Race, Genotype, and Azathioprine Discontinuation : A Cohort Study.

BACKGROUND: Thiopurines are an important class of immunosuppressants despite their risk for hematopoietic toxicity and narrow therapeutic indices. Benign neutropenia related to an ACKR1 variant (rs2814778-CC) is common among persons of African ancestries. OBJECTIVE: To test whether rs2814778-CC was associated with azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine dosing. DESIGN: Retrospective cohort study. SETTING: Two tertiary care centers. PATIENTS: Thiopurine users with White or Black race. MEASUREMENTS: Azathioprine discontinuation attributed to hematopoietic toxicity. Secondary outcomes included weight-adjusted final dose, leukocyte count, and change in leukocyte count. RESULTS: The rate of azathioprine discontinuation attributed to hematopoietic toxicity was 3.92 per 100 person-years among patients with the CC genotype (n = 101) and 1.34 per 100 person-years among those with the TT or TC genotype (n = 1365) (hazard ratio [HR] from competing-risk model, 2.92 [95% CI, 1.57 to 5.41]). The risk remained significant after adjustment for race (HR, 2.61 [CI, 1.01 to 6.71]). The risk associated with race alone (HR, 2.13 [CI, 1.21 to 3.75]) was abrogated by adjustment for genotype (HR, 1.13 [CI, 0.48 to 2.69]). Lower last leukocyte count and lower dosing were significant among patients with the CC genotype. Lower dosing was validated in an external cohort of 94 children of African ancestries prescribed the thiopurine 6-mercaptopurine (6-MP) for acute lymphoblastic leukemia. The CC genotype was independently associated with lower 6-MP dose intensity relative to the target daily dose of 75 mg/m2 (median, 0.83 [IQR, 0.70 to 0.94] for the CC genotype vs. 0.94 [IQR, 0.72 to 1.13] for the TT or TC genotype; P = 0.013). LIMITATIONS: Unmeasured confounding; data limited to tertiary centers. CONCLUSION: Patients with the CC genotype had higher risk for azathioprine discontinuation attributed to hematopoietic toxicity and lower thiopurine doses. Genotype was associated with those risks, even after adjustment for race. PRIMARY FUNDING SOURCE: National Institutes of Health.

Extracorporeal photopheresis chargemasters show haphazard billing practices.

BACKGROUND: United States healthcare spending continues to outpace other developed nations although efforts are being made to increase cost-transparency. Recent legislation requires hospitals to publish a chargemaster, a list of all billable procedure codes together with prices. Chargemaster prices have been shown to be highly variable, if available, and are not typically paid, but contribute to negotiated rates. Extracorporeal photopheresis (ECP) is performed for a limited number of indications and could serve as a marker of this variability. We investigated the availability of chargemaster documentation for ECP procedures and the variability of pricing as assessed by institutional characteristics. STUDY DESIGN AND METHODS: A list of centers with photopheresis systems was obtained from the device manufacturer and the institutional websites were analyzed for chargemaster list prices. Multivariate linear regressions were performed to compare impact of facility variables on chargemaster pricing. RESULTS: There are 139 locations in the US which are listed as referral centers for ECP; and chargemaster prices were available in 66.2% of these centers. The range was $571.48-183,452.00, maximum price 321 times greater than minimum, and the median price, after outlier exclusion, was $8989.06 (SD = $4361.72). ECP cost did not correlate with hospital size, facility type, ownership, number of hospitals in the referral region, hospital care intensity index, academic status, or region (p ≥ .05). CONCLUSIONS: Chargemaster costs for ECP procedures are highly variable and nonuniform, and the current data available for patients undergoing these specialized apheresis procedures is insufficient to afford patients the ability to compare prices.

An oral cavity squamous cell carcinoma quantitative histomorphometric-based image classifier of nuclear morphology can risk stratify patients for disease-specific survival.

Oral cavity squamous cell carcinoma is the most common type of head and neck carcinoma. Its incidence is increasing worldwide, and it is associated with major morbidity and mortality. It is often unclear which patients have aggressive, treatment refractory tumors vs those whose tumors will be more responsive to treatment. Better identification of patients with high- vs low-risk cancers could help provide more tailored treatment approaches and could improve survival rates while decreasing treatment-related morbidity. This study investigates computer-extracted image features of nuclear shape and texture on digitized images of H&E-stained tissue sections for risk stratification of oral cavity squamous cell carcinoma patients compared with standard clinical and pathologic parameters. With a tissue microarray cohort of 115 retrospectively identified oral cavity squamous cell carcinoma patients, 50 were randomly chosen as the modeling set, and the remaining 65 constituted the test set. Following nuclear segmentation and feature extraction, the Wilcoxon rank sum test was used to identify the five most prognostic quantitative histomorphometric features from the modeling set. These top ranked features were then combined via a machine learning classifier to construct the oral cavity histomorphometric-based image classifier (OHbIC). The classifier was then validated for its ability to risk stratify patients for disease-specific outcomes on the test set. On the test set, the classifier yielded an area under the receiver operating characteristic curve of 0.72 in distinguishing disease-specific outcomes. In univariate survival analysis, high-risk patients predicted by the classifier had significantly poorer disease-specific survival (P=0.0335). In multivariate analysis controlling for T/N-stage, resection margins, and smoking status, positive classifier results were independently predictive of poorer disease-specific survival: hazard ratio (95% confidence interval)=11.023 (2.62-46.38) and P=0.001. Our results suggest that quantitative histomorphometric features of local nuclear architecture derived from digitized H&E slides of oral cavity squamous cell carcinomas are independently predictive of patient survival.

Temporal modelling of the biofilm lifecycle (TMBL) establishes kinetic analysis of plate-based bacterial biofilm dynamics.

Bacterial biofilms are critical to pathogenesis and infection. They are associated with rising rates of antimicrobial resistance. Biofilms are correlated with worse clinical outcomes, making them important to infectious diseases research. There is a gap in knowledge surrounding biofilm kinetics and dynamics which makes biofilm research difficult to translate from bench to bedside. To address this gap, this work employs a well-characterized crystal violet biomass accrual and planktonic cell density assay across a clinically relevant time course and expands statistical analysis to include kinetic information in a protocol termed the TMBL (Temporal Mapping of the Biofilm Lifecycle) assay. TMBL's statistical framework quantitatively compares biofilm communities across time, species, and media conditions in a 96-well format. Measurements from TMBL can reliably be condensed into response features that inform the time-dependent behavior of adherent biomass and planktonic cell populations. Staphylococcus aureus and Pseudomonas aeruginosa biofilms were grown in conditions of metal starvation in nutrient-variable media to demonstrate the rigor and translational potential of this strategy. Significant differences in single-species biofilm formation are seen in metal-deplete conditions as compared to their controls which is consistent with the consensus literature on nutritional immunity that metal availability drives transcriptomic and metabolomic changes in numerous pathogens. Taken together, these results suggest that kinetic analysis of biofilm by TMBL represents a statistically and biologically rigorous approach to studying the biofilm lifecycle as a time-dependent process. In addition to current methods to study the impact of microbe and environmental factors on the biofilm lifecycle, this kinetic assay can inform biological discovery in biofilm formation and maintenance.

Concurrent Gabapentin and Opioid Use and Risk of Mortality in Medicare Recipients with Non-Cancer Pain.

Gabapentin is prescribed for pain and is perceived as safe generally. However, gabapentin can cause respiratory depression, exacerbated by concomitant central nervous system depressants (e.g., opioids), a concern for vulnerable populations. We compared mortality rates among new users of either gabapentin or duloxetine with or without concurrent opioids in the 20% Medicare sample. We conducted a new-user design retrospective cohort study, in Medicare enrollees ages 65-89 years with noncancer chronic pain and no severe illness who filled prescriptions between 2015 and 2018 for gabapentin (n = 233,060) or duloxetine (n = 34,009). Daily opioid doses, estimated in morphine milligram equivalents (MMEs), were classified into none, low (0 < MME < 50), and high (≥ 50 MME), based on Centers for Disease Control and Prevention (CDC) recommendations. The outcomes were all-cause mortality (primary) and out-of-hospital mortality (secondary). We used inverse probability of treatment weighting to adjust for differences between gabapentin and duloxetine users. During 116,707 person-years of follow-up, 1,379 patients died. All-cause mortality rate in gabapentin users was 12.16 per 1,000 person-years vs. 9.94 per 1,000 in duloxetine users. Risks were similar for users with no concurrent opioids (adjusted hazard ratio (aHR) = 1.03, 95% confidence interval (CI): 0.80-1.31) or low-dose daily opioids (aHR = 1.06, 95% CI: 0.63-1.76). However, gabapentin users receiving concurrent high-dose daily opioids had an increased rate of all-cause mortality compared with duloxetine users on high-dose opioids (aHR = 2.03, 95% CI: 1.19-3.46). Out-of-hospital mortality yielded similar results. In this retrospective cohort study of Medicare beneficiaries, concurrent use of high-dose opioids and gabapentin was associated with a higher all-cause mortality risk than that for concurrent use of high-dose opioids and duloxetine.

Duloxetine, Gabapentin, and the Risk for Acute Myocardial Infarction, Stroke, and Out-of-Hospital Death in Medicare Beneficiaries With Non-Cancer Pain.

OBJECTIVE: Duloxetine is a serotonin-norepinephrine reuptake inhibitor prescribed for musculoskeletal and other forms of chronic pain. Its dual pharmacologic properties have the potential to either raise or lower cardiovascular risk: adrenergic activity may increase the risk for acute myocardial infarction (AMI) and stroke, but antiplatelet activity may decrease risk. Gabapentin is another nonopioid medication used to treat pain, which is not thought to have adrenergic/antiplatelet effects. With the current emphasis on the use of nonopioid medications to treat patients with chronic pain, assessing cardiovascular risks associated with these medications among high-risk patients is important. MATERIALS AND METHODS: We conducted a retrospective cohort study among a 20% sample of Medicare enrollees, aged 65 to 89, with chronic pain who were new users between 2015 and 2018 of either duloxetine (n = 34,009) or gabapentin (n = 233,060). We excluded individuals with cancer or other life-threatening conditions at study drug initiation. The primary outcome was a composite of AMI, stroke, and out-of-hospital mortality. We adjusted for comorbidity differences with time-dependent inverse probability of treatment weighting. RESULTS: During 115,668 person-years of follow-up, 2361 patients had the composite primary outcome; the rate among new users of duloxetine was 16.7/1000 person-years compared with new users of gabapentin (21.1/1000 person-years), adjusted hazard ratio = 0.98 (95% CI: 0.83, 1.16). Results were similar for the individual components of the composite outcome as well as in analyses stratified by demographic and clinical characteristics. DISCUSSION: In summary, cohort Medicare patients with non-cancer pain beginning treatment with duloxetine had rates of AMI, stroke, and out-of-hospital mortality comparable to those who initiated gabapentin.

Predicted expression of genes involved in the thiopurine metabolic pathway and azathioprine discontinuation due to myelotoxicity.

TPMT and NUDT15 variants explain less than 25% of azathioprine-associated myelotoxicity. There are 25 additional genes in the thiopurine pathway that could also contribute to azathioprine myelotoxicity. We hypothesized that among TPMT and NUDT15 normal metabolizers, a score combining the genetically predicted expression of other proteins in the thiopurine pathway would be associated with a higher risk for azathioprine discontinuation due to myelotoxicity. We conducted a retrospective cohort study of new users of azathioprine who were normal TPMT and NUDT15 metabolizers. In 1201 White patients receiving azathioprine for an inflammatory disease, we used relaxed Least Absolute Shrinkage and Selection Operator (LASSO) regression to select genes that built a score for discontinuing azathioprine due to myelotoxicity. The score incorporated the predicted expression of AOX1 and NME1. Patients in the highest score tertile had a higher risk of discontinuing azathioprine compared to those in the lowest tertile (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.11-4.19, p = 0.024). Results remained significant after adjusting for a propensity score, including sex, tertile of calendar year at initial dose, initial dose, age at baseline, indication, prior TPMT testing, and the first 10 principal components of the genetic data (HR = 2.11, 95% CI = 1.08-4.13, p = 0.030). We validated the results in a cohort (N = 517 non-White patients and those receiving azathioprine to prevent transplant rejection) that included all other patients receiving azathioprine (HR = 2.00, (95% CI = 1.09-3.65, p = 0.024). In conclusion, among patients who were TPMT and NUDT15 normal metabolizers, a score combining the predicted expression of AOX1 and NME1 was associated with an increased risk for discontinuing azathioprine due to myelotoxicity.

Prostate cancer risk variants of the HOXB genetic locus.

The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case-control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E-9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E-11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E-8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.

Oropharyngeal Squamous Cell Carcinoma Morphology and Subtypes by Human Papillomavirus Type and by 16 Lineages and Sublineages.

Oropharyngeal squamous cell carcinoma (SCC) is increasing in incidence and, in Western countries, strongly associated with transcriptionally-active high-risk human papillomavirus (HPV). Within HPV-positive tumors, there is wide morphologic diversity with numerous histologic subtypes of SCC. There are also variable degrees of keratinization, anaplasia, stromal fibrosis, and maturing squamous differentiation. Unlike in the uterine cervix, where associations between HPV types and lineages/sublineages within types have been investigated with some clear correlations identified, little to no data exists for oropharyngeal SCC. In this study, for a large cohort of oropharyngeal SCC patients, we performed RTPCR for high-risk HPV. For the HPV positive patients, we sequenced the DNA of the entire HPV16 genome and determined lineages and sublineages, correlating HPV status, genotype, and HPV16 lineages/sublineages with SCC subtype and various histologic features. Of the 259 patients, 224 (86.5%) were high-risk HPV positive, of which 210/224 (93.8%) were HPV type 16 and 6/224 (2.7%) HPV type 33. Of the four HPV16 lineages, A was the most frequent (192/214 or 89.8%) and of the HPV16 A sublineages, A1 was the most frequent (112/210 or 53.3%). Patients with HPV negative tumors were more often keratinizing vs other types (23/35 or 65.7%) and thus more likely to have more maturing squamous differentiation and stromal desmoplasia. There was no significant correlation between HPV type (16 versus other), between HPV16 lineage (A versus others), or HPV16 A sublineages (A1 or A2 versus others) and morphologic type of SCC nor the various morphologic features of anaplasia/multinucleation, degree of keratinization, nor amount of stromal desmoplasia. In summary, in our cohort, there was no correlation between the type of HPV, the HPV 16 lineage or sublineage, and any of the histologic features or morphologic SCC subtypes.

8q24 genetic variation and comprehensive haplotypes altering familial risk of prostate cancer.

The 8q24 genomic locus is tied to the origin of numerous cancers. We investigate its contribution to hereditary prostate cancer (HPC) in independent study populations of the Nashville Familial Prostate Cancer Study and International Consortium for Prostate Cancer Genetics (combined: 2,836 HPC cases, 2,206 controls of European ancestry). Here we report 433 variants concordantly associated with HPC in both study populations, accounting for 9% of heritability and modifying age of diagnosis as well as aggressiveness; 183 reach genome-wide significance. The variants comprehensively distinguish independent risk-altering haplotypes overlapping the 648 kb locus (three protective, and four risk (peak odds ratios: 1.5, 4, 5, and 22)). Sequence of the near-Mendelian haplotype reveals eleven causal mutation candidates. We introduce a linkage disequilibrium-based algorithm discerning eight independent sentinel variants, carrying considerable risk prediction ability (AUC = 0.625) for a single locus. These findings elucidate 8q24 locus structure and correlates for clinical prediction of prostate cancer risk.

Anesthesia and Euthanasia of Brine Shrimp (Artemia franciscana).

Invertebrates are often overlooked as laboratory animals, yet they are commonly used in toxicology, developmental, cellular and molecular biology, and radiation studies with euthanasia as an endpoint. Little is known regarding appropriate euthanasia methods for invertebrate species, particularly for Artemia. Here, we evaluated the AVMA-recommended 2-step method of euthanasia in brine shrimp (Artemia franciscana). Artemia were exposed first to anesthetic solutions of 60% alcohol, 2.5 mg/L eugenol, or 4 g/L tricaine methanesulfonate (TMS) and then were transferred to euthanasia solutions of 70% alcohol, 95% alcohol, or 10% neutral buffered formalin. We examined time to anesthesia, behavioral response to anesthesia, anesthesia recovery, and time to euthanasia. Our results show that 2.5 mg/L eugenol and 4 g/L TMS inconsistently achieved anesthesia. Although 60% alcohol produced anesthesia, the time to anesthesia varied among replicate groups, and exposure resulted in an increase in abnormal behavior. We therefore do not recommend any of the tested anesthetic solutions for use in Artemia. Although all 3 euthanasia solutions were effective, more research is needed to provide recommendations regarding euthanasia for this species.

Expression and Significance of Cytokeratin 7, a Squamocolumnar Junction Marker, in Head and Neck Squamous Cell Carcinoma.

The favorable features of high-risk human papillomavirus (HPV) in the head and neck are limited to those harboring transcriptionally-active HPV, which occur predominantly in the oropharynx (OP). Factors rendering the OP susceptible to HPV oncogenesis are largely unexplored. The role of cytokeratin 7 (CK7) in predisposition to HPV and cancer in the cervix has been evaluated. However, its significance in the H&N is unknown. CK7 immunohistochemistry was performed on a tissue microarray cohort of OP and non-oropharyngeal (NOP) squamous cell carcinomas (SCC) with known clinical follow-up and HPV E6/7 mRNA status. Expression was graded based on the distribution (1 ≤ 33%, 2 = 33-66%, 3 ≥ 66%) and intensity (1 = weak, 2 = strong) with combined score of ≥ 2 considered positive. Survival analysis was performed. Seventy-four NOPSCCs and 204 OPSCCs were studied. HPV was positive in 2.7% of NOPSCCs and 70.9% of OPSCCs. CK7 was positive in 23.0% of OPSCCs and 14.8% of NOPSCCs (p = 0.2), and in 24.1% of HPV positive versus 17.2% of negative patients (p = 0.2). There was no correlation with age, race, gender, HPV status, histologic type, tumor subsite, treatment, stage, or co-morbidities, and CK7 expression was not significantly associated with overall or disease specific survival. In our series, CK7 is positive in ~ 25% of H&N SCCs, although usually only focally. While CK7 has been suspected to be overexpressed selectively in HPV-related OPSCCs due to their origination from tonsillar crypt epithelium, we did not find any significant difference by anatomic H&N subsite, nor by HPV status, for its expression and found no association with patient survival.

Genomic-Epidemiologic Evidence That Estrogens Promote Breast Cancer Development.

Background: Estrogens are a prime risk factor for breast cancer, yet their causal relation to tumor formation remains uncertain. A recent study of 560 breast cancers identified 82 genes with 916 point mutations as drivers in the genesis of this malignancy. Because estrogens play a major role in breast cancer development and are also known to regulate the expression of numerous genes, we hypothesize that the 82 driver genes are likely to be influenced by estrogens, such as 17ß-estradiol (E2), and the estrogen receptor ESR1 (ERα). Because different types of tumors are characterized by unique sets of cancer driver genes, we also argue that the fraction of driver genes regulated by E2-ESR1 is lower in malignancies not associated with estrogens, e.g., acute myeloid leukemia (AML).Methods: We performed a literature search of each driver gene to determine its E2-ESR1 regulation.Results: Fifty-three of the 82 driver genes (64.6%) identified in breast cancers showed evidence of E2-ESR1 regulation. In contrast, only 19 of 54 mutated driver genes (35.2%) identified in AML were linked to E2-ESR1. Among the 916 driver mutations found in breast cancers, 813 (88.8%) were linked to E2-ESR1 compared with 2,046 of 3,833 in AML (53.4%).Conclusions: Risk assessment revealed that mutations in estrogen-regulated genes are much more likely to be associated with elevated breast cancer risk, while mutations in unregulated genes are more likely to be associated with AML.Impact: These results increase the plausibility that estrogens promote breast cancer development. Cancer Epidemiol Biomarkers Prev; 27(8); 899-907. ©2018 AACR.

Is tumor cellularity in primary invasive breast carcinoma of prognostic significance?

Many methods of analysis to predict survival of invasive mammary carcinoma in the post-neoadjuvant setting utilize tumor cellularity alone or in combination with other tumor features. The goal of this study was to evaluate the prognostic value of tumor cellularity in primary non-treated carcinoma. We used 366 cases of invasive breast carcinoma to determine invasive tumor cellularity (%) by reviewing a representative excisional tumor section and correlated this with breast cancer recurrence (BCR) and overall mortality (OM). Mean patient age was 58 years (range, 21-91) and median follow-up was 87 months (range, 0.7-165). Of the cases, 25% were Nottingham grades I, 41% grade II, and 32% grade III. The Nottingham Prognostic Index (NPI) ranged from 2.06 to 6.8 (mean 3.93). Estrogen receptor was positive in 66% and negative in 25% of cases. Cellularity ranged from 2 to 99% (mean 47.6%). The OM hazard ratio increased by 1.73 for every unit increase in NPI (P < 0.00005; 95% confidence interval 1.45-2.05) The BCR hazard ratio increased by 2.011 for every unit increase in NPI BCR (P < 0.00005; 95% confidence interval 1.62-2.50). Cellularity, unadjusted for other covariates, was not significantly associated with either OM or BCR. When adjusted for NPI, cellularity still showed no significant relation to OM or BCR. The same analysis performed on estrogen receptor-positive and estrogen receptor-negative subgroups continued to show no relation between cellularity and OM or BCR. In conclusion, despite its utility in the neoadjuvant setting, we were unable to show that cellularity is predictive of survival in primary breast carcinomas.

Optimal diagnostic thresholds for diagnosis of orthostatic hypotension with a 'sit-to-stand test'.

OBJECTIVE: This study aimed to identify optimal blood pressure cut-offs to diagnose orthostatic hypotension during a sit-to-stand manoeuvre. METHODS: This was a cross-sectional study of patients and healthy controls from the Vanderbilt Autonomic Dysfunction Center. Blood pressure was measured while supine, seated and standing. Blood pressure changes were calculated from supine-to-standing and seated-to-standing. Orthostatic hypotension was diagnosed on the basis of a supine-to-standing SBP drop at least 20 mmHg or a DBP drop at least 10 mmHg. Receiver operator characteristic (ROC) curves identified optimal sit-to-stand cut-offs. RESULTS: Amongst the 831 individuals, more had systolic orthostatic hypotension [n = 354 (43%)] than diastolic orthostatic hypotension [n = 305 (37%)] during lying-to-standing. The ROC curves had good characteristics [SBP area under curve = 0.916 (95% confidence interval: 0.896-0.936), P < 0.001; DBP area under curve = 0.930 (95% confidence interval: 0.909-0.950), P < 0.001]. A sit-to stand SBP drop at least 15 mmHg had optimal test characteristics (sensitivity = 80.2%; specificity = 88.9%; positive predictive value = 84.2%; negative predictive value = 85.8%), as did a DBP drop at least 7 mmHg (sensitivity = 87.2%; specificity = 87.2%; positive predictive value = 80.1%; negative predictive value = 92.0%). CONCLUSIONS: A sit-to-stand manoeuvre with lower diagnostic cut-offs for orthostatic hypotension provides a simple screening test for orthostatic hypotension in situations wherein a supine-to-standing manoeuvre cannot be easily performed. Our analysis suggests that a SBP drop at least 15 mmHg or a DBP drop at least 7 mmHg best optimizes sensitivity and specificity of this sit-to-stand test.

Effect of CPOE user interface design on user-initiated access to educational and patient information during clinical care.

OBJECTIVE: Authors evaluated whether displaying context sensitive links to infrequently accessed educational materials and patient information via the user interface of an inpatient computerized care provider order entry (CPOE) system would affect access rates to the materials. DESIGN: The CPOE of Vanderbilt University Hospital (VUH) included "baseline" clinical decision support advice for safety and quality. Authors augmented this with seven new primarily educational decision support features. A prospective, randomized, controlled trial compared clinicians' utilization rates for the new materials via two interfaces. Control subjects could access study-related decision support from a menu in the standard CPOE interface. Intervention subjects received active notification when study-related decision support was available through context sensitive, visibly highlighted, selectable hyperlinks. MEASUREMENTS: Rates of opportunities to access and utilization of study-related decision support materials from April 1999 through March 2000 on seven VUH Internal Medicine wards. RESULTS: During 4,466 intervention subject-days, there were 240,504 (53.9/subject-day) opportunities for study-related decision support, while during 3,397 control subject-days, there were 178,235 (52.5/subject-day) opportunities for such decision support, respectively (p = 0.11). Individual intervention subjects accessed the decision support features at least once on 3.8% of subject-days logged on (278 responses); controls accessed it at least once on 0.6% of subject-days (18 responses), with a response rate ratio adjusted for decision support frequency of 9.17 (95% confidence interval 4.6-18, p < 0.0005). On average, intervention subjects accessed study-related decision support materials once every 16 days individually and once every 1.26 days in aggregate. CONCLUSION: Highlighting availability of context-sensitive educational materials and patient information through visible hyperlinks significantly increased utilization rates for study-related decision support when compared to "standard" VUH CPOE methods, although absolute response rates were low.

Inspiratory resistance improves postural tachycardia: a randomized study.

BACKGROUND: The objective of this study was to determine the effect of inspiratory resistance through an impedance threshold device (ITD) on orthostatic tolerance in patients with postural tachycardia syndrome. We hypothesized that the ITD would result in a greater negative intrathoracic pressure to enhance cardiac venous return, improve stroke volume, and reduce heart rate in these patients. METHODS AND RESULTS: We compared the effect of a sham device (sham, no resistance) versus an ITD (increased inspiratory resistance) in 26 patients with postural tachycardia syndrome in a randomized, single-blind, crossover study. Hemodynamic assessments were performed at baseline while supine and during head-up tilt to 70° for 10 minutes. We did not find differences in baseline hemodynamic parameters between the ITD and the sham devices. After 10 minutes of head-up tilt, the heart rate was lower with the ITD versus sham device (102±4 versus 109±4 beat/min, respectively; P=0.003). The ITD also improved stroke volume compared with the sham device (35±2 versus 26±1 mL; P=0.006). CONCLUSIONS: These findings suggest that increasing negative intrathoracic pressure with ITD breathing improves heart rate control in patients with postural tachycardia syndrome during upright posture. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Unique Identifier: NCT00962728.

Optimizing personalized bone marrow testing using an evidence-based, interdisciplinary team approach.

OBJECTIVES: To address the overuse of testing that complicates patient care, diminishes quality, and increases costs by implementing the diagnostic management team, a multidisciplinary system for the development and deployment of diagnostic testing guidelines for hematologic malignancies. METHODS: The team created evidence-based standard ordering protocols (SOPs) for cytogenetic and molecular testing that were applied by pathologists to bone marrow biopsy specimens on adult patients. Testing on 780 biopsy specimens performed during the six months before SOP implementation was compared with 1,806 biopsy specimens performed during the subsequent 12 months. RESULTS: After implementation, there were significant decreases in tests discordant with SOPs, omitted tests, and the estimated cost of testing to payers. The fraction of positive tests increased. Clinicians reported acceptance of the new procedures and perceived time savings. CONCLUSIONS: This process is a model for optimizing complex and personalized diagnostic testing.

A multistage genetic association study identifies breast cancer risk loci at 10q25 and 16q24.

BACKGROUND: Heritable risk for breast cancer includes an increasing number of common, low effect risk variants. We conducted a multistage genetic association study in a series of independent epidemiologic breast cancer study populations to identify novel breast cancer risk variants. METHODS: We tested 1,162 SNPs of greatest nominal significance from stage I of the Cancer Genetic Markers of Susceptibility breast cancer study (CGEMS; 1,145 cases, 1,142 controls) for evidence of replicated association with breast cancer in the Nashville Breast Cohort (NBC; 599 cases, 1,161 controls), the Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls), and BioVU Breast Cancer Study (BioVU; 1,172 cases, 1,172 controls). RESULTS: Among these SNPs, a series of validated breast cancer risk variants yielded expected associations in the study populations. In addition, we observed two previously unreported loci that were significantly associated with breast cancer risk in the CGEMS, NBC, and CBCS study populations and had a consistent, although not statistically significant, risk effect in the BioVU study population. These were rs1626678 at 10q25.3 near ENO4 and KIAA1598 (meta-analysis age-adjusted OR = 1.13 [1.07-1.20], P = 5.6 × 10(-5)), and rs8046508 at 16q23.1 in the eighth intron of WWOX (meta-analysis age-adjusted OR = 1.20 [1.10-1.31], P = 3.5 × 10(-5)). CONCLUSIONS: Our data supports the association of two novel loci, at 10q25.3 and 16q23.1, with risk of breast cancer. IMPACT: The expanding compendium of known breast cancer genetic risk variants holds increasing power for clinical risk prediction models of breast cancer, improving upon the Gail model.

Estrogen metabolism and exposure in a genotypic-phenotypic model for breast cancer risk prediction.

BACKGROUND: Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites. METHODS: We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE(2)), expressed as area under the curve metric (4-OHE(2)-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, and family history), which plausibly influence estrogen metabolism and the production of 4-OHE(2). We applied the model to two independent, population-based breast cancer case-control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls). RESULTS: In the GENICA study, premenopausal women at the 90th percentile of 4-OHE(2)-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE(2)-AUC percentile (95% CI: 1.7-3.2, P = 2.9 × 10(-7)). This relative risk was 1.89 (95% CI: 1.5-2.4, P = 2.2 × 10(-8)) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI: 1.3-2.6, P = 7.6 × 10(-4)), which increased to 1.83 (95% CI: 1.4-2.3, P = 9.5 × 10(-7)) when a history of proliferative breast disease was included in the model. CONCLUSIONS: The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk. IMPACT: The estrogen carcinogenesis-based model has the potential to provide personalized risk estimates.