Citations

Background: Variations in cardiac troponin concentrations by age, sex, and time between samples in patients with suspected myocardial infarction are not currently accounted for in diagnostic approaches. We aimed to combine these variables through machine learning to improve the assessment of risk for individual patients. Methods: A machine learning algorithm (myocardial-ischemic-injury-index [MI 3 ]) incorporating age, sex, and paired high-sensitivity cardiac troponin I concentrations, was trained on 3013 patients and tested on 7998 patients with suspected myocardial infarction. MI 3 uses gradient boosting to compute a value (0–100) reflecting an individual’s likelihood of a diagnosis of type 1 myocardial infarction and estimates the sensitivity, negative predictive value, specificity and positive predictive value for that individual. Assessment was by calibration and area under the receiver operating characteristic curve. Secondary analysis evaluated example MI 3 thresholds from the training set that identified patients as low risk (99% sensitivity) and high risk (75% positive predictive value), and performance at these thresholds was compared in the test set to the 99th percentile and European Society of Cardiology rule-out pathways. Results: Myocardial infarction occurred in 404 (13.4%) patients in the training set and 849 (10.6%) patients in the test set. MI 3 was well calibrated with a very high area under the receiver operating characteristic curve of 0.963 [0.956–0.971] in the test set and similar performance in early and late presenters. Example MI 3 thresholds identifying low- and high-risk patients in the training set were 1.6 and 49.7, respectively. In the test set, MI 3 values were <1.6 in 69.5% with a negative predictive value of 99.7% (99.5–99.8%) and sensitivity of 97.8% (96.7–98.7%), and were ≥49.7 in 10.6% with a positive predictive value of 71.8% (68.9–75.0%) and specificity of 96.7% (96.3–97.1%). Using these thresholds, MI 3 performed better than the European Society of Cardiology 0/3-hour pathway (sensitivity, 82.5% [74.5–88.8%]; specificity, 92.2% [90.7–93.5%]) and the 99th percentile at any time point (sensitivity, 89.6% [87.4–91.6%]); specificity, 89.3% [88.6–90.0%]). Conclusions: Using machine learning, MI 3 provides an individualized and objective assessment of the likelihood of myocardial infarction, which can be used to identify low- and high-risk patients who may benefit from earlier clinical decisions. Clinical Trial Registration: URL: https://www.anzctr.org.au . Unique identifier: ACTRN12616001441404.

Abstract Background: Mammographic breast density (MBD) is a strong breast cancer (BC) risk factor, but its biologic underpinnings are poorly understood. Use of estrogen plus progestin menopausal hormone therapy is linked to increased MBD and BC risk. Experimental data suggest that ratios of tumor promoting (5α-dihydroprogesterone [5αP]) and anti-tumorigenic (3α-dihydroprogesterone [3αP]) progesterone metabolite levels may be related to BC risk. However, relationships of endogenous progesterone and its metabolites with MBD and BC risk have not been established. Accordingly, we assessed levels of circulating progesterone and its metabolites with MBD. Methods: In this cross-sectional study, serum progesterone and its metabolites were quantified using a novel liquid chromatography-tandem mass spectrometry assay in 103 postmenopausal and 52 premenopausal (luteal menstrual cycle phase) women, ages 40-65, undergoing diagnostic image-guided ipsilateral breast biopsy. MBD was measured as percent fibroglandular volume (MBD-V) on pre-biopsy digital mammograms using single X-ray absorptiometry. Square-root transformed MBD-V was examined across tertile categories of progesterone/progesterone metabolites using age and body mass index (BMI)-adjusted linear regression models. Results: Concentrations of the hormones were as follows among postmenopausal women: progesterone [mean: 12.6 pmol/L (range: 5.2-45.8)], 3αP [5.6 pmol/L (1.4-18.8)], 5αP [100 pmol/L (16.7-388)], and 5αP/3αP ratio [26.1 (2.1-150)]; and among luteal phase premenopausal women: progesterone [2063 pmol/L (13.6-7098), 3αP [12.7 pmol/L (2.4-64.4)], 5αP [243 pmol/L (25.3-774)], 5αP/3αP ratio [25.9 (2.3-73.7)]. Among postmenopausal women, progesterone was positively associated with MBD-V (Tertile 3 vs. 1: β=0.68, p-trend=0.02). A similar borderline positive association was observed among premenopausal women (β=0.74, p-trend=0.10). Additional adjustment for circulating estradiol did not substantively alter observed associations. Levels of 3αP, 5αP and the 5αP/3αP ratio were not associated with MBD-V among pre- or postmenopausal women. Conclusions: Concentrations of progesterone and it metabolites show substantial inter-woman variation. We observed a positive association between endogenous progesterone and MBD-V among both postmenopausal and premenopausal luteal phase women. We did not observe an association with the ratio of 5αP to 3αP levels and MBD-V. These findings suggest the need for additional studies to understand the biological basis of the role of progesterone and its metabolites in MBD and BC risk. Citation Format: Manila Hada, Hannah Oh, Sharon Fan, Roni T. Falk, Berta Geller, Pamela Vacek, Donald Weaver, John Shepherd, Jeff Wang, Bo Fan, Amir P. Mahmoudzadeh, Serghei Malkov, Sally Herschorn, Louise A. Brinton, Xia Xu, Mark E. Sherman, Britton Trabert, Gretchen L. Gierach. Relationship of serum progesterone and progesterone metabolites with mammographic density [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 588.

AbstractThis was a single‐center, randomized controlled trial assessing the impact of a 3‐month (10‐16 weeks) conversion to everolimus with low‐exposure tacrolimus, as compared to remaining on full exposure tacrolimus with mycophenolate (NCT 02096107). Adult kidney transplant recipients with a functioning graft were eligible for participation. Goal troughs in the intervention arm were 2‐5 ng/mL for tacrolimus and 3‐8 ng/mL for everolimus, with tacrolimus maintained at 5‐12 ng/mL in the control arm; 60 were randomized (30 in each arm) and were well matched at baseline; mean age was 51 years and 57% were African‐American. At 12‐months, fibrosis scores (27.8% tacrolimus/mycophenolate vs 22.9% tacrolimus/everolimus, P = .391), acute rejection rates (7% tacrolimus/mycophenolate vs 3% tacrolimus/everolimus, P = .554), and graft function (mean eGFR tacrolimus/mycophenolate 56 ± 15 vs tacrolimus/everolimus 59 ± 14 mL/min/1.73 m2, P = .465) were similar between arms. The everolimus arm had significantly lower rates of CMV infection, severe BK infection, and improved BK viral clearance kinetics, as compared to the MPA arm. In this population, including a significant number of African‐Americans, an immunosuppression regimen of everolimus with low‐exposure tacrolimus provided similar efficacy to tacrolimus and mycophenolate, with significantly lower rates of BK and CMV.

Zebrafish are increasingly utilized to model cardiomyopathies and regeneration. Current methods evaluating cardiac function have known limitations, fail to reliably detect focal mechanics, and are not readily feasible in zebrafish. We developed a semiautomated, open-source method — displacement analysis of myocardial mechanical deformation (DIAMOND) — for quantitative assessment of 4D segmental cardiac function. We imaged transgenic embryonic zebrafish in vivo using a light-sheet fluorescence microscopy system with 4D cardiac motion synchronization. Our method permits the derivation of a transformation matrix to quantify the time-dependent 3D displacement of segmental myocardial mass centroids. Through treatment with doxorubicin, and by chemically and genetically manipulating the myocardial injury–activated Notch signaling pathway, we used DIAMOND to demonstrate that basal ventricular segments adjacent to the atrioventricular canal display the highest 3D displacement and are also the most susceptible to doxorubicin-induced injury. Thus, DIAMOND provides biomechanical insights into in vivo segmental cardiac function scalable to high-throughput research applications.

Purpose: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. Methods: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. Results: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. Conclusion: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Background: Little is known about how certain educational interventions may improve informed code status discussions by physician assistant (PA) and nurse practitioner students. Methods: This is a prospective, prospective, single academic center pilot study utilizing a short case-based PowerPoint that reviewed the differences between code status choices and the likelihood of survival to hospital discharge of attempted resuscitation after a cardiac arrest. Training occurred between September 1, 2017, and May 31, 2018. The study population included PA and adult gerontology acute care nurse practitioner (AGACNP) students during their inpatient internal medicine rotation (n = 9) and preclinical PA students (n = 5). Results: After training, there was a significant increase in knowledge in the likelihood of survival to hospital discharge ( P = .01) and comfort level in having an informed code status discussion (3.36 ± 0.81 vs 4.10 ± 0.80, P = .02). For questions related to identification of the correct code status, there were no significant differences before and after the intervention. Conclusion: A short case-based PowerPoint viewed by PA and AGACNP students increased the knowledge about the likelihood of survival to hospital discharge of attempted resuscitation after a cardiac arrest and increased the comfort level of having code status discussions with patients by PA and AGACNP students.

Key PointsHigh-circulating AREG (≥33 pg/mL) reclassifies additional patients into HR categories and further refines the Minnesota aGVHD risk score. Patients with aGVHD and AREG ≥33 pg/mL have lower rates of steroid response, higher NRM, and poorer OS.

Abstract Background: Pelvic inflammatory disease (PID) has been associated with ovarian cancer and Chlamydia trachomatis (chlamydia) is the leading cause of PID in the developed world. Primary infection with chlamydia is often asymptomatic and may persist for several months/years, thus ascertainment of PID in epidemiologic studies is challenging due to pervasive misclassification and under-reporting. To improve our understanding of the role of chlamydia and other infectious agents in developing ovarian cancer, we evaluated serologic markers of infection with incident ovarian cancer using a staged approach in two independent populations. Methods: Studies included: 1) a case-control study conducted in Poland of 278 ovarian cancer cases diagnosed from 2000 to 2003 and age- and study site-matched controls (n=556) and 2) a nested case-control study from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial including 160 women who eventually developed ovarian cancer and 159 matched controls. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between serologic marker titers and ovarian cancer risk using logistic regression adjusted for matching factors and potential confounders. We evaluated laboratory cutpoints indicative of prior chlamydia infection and tested more stringent marker thresholds, identified in Poland and applied in PLCO, that could be relevant for a PID-like infection. Results: In the Polish study, positivity for the chlamydia plasmid-encoded Pgp3 protein was associated with increased ovarian cancer risk [OR (95% CI): 1.63 (1.20-2.22)]; when a positive result was redefined at a higher titer, ovarian cancer risk increased [cutpoint 2: 2.00 (1.38-2.89); cutpoint 3 (max OR): 2.19 (1.29-3.73)]. All other chlamydia markers measured were associated with increased risk at the more stringent positivity threshold in Poland. In the prospective PLCO study, Pgp3 was associated with elevated risk at the laboratory cutpoint [1.43 (0.78-2.63)]; using higher thresholds, Pgp3 was associated with increased ovarian cancer risk [cutpoint 2: 2.25 (1.07-4.71); cutpoint 3: 2.53 (0.63-10.08)]. In both studies, markers of other infections (i.e., Mycoplasma genitalium, herpes simplex virus-2, human papillomavirus, herpes simplex virus-1, polyomavirus, hepatitis B, hepatitis C, Epstein Barr virus, cytomegalovirus) measured were not associated with risk. Conclusions: In two independent populations, the gold standard serologic marker of prior/current chlamydia infection (Pgp3) was associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. Although these findings need to be replicated, they suggest potential ovarian cancer risk reduction through targeted treatment of chlamydia infections. Citation Format: Britton Trabert, Tim Waterboer, Sally B. Coburn, Louise A. Brinton, Mark E. Sherman, Jolanta Lissowska, Beata Peplonska, Patricia Hartge, Michael Pawlita, Nicolas Wentzensen. Serologic markers of infectious agents and ovarian cancer: Markers of prior Chlamydia trachomatis infection associated with increased ovarian cancer risk in two independent populations [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 4942.