Hathcock, Matthew

T cell–mediated rejection (TCMR) is common after liver transplantation (LT), and it is often thought to have a minimum impact on outcomes. Because alloimmune response changes over time, we investigated the role of the timing of TCMR on patient and allograft survival and examined the risk factors for early and late TCMR. We reviewed protocol liver biopsies for 787 consecutive LT recipients with an 8.6‐year follow‐up. The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic steatohepatitis patients having the lowest incidence. Younger recipient age (P < 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use of deceased donor allografts (P = 0.01) were associated with increased risk of early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI, 0.79‐1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78‐1.34; P = 0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was associated with different risk factors. The majority of late TCMR (56.2%) episodes had no antecedent early TCMR, although moderate‐to‐severe early TCMR (HR, 2.85; 95% CI, 1.55‐5.23; P < 0.01) and steroid resistance (HR, 3.62; 95% CI, 1.87‐6.99; P < 0.01) were associated with late TCMR. Late TCMR increased risk of mortality (HR, 1.89; 95% CI, 1.35‐2.65; P = 0.001) and graft loss (HR, 1.71; 95% CI, 1.23‐2.37; P = 0.001). Thus, these data suggest that the timing and histologic grade of TCMR determine its impact on patient and allograft survival. Early mild TCMR episodes after LT do not adversely impact patient or allograft survival provided that they are adequately treated. The occurrence of late TCMR carries deleterious effects with increased longterm risk of graft loss and decreased survival. Patients with moderate‐to‐severe early TCMR are at an increased risk for late TCMR and warrant closer clinical follow‐up.

AbstractBackgroundRenal dysfunction occurs commonly after heart transplantation (HTx) with wide inter‐individual variability but whether a genetic predisposition exists in these patients is unknown. Genomewide association studies (GWAS) have not been performed to assess the association of genetic variation with change in renal function after HTx.MethodsClinical and demographic data of patients who underwent HTx and provided blood samples and consent for genetic analysis were included. Genotyping was performed using Illumina Infinium Human CoreExome v1.0 analysis kit. A GWAS utilizing linear regression models was performed with estimated glomerular filtration rate (eGFR) at 1 year as the phenotype after adjusting for baseline eGFR prior to HTx and conversion from calcineurin inhibitor to sirolimus as primary immunosuppression therapy.ResultsA total of 251 HTx recipients were genotyped for 314,903 single nucleotide polymorphisms (SNPs). The mean (SD) age was 50 (12.5) years; most patients were of European origin (n = 243, 96.8%) and males (n = 179, 71.3%). After adjustment for potential confounders, two variants, rs17033285 (P = 4.3 × 10−7) and rs4917601 (P = 6.46 × 10−7), in a long non‐coding RNA (lncRNA) gene LINC01121 and a pseudogene BTBD7P2, were identified to have a significant association with change in GFR at 1 year after HTx.ConclusionsOur first of its kind GWAS demonstrates that genetic variation affects renal function after HTx independent of other risk factors. Agnostic genetic approaches such as these may lead to identification of novel biological pathways such as the role of lncRNAs in the development of renal dysfunction post‐HTx.

Objective Using surveys to collect self-reported information on health and disease is commonly used in clinical practice and epidemiological research. However, the inconsistency of self-reported information collected longitudinally in repeated surveys is not well investigated. We aimed to investigate whether a socioeconomic status based on current housing characteristics, HOUsing-based SocioEconomic Status (HOUSES) index linking current address information to real estate property data, is associated with inconsistent self-reporting. Study setting and participants We performed a prospective cohort study using the Mayo Clinic Biobank (MCB) participants who resided in Olmsted County, Minnesota, USA, at the time of enrolment between 2009 and 2013, and were invited for a 4-year follow-up survey (n=11 717). Primary and secondary outcome measures Using repeated survey data collected at the baseline and 4 years later, the primary outcome was the inconsistency in survey results when reporting prevalent diseases, defined by reporting to have ‘ever’ been diagnosed with a given disease in the baseline survey but reported ‘never’ in the follow-up survey. Secondary outcome was the response rate for the 4-year follow-up survey. Results Among the MCB participants invited for the 4-year follow-up survey, 8508/11 717 (73%) responded to the survey. Forty-three per cent had at least one inconsistent self-reported disease. Lower HOUSES was associated with higher inconsistency rates, and the association remained significant after pertinent characteristics such as age and perceived general health (OR=1.46; 95% CI 1.17 to 1.84 for the lowest compared with the highest HOUSES decile). HOUSES was also associated with lower response rate for the follow-up survey (56% vs 77% for the lowest vs the highest HOUSES decile). Conclusion This study demonstrates the importance of using the HOUSES index that reflects current SES when using self-reporting through repeated surveys, as the HOUSES index at baseline survey was inversely associated with inconsistent self-report and the response rate for the follow-up survey.

INTRODUCTION: Increasing numbers of pregnant women are being treated for ADHD. The safety of ADHD medications in pregnancy have not been well studied, although studies suggest that methylphenidate use may lower birthweight compare to unexposed newborns. Our primary outcome was to evaluate if birthweight was lower among infants of women utilizing Adderall in our academic institution. METHODS: Maternal and infant pairs exposed to Adderall between January 2005 and December 2015 was identified in EMR based on active medication list during pregnancy. Patients were matched 2:1 with unexposed controls of similar age, gestational age at delivery, parity, infant sex and date of delivery. All charts were reviewed for known causes of IUGR or low birthweight. Statistical analysis of infant birthweight was done using generalized estimating equation blocking on matching. Medical histories were analyzed using Chi-Square test or Fishers exact test as appropriate. RESULTS: We identified 53 exposed pairs. The difference in mean birthweight for exposed vs unexposed infants was 26.9g which is not statistically or clinically significant (95% CI, P-value: (-141, 195), 0.75). A statistically significant difference was noted for exposed vs unexposed mothers for comorbid psychiatric illness and history of substance abuse (p = <0.0001). CONCLUSION: As Adderall use increases among childbearing women, understanding the risk to infants is crucial. With a limited sample size, our study suggests no significant difference in birthweight, which is a concern for women requiring medication in pregnancy. Women using Adderall may have higher rates of comorbid psychiatric disorders and substance use and may benefit from early screening.

The clinical utility of microbiome biomarkers depends on the reliable and reproducible nature of comparative results. Underappreciation of the variation associated with common demographic, health, and behavioral factors may confound associations of interest and generate false positives. Here, we present the Midwestern Reference Panel (MWRP), a resource for comparative gut microbiome studies conducted in the Midwestern United States. We analyzed the relationships between demographic and health behavior–related factors and the microbiota in this cohort, and estimated their effect sizes. Most variables investigated were associated with the gut microbiota. Specifically, body mass index (BMI), race, sex, and alcohol use were significantly associated with microbial β-diversity (P < 0.05, unweighted UniFrac). BMI, race and alcohol use were also significantly associated with microbial α-diversity (P < 0.05, species richness). Tobacco use showed a trend toward association with the microbiota (P < 0.1, unweighted UniFrac). The effect sizes of the associations, as quantified by adjusted R 2 values based on unweighted UniFrac distances, were small (< 1% for all variables), indicating that these factors explain only a small percentage of overall microbiota variability. Nevertheless, the significant associations between these variables and the gut microbiota suggest that they could still be potential confounders in comparative studies and that controlling for these variables in study design, which is the main objective of the MWRP, is important for increasing reproducibility in comparative microbiome studies.

Share 35 was implemented in 2013 to direct livers to the most urgent candidates by prioritizing Model for End‐Stage Liver Disease (MELD) ≥ 35 patients. We aim to evaluate this policy's impact on costs and mortality. Our study includes 834 wait‐listed patients and 338 patients who received deceased donor, solitary liver transplants at Mayo Clinic between January 2010 and December 2014. Of these patients, 101 (30%) underwent transplantation after Share 35. After Share 35, 29 (28.7%) MELD ≥ 35 patients received transplants, as opposed to 46 (19.4%) in the pre–Share 35 era (P = 0.06). No significant difference in 90‐day wait‐list mortality (P = 0.29) nor 365‐day posttransplant mortality (P = 0.68) was found between patients transplanted before or after Share 35. Mean costs were $3,049 (P = 0.30), $5226 (P = 0.18), and $10,826 (P = 0.03) lower post‐Share 35 for the 30‐, 90‐, and 365‐day pretransplant periods, and mean costs were $5010 (P = 0.41) and $5859 (P = 0.57) higher, and $9145 (P = 0.54) lower post‐Share 35 for the 30‐, 90‐, and 365‐day posttransplant periods. In conclusion, the added cost of transplanting more MELD ≥ 35 patients may be offset by pretransplant care cost reduction. Despite shifting organs to critically ill patients, Share 35 has not impacted mortality significantly. Liver Transplantation 23:11–18 2017 AASLD.

The clinical utility of microbiome biomarkers depends on the reliable and reproducible nature of comparative results. Underappreciation of the variation associated with common demographic, health, and behavioral factors may confound associations of interest and generate false positives. Here, we present the Midwestern Reference Panel (MWRP), a resource for comparative gut microbiome studies conducted in the Midwestern United States. We analyzed the relationships between demographic and health behavior-related factors and the microbiota in this cohort, and estimated their effect sizes. Most variables investigated were associated with the gut microbiota. Specifically, body mass index (BMI), race, sex, and alcohol use were significantly associated with microbial β-diversity (P < 0.05, unweighted UniFrac). BMI, race and alcohol use were also significantly associated with microbial α-diversity (P < 0.05, species richness). Tobacco use showed a trend toward association with the microbiota (P < 0.1, unweighted UniFrac). The effect sizes of the associations, as quantified by adjusted R 2 values based on unweighted UniFrac distances, were small (< 1% for all variables), indicating that these factors explain only a small percentage of overall microbiota variability. Nevertheless, the significant associations between these variables and the gut microbiota suggest that they could still be potential confounders in comparative studies and that controlling for these variables in study design, which is the main objective of the MWRP, is important for increasing reproducibility in comparative microbiome studies.

Abstract Background Frailty in non‐transplant populations increases morbidity and mortality. Muscle wasting is an important frailty characteristic. Low body mass index is used to measure wasting, but can over‐ or underestimate muscle mass. Computed tomography ( CT ) software can directly measure muscle mass. It is unknown if muscle wasting is important in lung transplantation. Aim and Methods The aim of this single‐center, retrospective cohort study was to determine whether pre‐transplant low muscle mass (as measured by CT using Slice‐O‐matic software at L2–L3 interspace) was associated with post‐transplantation mortality, hospital and intensive care unit length of stay ( LOS ), duration of mechanical ventilation, or primary graft dysfunction. Lung transplant recipients from 2000 to 2012 with a CT scan less than six months prior to transplant were included. Univariate, multivariate, and Kaplan–Meier analyses were conducted. Results Thirty‐six patients were included. Those with low muscle index (lower 25th percentile) had a worse survival (hazard ratio = 3.83; 95% confidence interval 1.42–10.3; p = 0.007) and longer hospital LOS by an estimated 7.2 d (p = 0.01) when adjusted for age and sex as compared to those with higher muscle index. Conclusion Low muscle index at lung transplantation is associated with worse survival and increased hospital LOS .

Background Socioeconomic status (SES) is an important predictor for outcomes of chronic diseases. However, it is often unavailable in clinical data. We sought to determine whether an individual housing-based SES index termed HOUSES can influence the likelihood of multiple chronic conditions (MCC) and hospitalisation in a community population. Methods Participants were residents of Olmsted County, Minnesota, aged >18 years, who were enrolled in Mayo Clinic Biobank on 31 December 2010, with follow-up until 31 December 2011. Primary outcome was all-cause hospitalisation over 1 calendar-year. Secondary outcome was MCC determined through a Minnesota Medical Tiering score. A logistic regression model was used to assess the association of HOUSES with the Minnesota tiering score. With adjustment for age, sex and MCC, the association of HOUSES with hospitalisation risk was tested using the Cox proportional hazards model. Results Eligible patients totalled 6402 persons (median age, 57 years; 25th–75th quartiles, 45–68 years). The lowest quartile of HOUSES was associated with a higher Minnesota tiering score after adjustment for age and sex (OR (95% CI) 2.4 (2.0 to 3.1)) when compared with the highest HOUSES quartile. Patients in the lowest HOUSES quartile had higher risk of all-cause hospitalisation (age, sex, MCC-adjusted HR (95% CI) 1.53 (1.18 to 1.98)) compared with those in the highest quartile. Conclusions Low SES, as assessed by HOUSES, was associated with increased risk of hospitalisation and greater MCC health burden. HOUSES may be a clinically useful surrogate for SES to assess risk stratification for patient care and clinical research.