Citations

Study Objective Serum creatinine ( S c r ) concentration is used to calculate estimated glomerular filtration rate (e GFR ) for medication dosing. Serum cystatin C (CysC) concentration has been proposed as an adjunct or alternative to S cr . This study sought to evaluate the possible impact of using CysC in eGFR equations on drug dose recommendations in hospitalized patients with infections. Design Retrospective analysis of prospectively collected data. Setting Large academic tertiary care medical center. Patients A total of 308 adults with suspected or documented infections and stable kidney function who were hospitalized between 2012 and 2015. Measurements and Main Results Standardized S c r and CysC measured at the time of antibiotic dosing were used to estimate GFR from the three Chronic Kidney Disease Epidemiology Collaborative ( CKD ‐ EPI ) equations using S c r (eGFR Cr ), CysC( eGFR CysC ), or a combination of S c r and CysC (eGFR Cr‐CysC ), and these values were compared with estimated creatinine clearance (eCl cr ) from the Cockcroft‐Gault equation (standard of care for drug dosage adjustments). The eGFR s were categorized into five common dosage adjustment strata (lower than 20, 20–49, 50–79, 80–130, and higher than 130 ml/min), and agreement between equations was tested with the weighted κ statistic. Recommended drug doses varied considerably between the eC l cr and the CKD ‐ EPI equations (weighted κ [95% confidence interval]: eGFR Cr 0.73 [0.68–0.79], eGFR CysC 0.42 [0.35–0.5], eGFR Cr‐CysC 0.65 [0.6–0.71]). If eGFR Cr, eGFR CysC , or eGFR Cr‐CysC were used instead of eC l cr to dose drugs, 11%, 12%, and 8% of doses, respectively, would be higher, and 12%, 38%, and 24% of doses, respectively, would be lower. Conclusion Significant discordance in drug doses was observed when the CKD ‐ EPI equations were used in place of eCl cr . When CysC was included in eGFR equations, recommended doses were often lower. Further study is needed to develop and test drug‐specific dosing guidelines that incorporate alternate renal biomarkers and/or more contemporary eGFR equations.

Abstract BACKGROUND Emergency department (ED) overuse is a costly and often neglected source of postdischarge resource utilization after spine surgery. Failing to investigate drivers of ED visits represents a missed opportunity to improve the value of care in spine patients. OBJECTIVE To identify the prevalence, drivers, and timing of ED visits following elective spine surgery. METHODS Patients undergoing elective spine surgery for degenerative disease at a major medical center were enrolled in a prospective longitudinal registry. Patient and surgery characteristics, and patient-reported outcomes were recorded at baseline and 3 mo after surgery, along with self-reported 90-d ED visits. A multivariable regression model was used to identify independent factors associated with 90-d ED visits. For a sample of patients presenting to our institution's ED, charts were reviewed to identify the reason and time to ED postdischarge. RESULTS Of 2762 patients, we found a 90-d ED visit rate of 9.4%. One-third of patients presented to our institution's ED and of these, 70% presented due to pain or medical concerns at 9 and 7 d postdischarge, respectively, with 60% presenting outside normal clinic hours. Independent risk factors for 90-d ED visits included younger age, preoperative opioid use, chronic obstructive pulmonary disorder, and more vertebral levels involved. CONCLUSION Nearly 10% of elective spine patients had 90-d ED visits not requiring readmission. Pain and medical concerns accounted for 70% of visits at our center, occurring within 10 d of discharge. This study provides the clinical details and a timeline necessary to guide individualized interventions to prevent unnecessary, costly ED visits after spine surgery.

Abstract Over 50 genetic variants have been associated with colorectal cancer (CRC) risk through genome-wide association studies (GWAS), yet these variants represent only a fraction of the total estimated heritability. CRC is a heterogenous disease with diverse tumor etiology. Assessing genetic risk in molecular subtypes may help to identify novel loci and characterize genetic risk among tumor subtypes. We used microsatellite instability (MSI), an established CRC classifier with etiological and therapeutic relevance, to define CRC subtypes for GWAS analyses. We conducted a case-case analysis to estimate odds ratios (OR) and 95% confidence intervals (CI) for association of genome-wide variants with microsatellite stable (MSS) versus unstable (MSI) carcinomas. We ran an inverse-variance weighted fixed-effects meta-analysis across GWAS in a discovery set of 4,163 population-based CRC cases with harmonized microsatellite instability (MSI) marker and imputed genotype data. For each analysis, we used log-additive logistic regression, adjusting for age, sex, and principal components to account for population substructure. We then followed up with replication of 102 SNPs that reached p-values less than 5x10-6 in 1,698 cases. A total of 845 (20.3%) cancer cases were microsatellite unstable in the discovery population and 174 (10.2%) were unstable in the replication population. No variants reached the genome-wide significance level of 5x10-8 in the discovery set. However, we identified two variants that reached a Bonferroni corrected p-value of 4.0x10-4 in the replication set. This included one variant in MLH1 (Replication: OR=1.74, 95% CI=1.53-1.98, p=1.63x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76x10-11) and one variant in LOC105377645 (Replication: OR=1.70, 95% CI=1.49-1.94, p=5.13x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76 x 10-11). The MLH1 gene is a DNA mismatch repair gene implicated in Lynch Syndrome, the hallmark of which is microsatellite instability. This is the first genome-wide scan to identify a common variant in MLH1 that is associated with CRC. This variant (minor allele frequency, MAF = 23% in this all European ancestry population) is located in the 5'-untranslated region of MLH1 and is thought to act as a long-range regulator of DCLK3, a potential tumor driver gene. The second variant, located in LOC105377645 with an MAF of 22%, is in an uncharacterized region of the genome and has not previously been implicated in cancer development. These findings suggest that accounting for molecular heterogeneity is important for discovery and characterization of genetic variants associated with CRC risk. We plan to run polytomous regression analyses, increase our sample size, and further investigate CRC subtypes by CIMP, BRAF mutation, KRAS mutation status. Citation Format: Tabitha A. Harrison, Yiwen Lu, Chenjie Zeng, Flora Qu, Kristin Anderson, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Andrew T. Chan, Jenny Chang-Claude, Graham G. Giles, Bethany Van Guelpen, Michael Hoffmeister, Mark A. Jenkins, Noralane M. Lindor, Roger L. Milne, Polly A. Newcomb, Reiko Nishihara, Michael O. Woods, Shuji Ogino, John D. Potter, Martha L. Slattery, Wei Sun, Stephen N. Thibodeau, Li Hsu, Ulrike Peters. Genome-wide association study by colorectal carcinoma subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 229.

Abstract Multiple myeloma (MM) is twice as common in African Americans (AA) compared to European Americans (EA). The reported familial clustering and the elevated MM risk among first-degree relatives of cases implicate genetic susceptibility. Previous genome-wide association studies (GWAS) in EA have identified 16 novel risk loci. In this study, we tested the generalizability of the established risk alleles to AA and conducted a meta-GWAS analysis using two sets of AA to identify additional novel common MM risk variants. In the first study, we genotyped 1,305 incident AA MM cases from the African American Multiple Myeloma Study (AAMMS) using the Illumina HumanCore GWAS array and compared them to 7,078 AA controls from the African Ancestry Prostate Cancer Consortium (AAPC) and African Ancestry Breast Cancer Consortium (AABC) using the Illumina 1M-Duo. In the second study, 95 additional AAMMS cases and 435 AA MM cases from the University of Arkansas for Medical Sciences (UAMS) were genotyped using the Illumina MegaBead Chip and compared to 2,390 AA controls from the Multiethnic Cohort. The Haplotype Reference Consortium (HRC) was used to impute the overlapping typed SNPS from each GWAS case and control set together. Per-allele risk associations were tested for 8,715,278 overlapping genotyped and imputed variants with >1% frequency and >0.8 imputation score using unconditional logistic regression in both sets, and the combined effects were estimated using a fixed-effect meta-analysis. Of the 16 reported risk loci discovered in EA, directional consistency was present for 15 variants; eight of these replicated at nominal significance p<0.05, with the most statistically significant variant being rs4487645 at 7p15.3 (OR=1.38, p=3.56×10-6). AA individuals with polygenic risk scores from these 16 variants (PRS) in the top 10% stratum had a 1.44-fold increased MM risk compared to those with a PRS in the 25th -75th percentiles. Additionally, we identified three suggestive novel loci located at 12q12, 9p24.3 and 9p13.1 at p<1×10-6, with ORs ranging from 1.25-1.55, but none reached genome-wide significance. The variant at 9p24.3 is located in an intron in the KANK1 gene and a correlated SNP in EAs (r2=0.5) is strongly associated with gene expression in neoplastic plasma cells (unpublished, Weinhold and Morgan). Our study replicated most of the reported risk loci discovered among EA, demonstrated that a PRS constructed using the 16 reported risk alleles was associated with MM risk, and provides suggestive evidence for additional loci associated with MM risk in AAs. Citation Format: Zhaohui Du, Chi Song, Kristin Rand, Niels Weinhold, David Van Den Berg, Amie Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William Blot, John David Carpten, Antoinette Stroup, Andrew Olshan, Wei Zhang, African Ancestry Breast & Prostate Consortium, Stephen Chanock, Jayesh Mehta, Graham A. Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Loic LeMarchand, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association studies of multiple myeloma among African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 223.

Background: Disruption of the extensor mechanism after total knee arthroplasty (TKA) is debilitating, and the reported results of numerous reconstructive options have varied. We previously reported the early results of 13 patients who underwent reconstruction of the extensor mechanism with use of Marlex mesh. The purpose of the current study was to assess results in a larger cohort of patients, with an emphasis on the survivorship of the mesh, clinical results, and complications. Methods: During the period of 2000 to 2015 at a single tertiary care academic institution, 77 patients (77 TKAs) underwent reconstruction with use of Marlex mesh for an extensor mechanism disruption (27 quadriceps tendon disruptions, 40 patellar tendon disruptions, and 10 patellar fractures). The mean patient age at the time of reconstruction was 65 years; 70% of the patients were female. The mean body mass index was 35 kg/m 2 . The mean follow-up was 4 years. Eighteen (23%) of the patients underwent mesh reconstruction with the primary TKA in place, and 59 (77%) had mesh reconstruction at the time of revision TKA. The mean time between disruption and reconstruction was 7 months. Twenty (26%) of the patients had previously undergone attempted extensor mechanism reconstruction at outside institutions. Results: Sixty-five of the 77 mesh reconstructions were in place at the time of the latest follow-up. Twelve patients experienced a failure that required mesh revision: 5 for patellar tendon rupture, 5 for quadriceps tendon rupture, and 2 for symptomatic lengthening. Four additional patients with mesh failure were treated nonoperatively with bracing. The 2-year survivorship free of mesh revision was 86% for patients with no prior reconstruction and 95% for patients with previous reconstructions of the extensor mechanism that did not involve Marlex mesh. Knee Society Score (KSS) results significantly improved following reconstruction (p < 0.001). Extensor lag improved by a mean of 26°, with mean postoperative extensor lag measuring 9° (p < 0.001). Conclusions: Reconstruction of the extensor mechanism with use of Marlex mesh is a viable option in patients with catastrophic disruption after TKA. At the time of the latest follow-up, 84% of the mesh reconstructions were in place and the functional outcomes were excellent, with mean improvement in extensor lag of 26°. Extended follow-up is required, but the results of this large series with a mean follow-up of 4 years are encouraging. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P &lt; 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P &lt; 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Background Hepatic steatosis is strongly associated with cardiovascular disease in the general population. Whether recurrent or de novo, it can occur in the allograft, but the impact on survival and long-term clinical outcomes remains unclear. In this study, we aim to determine both the frequency and impact of allograft steatosis on long-term posttransplant outcomes. Methods A retrospective review of 588 adult liver transplant (LT) recipients (1999-2006) was performed. Cox regression analysis (time-dependent) was used to evaluate differences in time to steatosis post-LT, patient survival, and cardiovascular outcomes. Results Mean age 51.9 ± 10.6 years, 64.6% males, underlying nonalcoholic steatohepatitis (NASH) (9.4%), previous tobacco (52%), pre-LT diabetes mellitus (30.3%), pre-LT hypertension (23.2%), and known cardiovascular disease (9.7%). Overall, 254 recipients developed allograft steatosis (at 10 years: 77.6% NASH recipients, 44.7% Non-NASH recipients). Risk factors for allograft steatosis were female sex (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.09-2.00; P = 0.014), hepatitis C virus diagnosis (HR, 2.49; 95% CI, 1.77-3.94; P < 0.001), and time-dependent BMI (per unit: HR, 1.08; 95% CI, 1.05-1.10; P < 0.001). Allograft steatosis was not associated with post-LT survival (P = 0.25) nor cardiovascular events (HR, 1.08; 95% CI, 0.73-1.59; P = 0.70). Underlying NASH associated with cardiovascular events (HR, 2.04; 95% CI, 1.37-3.04; P < 0.001). Conclusions Allograft steatosis is common but not associated with survival or cardiovascular events in this study. Larger prospective studies are needed to better define the natural history of allograft steatosis.

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P <5×10 − 8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P =4.4×10 −8 ) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P =4.3×10 −8 ) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 ( P =0.04; meta-analysis P =2.5×10 −9 ; heterogeneity, P =0.16) but not for 22q13 ( P =0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P =0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.