohort included adult patients who underwent ASC procedures within a large community practice from January 2010 to December 2014. Patients were categorized into two groups: unplanned postoperative hospital/ICU admission within 24 hr of procedure or uneventful discharge. Demographics, comorbidities, anesthesia type, procedure type, procedure group, and ASC facility were assessed. RESULTS: Of the 211,389 patients included, there were 211,147 uneventful discharges (99.89%) and 242 unplanned hospital admissions (0.11%), of which 75 were ICU admissions (0.04%). The multivariable logistic regression model for hospital admission showed an increased risk associated with age > 50 yr (odds ratio [OR], 1.53); American Society of Anesthesiologists (ASA) physical status (III vs II: OR, 1.45; IV vs II: OR, 1.88), comorbidity (chronic obstructive pulmonary disease: OR, 2.63; diabetes mellitus: OR, 1.62; transient ischemic attack: OR, 2.48) procedure (respiratory: OR, 2.92; digestive: OR, 2.66; musculoskeletal system: OR, 2.53), anesthetic management (general anesthesia [GA] and peripheral nerve block vs GA: OR, 1.79), and ASC facility (189BB: OR, 2.29; 30E9A: OR, 7.41; and BD21F: OR, 1.69). The multivariable logistic regression model for ICU admission showed increased risk of unplanned ICU admission associated with ASA physical status (ASA III vs II: OR, 3.0; ASA IV vs II: OR, 8.52), procedure (musculoskeletal system: OR, 2.45), and ASC facility (00E6C: OR, 3.14; 189BB: OR, 2.77; 30E9A: OR, 2.59; and BD21F: OR, 3.71). CONCLUSION: While a small percentage of adult patients who underwent ASC procedures required unplanned hospital admission (0.07%), approximately one-third of these admissions were to the ICU (0.04%). Facility was at least as strong a predictor of hospital admission as the patient- and/or procedure-specific variables.

RéSUMé: OBJECTIF: Nous avons estimé le taux d'admissions non planifiées à l'hôpital et à l'unité de soins intensifs (USI) après des interventions dans des centres de chirurgie ambulatoire (CCA), et identifié les facteurs associés à leur survenue. MéTHODE: Cette étude de cohorte rétrospective a porté sur des patients adultes ayant subi une intervention dans un CCA appartenant à une grande pratique communautaire entre janvier 2010 et décembre 2014. Les patients ont été catégorisés en deux groupes : admission postopératoire non planifiée à l'hôpital/USI dans les 24 h suivant l'intervention ou congé sans incident. Les données démographiques, les comorbidités, le type d'anesthésie, le type d'intervention, le groupe d'intervention et l'établissement de CCA ont été évalués. RéSULTATS: Parmi les 211 389 patients inclus, il y a eu 211 147 congés sans incident (99,89 %) et 242 admissions non planifiées à l'hôpital (0,11 %), 75 desquelles étaient des admissions à l'USI (0,04 %). Le modèle de régression logistique multivariée des admissions hospitalières a montré un risque accru associé à un âge > 50 ans (rapport de cotes [RC], 1,53); au statut physique ASA (American Society of Anesthesiologists) (III vs II : RC, 1,45; IV vs II : RC, 1,88), aux comorbidités (maladie pulmonaire obstructive chronique : RC, 2,63; diabète: RC, 1,62; accident ischémique transitoire : RC, 2,48); à l'intervention (respiratoire : RC, 2,92; digestive : RC, 2,66; appareil locomoteur : RC, 2,53); à la prise en charge anesthésique (anesthésie générale [AG] et bloc nerveux périphérique vs AG : RC, 1,79) et établissement de CCA (189BB : RC, 2,29; 30E9A : RC, 7,41; et BD21F : RC, 1,69). Le modèle de régression logistique multivariée des admissions à l'USI a montré un risque accru d'admission non planifiée à l'USI associé au statut physique ASA (ASA III vs II: RC, 3,0; ASA IV vs II: RC, 8,52), à l'intervention (appareil locomoteur : RC, 2,45), et à l'établissement de CCA (00E6C: RC, 3,14; 189BB: RC, 2,77; 30E9A: RC, 2,59; et BD21F: RC, 3,71). CONCLUSION: Alors qu'un faible pourcentage de patients adultes ayant subi des interventions en CCA ont nécessité une admission non planifiée à l'hôpital (0,11 %), environ un tiers de ces admissions étaient à l'USI (0,04 %). L'établissement était un prédicteur au moins aussi puissant d'admission à l'hôpital que les variables spécifiques au patient et/ou à l'intervention.

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.

OBJECTIVE: Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described. DESIGN: Retrospective cohort. SETTING: Single-center university hospital. PARTICIPANTS: A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015. INTERVENTIONS: The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution. MEASUREMENTS AND MAIN RESULTS: Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q3 = 32.6 v CUF < Q1 = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001). CONCLUSIONS: Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.

A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.

BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.

A comparison of antibiotic prophylaxis regimens to decrease the risk of post-procedure urinary tract infection after onabotulinum toxin A injection.

INTRODUCTION AND HYPOTHESIS: To evaluate the risk of post-injection urinary tract infection (UTI) after onabotulinumtoxin A (BTX-A) treatment based on the timing of when antibiotic prophylaxis is started. METHODS: This is a retrospective cohort study of 111 women with refractory idiopathic overactive bladder who underwent intradetrusor injection of BTX-A. Two cohorts were identified: (1) 67 women who started antibiotic prophylaxis with ciprofloxacin 1 day prior to injection; (2) 44 women who received antibiotic prophylaxis with ciprofloxacin after injection only. We assessed for post-injection UTI within 90 days after BTX-A. Multivariable logistic regression was performed to adjust for potential confounders. RESULTS: One hundred eleven women underwent BTX-A. In total, 30 (27%) had a UTI within 90 days; these included 15/67 (22%) of those who started antibiotics 1 day prior to injection and 15/44 (34%) of those receiving antibiotics after injection. While the unadjusted analysis showed no significant associations between timing of antibiotic administration and UTI (OR = 0.56; 95% CI = 0.24, 1.30; p = 0.18), an adjusted analysis showed the pre-procedure antibiotic group had a significant reduction in post-procedure UTI after controlling for age, history of UTI, diabetes, and urinary retention requiring catheterization (OR = 0.23; 95% CI = 0.07, 0.73; p = 0.01). CONCLUSIONS: Starting antibiotics 1 day prior to BTX-A injection decreases the odds of post-injection UTI compared with women who use post-procedure antibiotic prophylaxis over shorter duration. Consideration should be given to beginning antibiotic prophylaxis prior to the procedure and continuing it for 4 total days to decrease the risk of UTI.

Apolipoprotein L1 (APOL1) Coding Variants Are Associated With Creatinine Rise After Cardiac Surgery.

OBJECTIVE: Acute kidney injury (AKI) is a complication of cardiac surgery that is considerably more common in African Americans (1.5-fold). Although homozygous status for apolipoprotein L1 (APOL1) risk alleles is associated with chronic kidney disease in individuals of African ancestry, whether these coding variants confer AKI risk is unknown. The present study examined whether APOL1 homozygous risk allele status was associated with AKI in African Americans after cardiac surgery. DESIGN: Retrospective analysis of a cohort. SETTING: Single-center university hospital. PARTICIPANTS: African American patients from the CATHeterization GENetics study cohort who underwent cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Genotyping of APOL1 alleles. MEASUREMENTS AND MAIN RESULTS: Data from 125 African American patients included 12 APOL1 risk (ie, homozygous for risk alleles) patients and 113 APOL1 control (ie, wildtype or heterozygous for risk alleles) patients. The primary outcome to reflect AKI was peak serum creatinine rise after surgery relative to the preoperative creatinine (%ΔCr). The secondary outcome was Kidney Disease: Improving Global Outcomes (KDIGO) AKI criteria. In the primary analysis, peak creatinine rise was higher in risk compared with control patients in both univariate (%ΔCr 69.1 v 29.6%; p = 0.005) and multivariate regression (%ΔCr 88.5 v 43.7%; p = 0.006) analyses. For the secondary outcome, a trend toward KDIGO AKI development was noted in APOL1 risk patients, but this was not statistically significant. CONCLUSIONS: African American cardiac surgery patients homozygous for APOL1 chronic kidney disease risk variants averaged a more than 2-fold higher postoperative creatinine rise even after adjustment for other risk factors, suggesting these alleles also are independent risk factors for AKI.