Elements of Weight Management Among Pre-Kidney Transplant Candidates: The Patient Perspective.

Obesity and related comorbidities heighten risks for complications in kidney transplant settings. While pre-transplant patients often have access to nutrition counseling and health support, literature is limited on patients' perceptions of weight and motivation to lose weight prior to transplantation. We conducted a survey among ≥18-year-old patients on the kidney transplant waitlist at a single center. Questions addressed weight perception, motivation for weight loss, available resources, and engagement in physical activity. Medical records provided demographic and clinical data. Statistical tests analyzed quantitative data, while free-text responses were thematically grouped and described. Of 1055 patients, 291 responded and were matched with demographic data. Perceived weight changes correlated with actual changes in body mass index (BMI) (<24.9) were more receptive to weight center resources (<30 kg/m2) are most interested in weight loss resources and demonstrate motivation. Furthermore, pre-transplant nutrition counseling correlates with healthier behaviors. Integrating patients' perspectives enhances pre-transplant protocols by encouraging active involvement in health decisions.

Disruption of a GATA2-TAL1-ERG regulatory circuit promotes erythroid transition in healthy and leukemic stem cells.

Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These transitions are disrupted during leukemic transformation, but knowledge of the gene regulatory changes underpinning this process is elusive. We hypothesized that identifying core gene regulatory networks in healthy hematopoietic and leukemic cells could provide insights into network alterations that perturb cell state transitions. A heptad of transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, and RUNX1) bind key hematopoietic genes in human CD34+ hematopoietic stem and progenitor cells (HSPCs) and have prognostic significance in acute myeloid leukemia (AML). These factors also form a densely interconnected circuit by binding combinatorially at their own, and each other's, regulatory elements. However, their mutual regulation during normal hematopoiesis and in AML cells, and how perturbation of their expression levels influences cell fate decisions remains unclear. In this study, we integrated bulk and single-cell data and found that the fully connected heptad circuit identified in healthy HSPCs persists, with only minor alterations in AML, and that chromatin accessibility at key heptad regulatory elements was predictive of cell identity in both healthy progenitors and leukemic cells. The heptad factors GATA2, TAL1, and ERG formed an integrated subcircuit that regulates stem cell-to-erythroid transition in both healthy and leukemic cells. Components of this triad could be manipulated to facilitate erythroid transition providing a proof of concept that such regulatory circuits can be harnessed to promote specific cell-type transitions and overcome dysregulated hematopoiesis.

Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes.

Promoters are DNA sequences that have an essential role in controlling gene expression. While recent whole cancer genome analyses have identified numerous hotspots of somatic point mutations within promoters, many have not yet been shown to perturb gene expression or drive cancer development. As such, positive selection alone may not adequately explain the frequency of promoter point mutations in cancer genomes. Here we show that increased mutation density at gene promoters can be linked to promoter activity and differential nucleotide excision repair (NER). By analysing 1,161 human cancer genomes across 14 cancer types, we find evidence for increased local density of somatic point mutations within the centres of DNase I-hypersensitive sites (DHSs) in gene promoters. Mutated DHSs were strongly associated with transcription initiation activity, in which active promoters but not enhancers of equal DNase I hypersensitivity were most mutated relative to their flanking regions. Notably, analysis of genome-wide maps of NER shows that NER is impaired within the DHS centre of active gene promoters, while XPC-deficient skin cancers do not show increased promoter mutation density, pinpointing differential NER as the underlying cause of these mutation hotspots. Consistent with this finding, we observe that melanomas with an ultraviolet-induced DNA damage mutation signature show greatest enrichment of promoter mutations, whereas cancers that are not highly dependent on NER, such as colon cancer, show no sign of such enrichment. Taken together, our analysis has uncovered the presence of a previously unknown mechanism linking transcription initiation and NER as a major contributor of somatic point mutation hotspots at active gene promoters in cancer genomes.

Evaluating the role of race and medication in protection of uterine fibroids by type 2 diabetes exposure.

BACKGROUND: Uterine fibroids (UF) affect 77% of women by menopause, and account for $9.4 billion in annual healthcare costs. Type-2-diabetes (T2D) has inconsistently associated with protection from UFs in prior studies. To further evaluate the relationship between T2D and UFs we tested for association between T2D and UF risk in a large clinical population as well as the potential differences due to T2D medications and interaction with race. METHODS: This nested case-control study is derived from a clinical cohort. Our outcome was UF case-control status and our exposure was T2D. UF outcomes and T2D exposure were classified using validated electronic medical record (EMR) algorithms. Logistic regression, adjusted for covariates, was used to model the association between T2D diagnosis and UF risk. Secondary analyses were performed evaluating the interaction between T2D exposure and race and stratifying T2D exposed subjects by T2D medication being taken. RESULTS: We identified 3,789 subjects with UF outcomes (608 UF cases and 3,181 controls), 714 were diabetic and 3,075 were non-diabetic. We observed a nominally significant interaction between T2D exposure and race in adjusted models (interaction p = 0.083). Race stratified analyses demonstrated more protection by T2D exposure on UF risk among European Americans (adjusted odds ratio [aOR] = 0.50, 95% CI 0.35 to 0.72) than African Americans (aOR = 0.76, 95% CI 0.50 to 1.17). We also observed a protective effect by T2D regardless of type of T2D medication being taken, with slightly more protection among subjects on insulin treatments (European Americans aOR = 0.42, 95% CI 0.26 to 0.68; African Americans aOR = 0.60, 95% CI 0.36 to 1.01). CONCLUSIONS: These data, conducted in a large population of UF cases and controls, support prior studies that have found a protective association between diabetes presence and UF risk and is further modified by race. Protection from UFs by T2D exposure was observed regardless of medication type with slightly more protection among insulin users. Further mechanistic research in larger cohorts is necessary to reconcile the potential role of T2D in UF risk.

Does BMI affect the accuracy of preoperative axillary ultrasound in breast cancer patients?

INTRODUCTION: Obesity affects 36 % of American women and is a well-documented breast cancer risk factor. Preoperative axillary ultrasound (AUS) is used routinely for axillary staging in newly diagnosed breast cancer patients; However, the impact of obesity on the usefulness of AUS is unknown. Our aim was to evaluate the effect of body mass index (BMI) on the performance of AUS. METHODS: From our prospective breast surgery database, we identified 1,510 consecutive invasive breast cancers in patients undergoing primary surgery, including axillary operation, from January 2010 to July 2013. Preoperative AUS was performed in 1,375 cases (91 %). We analyzed patient, pathology and imaging data. RESULTS: Median BMI was 27.4 and 479 patients (36 %) were classified as obese (BMI ≥ 30). Most tumors were T1 (71 %) and estrogen receptor-positive (87 %). AUS was suspicious in 401 (29 %) patients, of whom 374 had ultrasound-guided lymph node fine-needle aspiration (FNA). Overall, 124 patients (33.2 %) were FNA positive. FNA identified disease preoperatively in 35.8 % of node-positive obese patients. For all BMI categories (normal, overweight, obese), AUS was predictive of pathologic nodal status (p < 0.0001). AUS sensitivity did not differ across BMI categories, while specificity and accuracy were better for overweight (p = 0.001 and 0.008, respectively) and obese (p = 0.007 and 0.02, respectively) patients, than for normal-BMI patients. CONCLUSIONS: Despite theoretical concern regarding both potential technical challenges and obesity-related lymph node alterations, the sensitivity of preoperative AUS for detecting nodal metastasis was similar in obese and non-obese patients, while specificity was better in obese patients. Preoperative AUS is valuable for preoperative nodal staging of obese breast cancer patients.

Opioid use after cardiac surgery in children with Down syndrome.

OBJECTIVES: To determine the cumulative opioid doses administered to patients with Down syndrome after cardiac surgery and compare them with patients without Down syndrome. DESIGN: Retrospective observational comparative study. SETTING: PICU in a university-affiliated freestanding pediatric teaching hospital. PATIENTS: Infants and children who presented to our institution for heart surgery after July 1, 2008, and met the following criteria: 1) no opioid medications for 48 hours prior to surgery, 2) sternotomy approach with primary closure, and 3) no additional operative procedures in the 5 days after surgery. All patients with Down syndrome were included, and patients without Down syndrome with similar age, type of cardiac lesion, and length of surgical procedure were selected in a ~2:1 ratio, blinded to opioid exposure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and demographic data were extracted from electronic medical record data. Univariate analyses and multivariate linear regression modeling were performed to determine the influence of Down syndrome, patient characteristics, and clinical covariates on weight-adjusted opioid dose. The differences in median cumulative opioid doses between those with Down syndrome (n = 44) and those without Down syndrome (n = 77) were not significant in the first 24 hours (+0.39 mg/kg [95% CI, -0.45 to +1.39 mg/kg]) or 96 hours (+0.54 mg/kg [95% CI, -0.59 to +2.07 mg/kg]) after surgery. Age, cardiac bypass time, benzodiazepines, and neuromuscular blocking agents were significantly correlated with opioid dose, but Down syndrome, gender, pain score, creatinine, acetaminophen, nonsteroidal anti-inflammatory drugs, and steroid medications were not. Patients with Down syndrome had longer hospital stays; in multivariate analysis, higher opioid exposures in the first 96 hours after surgery and higher peak serum creatinine values correlated with longer hospitalization. CONCLUSIONS: This cohort did not provide evidence for opioid resistance in patients with Down syndrome. Younger age, longer cardiac bypass time, exposure to benzodiazepines, and neuromuscular blockade did correlate with increased opioid doses after cardiac surgery.

Diagnostic Obscurity of Gastrointestinal Subepithelial Tumors: An Organizing Gastric Hematoma Requiring En Bloc Resection.

Gastric subepithelial tumors (SETs) are often incidentally found during examinations of the gastrointestinal tract. Able to arise from any layer of the stomach, these tumors are predominantly asymptomatic and are classified as either benign or malignant based on size, consistency, shape, and mobility as determined by endoscopic evaluation. We present the first reported case of a gastric SET presenting as a chronic organizing hematoma. In doing so, we discuss the necessity of multimodal imaging techniques and multidisciplinary management in identifying often obscure gastric SETs to intervene on potentially malignant masses early.

COVID-19 infection and vaccination rarely impact HLA antibody profile in waitlisted renal transplant candidates- a multicenter cohort.

Although rare, infection and vaccination can result in antibodies to human leukocyte antigens (HLA). We analyzed the effect of SARS-CoV-2 infection or vaccination on HLA antibodies in waitlisted renal transplant candidates. Specificities were collected and adjudicated if the calculated panel reactive antibodies (cPRA) changed after exposure. Of 409 patients, 285 (69.7 %) had an initial cPRA of 0 %, and 56 (13.7 %) had an initial cPRA > 80 %. The cPRA changed in 26 patients (6.4 %), 16 (3.9 %) increased, and 10 (2.4 %) decreased. Based on cPRA adjudication, cPRA differences generally resulted from a small number of specificities with subtle fluctuations around the borderline of the participating centers' cutoff for unacceptable antigen listing. All five COVID recovered patients with an increased cPRA were female (p = 0.02). In summary, exposure to this virus or vaccine does not increase HLA antibody specificities and their MFI in approximately 99 % of cases and 97 % of sensitized patients. These results have implications for virtual crossmatching at the time of organ offer after SARS-CoV-2 infection or vaccination, and these events of unclear clinical significance should not influence vaccination programs.

Revisiting the "Weekend Effect" on Adult and Pediatric Liver and Kidney Offer Acceptance.

BACKGROUND Weekends can impose resource and manpower constraints on hospitals. Studies using data from prior allocation schemas showed increased adult organ discards on weekends. We examined the impact of day of the week on adult and pediatric organ acceptance using contemporary data. MATERIAL AND METHODS Retrospective analysis of UNOS-PTR match-run data of all offers for potential kidney and liver transplant from 1/1/2016 to 7/1/2021 were examined to study the rate at which initial offers were declined depending on day of the week. Risk factors for decline were also evaluated. RESULTS Of the total initial adult/pediatric liver and kidney offers, the fewest offers occurred on Mondays and Sundays. The decline rate for adult/pediatric kidneys was highest on Saturdays and lowest on Tuesdays. The decline rate for adult livers was highest on Saturday and lowest on Wednesday. In contrast, the decline rate for pediatric livers was highest on Tuesdays and lowest on Wednesdays. Independent risk factors from multivariate analysis of the adult/pediatric kidney and liver decline rate were analyzed. The weekend offer remains an independent risk factor for adult kidney and liver offer declines, but for pediatric offers, these were not significant independent risk factors. CONCLUSIONS Although allocation systems have changed, and the availability of kidneys and livers have increased in the USA over the past 5 years, the weekend effect remains significant for adult liver and kidney offers for declines. Interestingly, the weekend effect was not seen for pediatric liver and kidney offers.

Mastalgia is Not An Indication for Mammogram.

BACKGROUND: Mastalgia is a common breast complaint that is worrisome to patients. This study was performed to determine if mastalgia is a sign of breast cancer and to evaluate the benefit of its work up. METHODS: Retrospective review of prospectively collected data on 8960 consecutive patients at a safety net institution from June 1, 2006 to December 31, 2020. Data on patient reported mastalgia and diagnosis of breast cancer were collected. RESULTS: 8960 patients had a mean age of 45 years. The population was predominantly underinsured, 70% Hispanic, and 16% had adequate health literacy. Approximately 31% (2820 of 8960) of patients presented with a complaint of breast pain. Of 2820 patients with breast pain, 20 (0.7%) were found to have breast cancer. The average age of patients with breast cancer was 49 years. Physical examination identified a mass in 6 patients and only 3 patients had pain limited to the side of the cancer (10 bilateral, 7 contralateral). Of 1280 patients who were under age 40 years, 88% underwent breast imaging. The Cancer Detection Rate (CDR) was 0.9 per 1000 examinations. For 950 patients age 40 to 49 years and 590 patients age 50 years and older, 98% and 99% underwent breast imaging, respectively. The CDR was 10 per 1000 examinations for age 40 to 49 and 14 per 1000 examinations for age 50 years and older. CONCLUSIONS: Mastalgia is rarely associated with breast cancer. In the absence of other findings, imaging of patients less than age 40 is not recommended. Any workup beyond routine screening mammography in age-appropriate patients, to identify the "cause" of breast pain, does not seem warranted.

NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations.

BACKGROUND: A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER)+ versus ER- cancer. RESULTS: We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER+ tumors (p = 0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p = 0.0062). Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015), but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain. CONCLUSION: This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER+ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER+ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.

Scarcity of Recurrent Regulatory Driver Mutations in Colorectal Cancer Revealed by Targeted Deep Sequencing.

BACKGROUND: Genetic testing of cancer samples primarily focuses on protein-coding regions, despite most mutations arising in noncoding DNA. Noncoding mutations can be pathogenic if they disrupt gene regulation, but the benefits of assessing promoter mutations in driver genes by panel testing has not yet been established. This is especially the case in colorectal cancer, for which few putative driver variants at regulatory elements have been reported. METHODS: We designed a unique target capture sequencing panel of 39 colorectal cancer driver genes and their promoters, together with more than 35 megabases of regulatory elements focusing on gene promoters. Using this panel, we sequenced 95 colorectal cancer and matched normal samples at high depth, averaging 170× and 82× coverage, respectively. RESULTS: Our target capture sequencing design enabled improved coverage and variant detection across captured regions. We found cases with hereditary defects in mismatch and base excision repair due to deleterious germline coding variants, and we identified mutational spectra consistent with these repair deficiencies. Focusing on gene promoters and other regulatory regions, we found little evidence for base or region-specific recurrence of functional somatic mutations. Promoter elements, including TERT, harbored few mutations, with none showing strong functional evidence. Recurrent regulatory mutations were rare in our sequenced regions in colorectal cancer, though we highlight some candidate mutations for future functional studies. CONCLUSIONS: Our study supports recent findings that regulatory driver mutations are rare in many cancer types and suggests that the inclusion of promoter regions into cancer panel testing is currently likely to have limited clinical utility in colorectal cancer.

An unusual association between hemophagocytic lymphohistiocytosis, mixed connective tissue disease, and autoimmune hemolytic anemia: A case report.

RATIONALE: In the adult patient, hemophagocytic lymphohistiocytosis (HLH) is uncommon and frequently difficult to diagnose due to its nonspecific presentation and numerous complications. PATIENT CONCERNS: Herein, we present the case of a 25-year-old female who initially presented for evaluation of persistent fevers and fatigue. She was found to have splenomegaly, generalized lymphadenopathy, pancytopenia, and acute hepatic failure. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Her course was further complicated by the development of nephrotic syndrome and autoimmune hemolytic anemia (AIHA). Antinuclear antibody and ribonucleoprotein were positive, with concurrent physical examination findings, indicating underlying mixed connective tissue disease (MCTD). Ferritin was greater than 40,000 ng/dL. Viral studies, including hepatitis A, B, and C, cytomegalovirus, and Epstein-Barr virus were negative. On the basis of her clinical presentation, a diagnosis of HLH secondary to MCTD was made. This was later confirmed on liver biopsy. She was started on high-dose prednisone and her symptoms completely resolved. She was then transitioned to azathioprine, hydroxychloroquine, prophylactic antibiotics, and a prednisone taper for long-term management. LESSONS: This case is notable for the association of both AIHA and MCTD with HLH, providing support for a possible relationship between these 3 conditions.

The non-coding RNA landscape of human hematopoiesis and leukemia.

Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.

Alpha2A adrenergic receptor genetic variation contributes to hyperglycemia after myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is frequently associated with transient hyperglycemia even in patients without pre-existing diabetes. Acute stress can lead to increased blood glucose through the effect of catecholamines on alpha2A-adrenergic receptors (α2A-ARs) present in pancreatic islet ß-cells. Variation in the gene (ADRA2A) that encodes the α2A-AR affects insulin release and glucose control and may play a particularly important role during times of stress. METHODS: We performed a retrospective cohort study using de-identified electronic medical records linked to a DNA repository in 521 Caucasians and 55 African-American non-diabetic patients with AMI. We examined the association between admission blood glucose concentrations and ten selected ADRA2A SNPs in Caucasians. RESULTS: Three ADRA2A SNPS were associated with stress-induced hyperglycemia in Caucasians. Individuals homozygous for the rs10885122 variant (n=9) had a 23% lower admission glucose (geometric mean [95% CI], 99 [83-118]mg/dl) compared with non-carriers (121 [118-125] mg/dl; n=401; P=0.001). Admission glucose was 14% higher in rs1800544 variant homozygotes (134 [119-150]mg/dl; n=36) compared to non-carriers (118 [115-121]mg/dl; n=290, P=0.046). Furthermore, homozygotes of the rs553668 variant (n=13) had a 13% higher glucose (133 [110-160]mg/dl) compared to non-carriers (118 [115-122]mg/dl; n=366; P=0.056). Haplotypes including these ADRA2A SNPs were associated with higher admission glucose levels. CONCLUSIONS: Three ADRA2A genetic variants are associated with blood glucose and stress-induced hyperglycemia after AMI in Caucasians.

Systematic Screening of Promoter Regions Pinpoints Functional Cis-Regulatory Mutations in a Cutaneous Melanoma Genome.

UNLABELLED: With the recent discovery of recurrent mutations in the TERT promoter in melanoma, identification of other somatic causal promoter mutations is of considerable interest. Yet, the impact of sequence variation on the regulatory potential of gene promoters has not been systematically evaluated. This study assesses the impact of promoter mutations on promoter activity in the whole-genome sequenced malignant melanoma cell line COLO-829. Combining somatic mutation calls from COLO-829 with genome-wide chromatin accessibility and histone modification data revealed mutations within promoter elements. Interestingly, a high number of potential promoter mutations (n = 23) were found, a result mirrored in subsequent analysis of TCGA whole-melanoma genomes. The impact of wild-type and mutant promoter sequences were evaluated by subcloning into luciferase reporter vectors and testing their transcriptional activity in COLO-829 cells. Of the 23 promoter regions tested, four mutations significantly altered reporter activity relative to wild-type sequences. These data were then subjected to multiple computational algorithms that score the cis-regulatory altering potential of mutations. These analyses identified one mutation, located within the promoter region of NDUFB9, which encodes the mitochondrial NADH dehydrogenase (ubiquinone) 1 beta subcomplex 9, to be recurrent in 4.4% (19 of 432) of TCGA whole-melanoma exomes. The mutation is predicted to disrupt a highly conserved SP1/KLF transcription factor binding motif and its frequent co-occurrence with mutations in the coding sequence of NF1 supports a pathologic role for this mutation in melanoma. Taken together, these data show the relatively high prevalence of promoter mutations in the COLO-829 melanoma genome, and indicate that a proportion of these significantly alter the regulatory potential of gene promoters. IMPLICATIONS: Genomic-based screening within gene promoter regions suggests that functional cis-regulatory mutations may be common in melanoma genomes, highlighting the need to examine their role in tumorigenesis.

Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality.

OBJECTIVES: Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality. METHODS: By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32,415 adults with a cancer diagnosis at Vanderbilt and 79,258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index. RESULTS: Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR. CONCLUSIONS: EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.

Extracting and standardizing medication information in clinical text - the MedEx-UIMA system.

Extraction of medication information embedded in clinical text is important for research using electronic health records (EHRs). However, most of current medication information extraction systems identify drug and signature entities without mapping them to standard representation. In this study, we introduced the open source Java implementation of MedEx, an existing high-performance medication information extraction system, based on the Unstructured Information Management Architecture (UIMA) framework. In addition, we developed new encoding modules in the MedEx-UIMA system, which mapped an extracted drug name/dose/form to both generalized and specific RxNorm concepts and translated drug frequency information to ISO standard. We processed 826 documents by both systems and verified that MedEx-UIMA and MedEx (the Python version) performed similarly by comparing both results. Using two manually annotated test sets that contained 300 drug entries from medication list and 300 drug entries from narrative reports, the MedEx-UIMA system achieved F-measures of 98.5% and 97.5% respectively for encoding drug names to corresponding RxNorm generic drug ingredients, and F-measures of 85.4% and 88.1% respectively for mapping drug names/dose/form to the most specific RxNorm concepts. It also achieved an F-measure of 90.4% for normalizing frequency information to ISO standard. The open source MedEx-UIMA system is freely available online at http://code.google.com/p/medex-uima/.

ICD-9 tobacco use codes are effective identifiers of smoking status.

OBJECTIVE: To evaluate the validity of, characterize the usage of, and propose potential research applications for International Classification of Diseases, Ninth Revision (ICD-9) tobacco codes in clinical populations. MATERIALS AND METHODS: Using data on cancer cases and cancer-free controls from Vanderbilt's biorepository, BioVU, we evaluated the utility of ICD-9 tobacco use codes to identify ever-smokers in general and high smoking prevalence (lung cancer) clinic populations. We assessed potential biases in documentation, and performed temporal analysis relating transitions between smoking codes to smoking cessation attempts. We also examined the suitability of these codes for use in genetic association analyses. RESULTS: ICD-9 tobacco use codes can identify smokers in a general clinic population (specificity of 1, sensitivity of 0.32), and there is little evidence of documentation bias. Frequency of code transitions between 'current' and 'former' tobacco use was significantly correlated with initial success at smoking cessation (p<0.0001). Finally, code-based smoking status assignment is a comparable covariate to text-based smoking status for genetic association studies. DISCUSSION: Our results support the use of ICD-9 tobacco use codes for identifying smokers in a clinical population. Furthermore, with some limitations, these codes are suitable for adjustment of smoking status in genetic studies utilizing electronic health records. CONCLUSIONS: Researchers should not be deterred by the unavailability of full-text records to determine smoking status if they have ICD-9 code histories.