Design and methods of the Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen SignificantlY) study: An investigator-blinded randomized controlled trial of education and feedback intervention to reduce inappropriate echocardiograms.

BACKGROUND: Appropriate use criteria (AUC) for transthoracic echocardiography (TTE) were developed to address concerns regarding inappropriate use of TTE. A previous pilot study suggests that an educational and feedback intervention can reduce inappropriate TTEs ordered by physicians in training. It is unknown if this type of intervention will be effective when targeted at attending level physicians in a variety of clinical settings. AIMS: The aim of this international, multicenter study is to evaluate the hypothesis that an AUC-based educational and feedback intervention will reduce the proportion of inappropriate echocardiograms ordered by attending physicians in the ambulatory environment. METHODS: In an ongoing multicentered, investigator-blinded, randomized controlled trial across Canada and the United States, cardiologists and primary care physicians practicing in the ambulatory setting will be enrolled. The intervention arm will receive (1) a lecture outlining the AUC and most recent available evidence highlighting appropriate use of TTE, (2) access to the American Society of Echocardiography mobile phone app, and (3) individualized feedback reports e-mailed monthly summarizing TTE ordering behavior including information on inappropriate TTEs and brief explanations of the inappropriate designation. The control group will receive no education on TTE appropriate use and order TTEs as usual practice. CONCLUSIONS: The Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly in an education RCT) study is the first multicenter randomized trial of an AUC-based educational intervention. The study will examine whether an education and feedback intervention will reduce the rate of outpatient inappropriate TTEs ordered by attending level cardiologists and primary care physicians (www.clinicaltrials.gov identifier NCT02038101).

A smartphone version of the Faces Pain Scale-Revised and the Color Analog Scale for postoperative pain assessment in children.

BACKGROUND: Effective pain assessment is essential during postoperative recovery. Extensive validation data are published supporting the Faces Pain Scale-Revised (FPS-R) and the Color Analog Scale (CAS) in children. Panda is a smartphone-based application containing electronic versions of these scales. OBJECTIVES: To evaluate agreement between Panda and original paper/plastic versions of the FPS-R and CAS and to determine children's preference for either Panda or original versions of these scales. METHODS: ASA I-III children, 4-18 years, undergoing surgery were assessed using both Panda and original versions of either the FPS-R or CAS. Pain assessments were conducted within 10 min of waking from anesthesia and 30 min later. RESULTS: Sixty-two participants, median (range) age 7.5 (4-12) years, participated in the FPS-R trial; Panda scores correlated strongly with the original scores at both time points (Pearson's r > 0.93) with limits of agreement within clinical significance (80% CI). Sixty-six participants, age 13 (5-18) years, participated in the CAS trial. Panda scores correlated strongly with the original scores at both time points (Pearson's r > 0.87); mean pain scores were higher (up to +0.47 out of 10) with Panda than with the original tool, representing a small systematic bias, but limits of agreement were within clinical significance. Most participants who expressed a preference preferred Panda over the original tool (81% of FPS-R, 76% of CAS participants). CONCLUSION: The Panda smartphone application can be used in lieu of the original FPS-R and CAS for assessment of pain in children. Children's preference for Panda may translate to improved cooperation with self-report of pain.

The safety of modern anesthesia for children with long QT syndrome.

BACKGROUND: Patients with long QT syndrome (LQTS) may experience a clinical spectrum of symptoms, ranging from asymptomatic, through presyncope, syncope, and aborted cardiac arrest, to sudden cardiac death. Arrhythmias in LQTS are often precipitated by autonomic changes. This patient population is believed to be at high risk for perioperative arrhythmia, specifically torsades de pointes (TdP), although this perception is largely based on limited literature that predates current anesthetic drugs and standards of perioperative monitoring. We present the largest multicenter review to date of anesthetic management in children with LQTS. METHODS: We conducted a multicentered retrospective chart review of perioperative management of children with clinically diagnosed LQTS, aged 18 years or younger, who received general anesthesia (GA) between January 2005 and January 2010. Data from 8 institutions were collated in an anonymized database. RESULTS: One hundred three patients with LQTS underwent a total of 158 episodes of GA. The median (interquartile range) age and weight of the patients at the time of GA was 9 (3-15) years and 30.3 (15.4-54) kg, respectively. Surgery was LQTS-related in 81 (51%) GA episodes (including pacemaker, implantable cardioverter-defibrillator, and loop recorder insertions and revisions and lead extractions) and incidental in 77 (49%). ß-blocker therapy was administered to 76% of patients on the day of surgery and 47% received sedative premedication. Nineteen percent of patients received total IV anesthesia, 30% received total inhaled anesthesia, and the remaining 51% received a combination. No patient received droperidol. There were 5 perioperative episodes of TdP, all in neonates or infants, all in surgery that was LQTS-related, and none of which was overtly attributable to anesthetic regimen. Thus the incidence (95% confidence interval) of perioperative TdP in incidental versus LQTS-related surgery was 0/77 (0%; 0%-5%) vs 5/81 (6.2%; 2%-14%). CONCLUSIONS: With optimized perioperative management, modern anesthesia for incidental surgery in patients with LQTS is safer than anecdotal case report literature might suggest. Our series suggests that the risk of perioperative TdP is concentrated in neonates and infants requiring urgent interventions after failed first-line management of LQTS.

Identifying a rapid bolus dose of dexmedetomidine (ED50) with acceptable hemodynamic outcomes in children.

BACKGROUND: Dexmedetomidine is a highly sensitive, specific α2 adrenoceptor agonist with anxiolytic, sedative, and analgesic effects. Administration is recommended as a loading dose infused over 10 min. Clinical experience and a previous study suggested a shorter time frame might be used without causing adverse hemodynamic effects. OBJECTIVE: To determine the dexmedetomidine dose that can be given as a rapid 5 s bolus to healthy children during total intravenous anesthesia (TIVA) without causing significant hemodynamic effects. METHODS: ASA I-II children, aged 5-9 years, having elective surgery under TIVA were recruited. The up-and-down sequential study design was employed to determine the effective dose of dexmedetomidine, starting at 0.3 mcg·kg(-1) with 0.1 mcg·kg(-1) intervals, which caused no hemodynamic response in half the subjects (ED50). Positive responses were defined as mean blood pressure (MAP) and/or heart rate (HR) changes ≥30% from baseline. Three parametric estimators and one nonparametric estimator were used to determine the ED50. RESULTS: Twenty-one subjects with median age 7.1 (range 5.4-9.5) years and median weight 23.6 (range 16.2-36.7) kg were recruited. A maximum median HR decrease of 20 b·min(-1) occurred at 50 s and a maximum median MAP increase of 12.5 mmHg occurred at 100 s after bolus dose administration. Fifteen subjects (71%) had a HR <60 b·min(-1) while one subject had a HR <40 b·min(-1) (minimum 35 b·min(-1)) for 60 s following the dexmedetomidine bolus. Four estimators led to an ED50 estimate for dexmedetomidine of 0.49 mcg·kg(-1) [95% CI 0.26-0.80 mcg·kg(-1)]. CONCLUSION: The ED50 of dexmedetomidine administered over 5 s without significant hemodynamic compromise is 0.49 mcg·kg(-1). Further work is needed to determine the 'safe' (ED5 or less) and effective dose for desired perioperative clinical outcomes.

Emergence delirium in children: a randomized trial to compare total intravenous anesthesia with propofol and remifentanil to inhalational sevoflurane anesthesia.

BACKGROUND: Emergence delirium (ED) refers to a variety of behavioral disturbances commonly seen in children following emergence from anesthesia. Vapor-based anesthesia with sevoflurane, the most common pediatric anesthetic technique, is associated with the highest incidence of ED. Propofol has been shown to reduce ED, but these studies have been methodologically limited. OBJECTIVE: To conduct a randomized-controlled trial comparing the incidence of ED in children following sevoflurane (SEVO) anesthesia and propofol-remifentanil total intravenous anesthesia (TIVA). METHODS: One hundred and twelve children, ASA I-II, aged ≥ 2 and ≤ 6 years, undergoing strabismus repair, were assigned to receive TIVA (intravenous induction and maintenance of anesthesia with propofol and remifentanil) or SEVO (inhalational induction and maintenance of anesthesia with sevoflurane). Parent-child induction behavior was scored using the Perioperative Adult Child Behavior Interaction Scale (PACBIS). Postoperatively, ED was assessed by a masked investigator using the Pediatric Anesthesia Emergence Delirium (PAED) Scale and pain using the Face, Legs, Activity, Cry, Consolability (FLACC) Scale every 5 min. RESULTS: Data are reported for 94 subjects. Incidence of ED was higher with SEVO (38.3% vs 14.9%, P = 0.018). There was no difference in the median PACBIS score. A higher FLACC score was seen with SEVO (median 3 vs 1, P = 0.033). Subjects experiencing ED had higher FLACC scores vs those unaffected by ED (median 7 vs 1, P < 0.0001). CONCLUSION: There was a lower incidence of ED after TIVA. Both intravenous and inhalational inductions were similarly well-tolerated. The use of TIVA was associated with reduced postoperative pain as measured using FLACC scores.

Monitoring nociception during general anesthesia with cardiorespiratory coherence.

A novel wavelet transform cardiorespiratory coherence (WTCRC) algorithm has been developed to measure the autonomic state. WTCRC may be used as a nociception index, ranging from 0 (no nociception, strong coherence) to 100 (strong nociception, low coherence). The aim of this study is to estimate the sensitivity of the algorithm to nociception (dental dam insertions) and antinociception (bolus doses of anesthetic drugs). WTCRC's sensitivity is compared to mean heart rate (HRmean) and mean non-invasive blood pressure (NIBPmean), which are commonly used clinical signs. Data were collected from 48 children receiving general anesthesia during dental surgery. The times of dental dam insertion and anesthetic bolus events were noted in real-time during surgeries. 42 dental dam insertion and 57 anesthetic bolus events were analyzed. The change in average WTCRC, HRmean, and NIBPmean was calculated between a baseline period before each event and a response period after. A Wilcoxon rank-sum test was used to compare changes. Dental dam insertion changed the WTCRC nociception index by an average of 14 (82 %) [95 % CI from 7.4 to 19], HRmean by 7.3 beats/min (8.1 %) [5.6-9.6], and NIBPmean by 8.3 mmHg (12 %) [4.9-13]. A bolus dose of anesthetics changed the WTCRC by -15 (-50 %) [-21 to -9.3], HRmean by -4.8 beats/min (4.6 %) [-6.6 to -2.9], and NIBPmean by -2.6 mmHg (3.4 %) [-4.7 to -0.50]. A nociception index based on cardiorespiratory coherence is more sensitive to nociception and antinociception than are HRmean or NIBPmean. The WTCRC algorithm shows promise for noninvasively monitoring nociception during general anesthesia.

An allometric model to estimate fluid requirements in children following burn injury.

OBJECTIVES: To evaluate the ability of an allometric 3/4 Power Model combined with the Galveston Formula (Galveston-3/4 PM Formula) to predict fluid resuscitation requirements in children suffering burn injuries in comparison with the frequently used Parkland Formula and Galveston Formula using the Du Bois formula for surface area estimation (Galveston-DB Formula). AIM: To demonstrate that the Galveston-3/4 PM Formula is clinically equivalent to the Galveston-DB Formula for the estimation of fluid requirements in pediatric burn injury cases. BACKGROUND: Fluid resuscitation requirements differ in children suffering burn injuries when compared to adults. The Parkland Formula works well for normal weight adults but underestimates fluid requirements when indiscriminately applied to pediatric burn patients. The Galveston-DB Formula accounts for the change in body composition with age by using a body surface area (BSA) model but requires the measurement of height. The allometric model, using an exponent of 3/4, accounts for the dependence of a physiological variable on body mass without requiring height measurement and can be applied to estimate fluid requirements after burn injury in children. METHODS: Comparisons were performed between the hourly calculated fluid requirements for the first 8 h following 20%, 40%, and 60% BSA burns using the Parkland Formula, the Galveston-DB Formula and Galveston-3/4 PM Formula for children 2-23 kg. RESULTS: In children less than 23 kg, the fluid requirements predicted by the Galveston-3/4 PM Formula are well correlated with those predicted by the Galveston-DB Formula (R2 = 0.997, P < 0.0001) and are much better than of the predictions made with the Parkland Formula, especially for children <10 kg. CONCLUSIONS: For the purposes of clinical estimation of fluid requirements, the Galveston-3/4 PM Formula is indistinguishable from the Galveston-DB Formula in children 23 kg or less.

Association Between Transthoracic Echocardiography Appropriateness and Echocardiographic Findings.

BACKGROUND: The association between appropriate use criteria and echocardiographic findings in patients with chronic cardiovascular diseases is unknown. METHODS: As a substudy of the Echo WISELY (Will Inappropriate Scenarios for Echocardiography Lessen Significantly) trial, 9,230 transthoracic echocardiographic (TTE) examinations from six Ontario academic hospitals were linked to a registry of echocardiographic findings. The TTE studies were rated appropriate), rarely appropriate, or may be appropriate according to the 2011 appropriate use criteria. TTE findings of appropriately ordered examinations were compared with those of rarely appropriate examinations for specific disease subsets, including heart failure and valvular heart disease. RESULTS: There were 7,574, 1,087, and 569 TTE examinations ordered for appropriate, rarely appropriate, and may be appropriate indications, and of the 7,574 appropriate studies, 6,399 were ordered for specific indications and 1,175 for general indications. TTE examinations ordered for general indications had lower rates of left ventricular dysfunction (19.6% vs 9.1%, P < .001) and moderate to severe aortic stenosis (15.5% vs 2.6%, P < .001). Of the 2,395 TTE examinations ordered for patients with heart failure, appropriately ordered studies were more likely to result in left ventricular segmental abnormality (37.0% vs 24.9%, P = .012) but similar rates of right ventricular dilatation (15.4% vs 14.7%, P = .79), right ventricular dysfunction (14.8% vs 11.3%, P = .22), and moderate to severe mitral regurgitation (12.1% vs 9.2%, P = .35). Of the 2,859 studies ordered to assess valvular heart disease, appropriately ordered studies were significantly more likely to find moderate to severe valvular pathology, including aortic stenosis (30.4% vs 24.6%, P = .008), aortic regurgitation (8.9% vs 1.6%, P < .001), mitral stenosis (6.7% vs 3.1%, P = .002), and mitral regurgitation (16.1% vs 6.1%, P < .001), but similar rates of tricuspid regurgitation (11.2% vs 13.0%, P = .60). CONCLUSIONS: Overall, appropriately ordered TTE examinations for heart failure and valvular heart disease were significantly more likely to have abnormal findings than rarely appropriate examinations. TTE studies ordered for general indications had fewer, although still a significant proportion, of abnormalities compared with studies ordered for specific indications.

Improving the Appropriate Use of Transthoracic Echocardiography: The Echo WISELY Trial.

BACKGROUND: Appropriate use criteria (AUC) have defined transthoracic echocardiogram (TTE) indications for which there is a clear lack of benefit as rarely appropriate (rA). OBJECTIVES: This study sought to investigate the impact of an AUC-based educational intervention on outpatient TTE ordering by cardiologists and primary care providers. METHODS: The authors conducted a prospective, investigator-blinded, multicenter, randomized controlled trial of an AUC-based educational intervention aimed at reducing rA outpatient TTEs. The study was conducted at 8 hospitals across 2 countries. The authors randomized cardiologists and primary care providers to receive either intervention or control (no intervention). The primary outcome measure was the proportion of rA TTEs. RESULTS: One hundred and ninety-six physicians were randomized, and 179 were included in the analysis. From December 2014 to April 2016, the authors assessed 14,697 TTEs for appropriateness, of which 99% were classifiable using the 2011 AUC. The mean proportion of rA TTEs was significantly lower in the intervention versus the control group (8.8% vs. 10.1%; odds ratio [OR]: 0.75; 95% confidence interval [CI]: 0.57 to 0.99; p = 0.039). In physicians who ordered, on average, at least 1 TTE per month, there was a significantly lower proportion of rA TTEs in the intervention versus the control group (8.6% vs. 11.1%; OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.047). There was no difference in the TTE ordering volume between the intervention and control groups (mean 77.7 ± 89.3 vs. 85.4 ± 111.4; p = 0.83). CONCLUSIONS: An educational intervention reduced the number of rA TTEs ordered by attending physicians in a variety of ambulatory care environments. This may prove to be an effective strategy to improve the use of imaging. (A Multi-Centered Feedback and Education Intervention Designed to Reduce Inappropriate Transthoracic Echocardiograms [Echo WISELY]; NCT02038101).

Direct interactions with both p27 and Cdk2 regulate Spy1-mediated proliferation in vivo and in vitro.

Families of cyclin-like proteins have emerged that bind and activate cyclin dependent kinases (Cdk)s, directing the phosphorylation of noncanonical Cdk substrates. One of these proteins, Spy1, has demonstrated the unique ability to directly bind and activate both Cdk1 and Cdk2, as well as binding and promoting the degradation of at least one Cdk inhibitor, p27(Kip1). Spy1 accelerates somatic cell growth and proliferation and is implicated in a number of human cancers including the breast, brain and liver. Herein we isolate key residues mediating the direct interaction with p27. We use mutants of Spy1 to determine the physiological role of direct interactions with distinct binding partners Cdk2 and p27. We demonstrate that disrupting the direct interaction with either Spy1 binding partner decreased endogenous activity of Cdk2, as well as Spy1-mediated proliferation. However, only the direct interaction with p27 was essential for Spy1-mediated effects on p27 stability. In vivo neither mutation completely prevented tumorigenesis, although each mutation slowed the rate of Spy1-mediated tumorigenesis and decreased overall tumor volumes. This work supports the conclusion that direct interaction with both p27 and Cdk2 contribute to Spy1-mediated effects on cell growth. It is important to elucidate the dynamics of these interactions and to consider these data when assessing functional outcomes.

Estimation of respiratory rate from photoplethysmographic imaging videos compared to pulse oximetry.

We present a study evaluating two respiratory rate estimation algorithms using videos obtained from placing a finger on the camera lens of a mobile phone. The two algorithms, based on Smart Fusion and empirical mode decomposition (EMD), consist of previously developed signal processing methods to detect features and extract respiratory induced variations in photoplethysmographic signals to estimate respiratory rate. With custom-built software on an Android phone, photoplethysmographic imaging videos were recorded from 19 healthy adults while breathing spontaneously at respiratory rates between 6 to 32 breaths/min. Signals from two pulse oximeters were simultaneously recorded to compare the algorithms' performance using mobile phone data and clinical data. Capnometry was recorded to obtain reference respiratory rates. Two hundred seventy-two recordings were analyzed. The Smart Fusion algorithm reported 39 recordings with insufficient respiratory information from the photoplethysmographic imaging data. Of the 232 remaining recordings, a root mean square error (RMSE) of 6 breaths/min was obtained. The RMSE for the pulse oximeter data was lower at 2.3 breaths/min. RMSE for the EMD method was higher throughout all data sources as, unlike the Smart Fusion, the EMD method did not screen for inconsistent results. The study showed that it is feasible to estimate respiratory rates by placing a finger on a mobile phone camera, but that it becomes increasingly challenging at respiratory rates greater than 20 breaths/min, independent of data source or algorithm tested.

Respiratory rate assessment from photoplethysmographic imaging.

We present a study investigating the suitability of a respiratory rate estimation algorithm applied to photoplethysmographic imaging on a mobile phone. The algorithm consists of a cascade of previously developed signal processing methods to detect features and extract respiratory induced variations in photoplethysmogram signals to estimate respiratory rate. With custom-built software on an Android phone (Camera Oximeter), contact photoplethysmographic imaging videos were recorded using the integrated camera from 19 healthy adults breathing spontaneously at respiratory rates between 6 and 40 breaths/min. Capnometry was simultaneously recorded to obtain reference respiratory rates. Two hundred and ninety-eight Camera Oximeter recordings were available for analysis. The algorithm detected 22 recordings with poor photoplethysmogram quality and 46 recordings with insufficient respiratory information. Of the 232 remaining recordings, a root mean square error of 5.9 breaths/min and a median absolute error of 2.3 breaths/min was obtained. The study showed that it is feasible to estimate respiratory rates by placing a finger on a mobile phone camera, but that it becomes increasingly challenging at respiratory rates higher than 20 breaths/min.

Real-time cardiorespiratory coherence is blind to changes in respiration during general anesthesia.

PURPOSE: A novel real-time cardiorespiratory coherence (CRC) algorithm has been developed to monitor nociception during general anesthesia. CRC uses custom designed filters to track and analyze the respiratory sinus arrhythmia (RSA) as it moves in time and frequency. CRC is a form of sensor fusion between heart rate and respiration, estimating the strength of linear coupling between the two signals. The aim of this study was to estimate the effect of changes in respiration rate (RR) and peak airway pressure (PPaw) on CRC. The response of CRC was compared to a prior offline wavelet-based algorithm (WTCRC) as well as traditional univariate heart rate variability (HRV) measures. A nociception index was created for each algorithm, ranging from 0 (no nociception) to 100 (strong nociception). METHODS: Following ethics approval and informed consent, data were collected from 48 children receiving general anesthesia during dental surgery. The times of change in RR and PPaw events were noted in real-time. A total of 43 RR and 35 PPaw change events were analyzed post hoc in pseudo real-time. The nociception index averages were compared between a baseline period and a response period around each event. A Wilcoxon rank-sum test was used to compare changes. RESULTS: The change in RR changed the CRC nociception index by an average of -2.2 [95% CI from -10 to 4.7] (P > 0.3), and the change in PPaw changed the CRC nociception index by an average of 5.4 [-1.0 to 11] (P > 0.1). The changes were smaller than those of many traditional HRV measures. CONCLUSIONS: Real-time CRC was blind to the changes in respiration, and was less sensitive than many of the traditional HRV measures. A nociception index based on CRC can thus function across a wider range of respiratory conditions than can many traditional univariate HRV measures. The real-time CRC algorithm shows promise for monitoring nociception during general anesthesia.

Real-time cardiorespiratory coherence detects antinociception during general anesthesia.

Heart rate variability (HRV) may provide anesthesiologists with a noninvasive tool for monitoring nociception during general anesthesia. A novel real-time cardiorespiratory coherence (CRC) algorithm has been developed to analyze the strength of linear coupling between heart rate (HR) and respiration. CRC values range from 0 (low coherence, strong nociception) to 1 (high coherence, no nociception). The algorithm uses specially designed filters to operate in real-time, minimizing computational complexity and time delay. In the standard HRV high frequency band of 0.15 - 0.4 Hz, the real-time delay is only 5.25 - 3.25 s. We have assessed the algorithm's response to 60 anesthetic bolus events (a large dose of anesthetics given over a short time; strongly antinociceptive) recorded in 47 pediatric patients receiving general anesthesia. Real-time CRC responded strongly to bolus events, changing by an average of 30%. For comparison, three traditional measures of HRV (LF/HF ratio, SDNN, and RMSSD) responded on average by only 3.8%, 14%, and 3.9%, respectively. Finally, two traditional clinical measures of nociception (HR and blood pressure) responded on average by only 3.9% and 0.91%, respectively. CRC may thus be used as a real-time nociception monitor during general anesthesia.

Wavelet transform cardiorespiratory coherence detects patient movement during general anesthesia.

Heart rate variability (HRV) may provide anesthesiologists with a noninvasive tool for monitoring nociception during general anesthesia. A novel wavelet transform cardiorespiratory coherence (WTCRC) algorithm has been developed to calculate estimates of the linear coupling between heart rate and respiration. WTCRC values range from 1 (high coherence, no nociception) to 0 (low coherence, strong nociception). We have assessed the algorithm's ability to detect movement events (indicative of patient response to nociception) in 39 pediatric patients receiving general anesthesia. Sixty movement events were recorded during the 39 surgical procedures. Minimum and average WTCRC were calculated in a 30 second window surrounding each movement event. We used a 95% significance level as the threshold for detecting nociception during patient movement. The 95% significance level was calculated relative to a red noise background, using Monte Carlo simulations. It was calculated to be 0.7. Values below this threshold were treated as successful detection. The algorithm was found to detect movement with sensitivity ranging from 95% (minimum WTCRC) to 65% (average WTCRC). The WTCRC algorithm thus shows promise for noninvasively monitoring nociception during general anesthesia, using only heart rate and respiration.

The Spy1/RINGO family represents a novel mechanism regulating mammary growth and tumorigenesis.

Spy1A is a unique cell cycle activator known to mediate cell cycle progression and override the DNA damage response. This study focused on determining the role of this protein on postnatal mammary gland morphogenesis and neoplasia. Herein, we show that Spy1A levels are tightly regulated during mammary gland development and that ectopic expression stimulates precocious development and results in disrupted morphology of the gland. This follows the same trend as the oncogene c-Myc, and we show that Spy1A expression is regulated downstream of c-Myc signaling. Importantly, we show that overexpression of Spy1A accelerates tumorigenesis in vivo. Collectively, this work is the first report that the Spy1/RINGO family of proteins may play an essential role in regulating both normal and abnormal growth processes in the breast.