Features of Cirrhotic Cardiomyopathy Early in the Lives of Infants With Biliary Atresia Correlate With Outcomes Following Kasai Portoenterostomy.

Cirrhotic cardiomyopathy (CCM), detected during two-dimensional echocardiography (2DE), is prevalent in patients with biliary atresia (BA) awaiting transplant. Whether CCM occurs early in the lives of infants with BA is unknown. The aim of this study was to explore the incidence and consequence of CCM in patients with BA, focusing on the earliest ages when 2DE was performed. A cohort of 78 patients with BA at a single center underwent 2DE (median age = 132 days) during the first year of life. Left ventricular mass index (LVMI) to upper limit of normal (ULN) ratio ≥ 1.0 was present in 60% of patients who never underwent Kasai portoenterostomy (KPE; n = 15), 49% with nondraining KPE (n = 41), and 21% with draining KPE (n = 19). Patients with a draining KPE (median age at 2DE = 72 days) had a lower LVMI/ULN ratio (0.75 [interquartile range [IQR] 0.70, 0.91]) compared to those with a nondraining KPE (0.99 [IQR 0.78, 1.17] median age of 141 days; P = 0.012). In those whose 2DE was performed within 7 days of KPE (n = 19, median age of 61 days), the LVMI/ULN ratio was lower in those with a future draining KPE (0.73 [IQR 0.66, 0.75]) compared to the group with a future nondraining KPE (1.03 [IQR 0.88, 1.08], P = 0.002). Logistic regression modeling revealed LVMI/ULN ratio ≥ 1.0 as a predictor of KPE outcome, with an odds ratio of 16.7 (95% confidence interval 1.36-204; P = 0.028) for a future nondraining KPE compared to those with a LVMI/ULN ratio < 1.0. Conclusion: 2DE early in the lives of patients with BA revealed features of CCM that correlated with future outcomes. If validated in a multicenter study, this could lead to 2DE as a useful clinical tool in the care of infants with BA.

Association of Digoxin With Preserved Echocardiographic Indices in the Interstage Period: A Possible Mechanism to Explain Improved Survival?

Background For patients with hypoplastic left heart syndrome, digoxin has been associated with reduced interstage mortality after the Norwood operation, but the mechanism of this benefit remains unclear. Preservation of right ventricular (RV) echocardiographic indices has been associated with better outcomes in hypoplastic left heart syndrome. Therefore, we sought to determine whether digoxin use is associated with preservation of the RV indices in the interstage period. Methods and Results We conducted a retrospective cohort study of prospectively collected data using the public use data set from the Pediatric Heart Network Single Ventricle Reconstruction trial, conducted in 15 North American centers between 2005 and 2008. We included all patients who survived the interstage period and had echocardiographic data post-Norwood and pre-Glenn operations. We used multivariable linear regression to compare changes in RV parameters, adjusting for relevant covariates. Of 289 patients, 94 received digoxin at discharge post-Norwood. There were no significant differences in baseline clinical characteristics or post-Norwood echocardiographic RV indices (RV end-diastolic volume indexed, RV end-systolic volume indexed, ejection fraction) in the digoxin versus no-digoxin groups. At the end of the interstage period and after adjustment for relevant covariates, patients on digoxin had better preserved RV indices compared with those not on digoxin for the ΔRV end-diastolic volume (11 versus 15 mL, P=0.026) and the ΔRV end-systolic volume (6 versus 9 mL, P=0.009) with the indexed ΔRV end-systolic volume (11 versus 20 mL/BSA1.3, P=0.034). The change in the RV ejection fraction during the interstage period between the 2 groups did not meet statistical significance (-2 versus -5, P=0.056); however, the trend continued to be favorable for the digoxin group. Conclusions Digoxin use during the interstage period is associated with better preservation of the RV volume and tricuspid valve measurements leading to less adverse remodeling of the single ventricle. These findings suggest a possible mechanism of action explaining digoxin's survival benefit during the interstage period.

Multitask convolutional neural network for acoustic localization of a transiting broadband source using a hydrophone array.

A multitask convolutional neural network (CNN) is trained to localize the instantaneous position of a motorboat throughout its transit past a wide aperture linear array of hydrophones located 1 m above the sea floor in water 20 m deep. A cepstrogram database for each hydrophone and a cross-correlogram database for each pair of adjacent hydrophones are compiled for multiple motorboat transits. Cepstrum-based and correlation-based feature vectors (along with ground-truth source bearing and range data) form the inputs to train three CNNs so that they can predict the instantaneous source range and bearing for other "unseen" motorboat transits. It is shown that CNNs operating on multi-sensor cepstrum-based feature maps are able to predict the instantaneous range and bearing of a transiting motorboat, even when the source is near an endfire direction. Also, multi-sensor generalised cross correlation-based feature maps are able to predict the range and bearing of a transiting motorboat in the presence of interfering multipath arrivals. When compared with the cepstrum-only CNN, cross correlation-only CNN, and the conventional model-based method of passive ranging by wavefront curvature, the combined cepstrum-cross correlation CNN is shown to provide superior source localization performance in a multipath underwater acoustic environment.

Optimal therapeutic targeting by HDAC inhibition in biopsy-derived treatment-naïve diffuse midline glioma models.

BACKGROUND: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response. METHODS: HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response. RESULTS: Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth. CONCLUSIONS: Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents.

Myocardial deformation as a predictor of right ventricular pacing-induced cardiomyopathy in the pediatric population.

INTRODUCTION: Right ventricular pacing is associated with pacemaker induced cardiomyopathy and lesser degrees of pacing-induced LV dysfunction (PIVD) manifested by a reduction in left ventricular ejection fraction (LVEF). Our objective was to determine whether apical 4 chamber strain (A4C) by echocardiography can identify patients at risk of PIVD before LVEF declines. METHODS AND RESULTS: A retrospective chart review of patients (0-21 years) who had a pacemaker with a ventricular lead placed between 2011 and 2017 was performed. Patients were divided into group A (LVEF <55% and/or >10% decline in LVEF within 12 months of pacemaker placement) and group B. Data have collected before and 1 and 12 months postpacemaker implantation. There were 30 patients in the group A and 60 in group B. At 1 and 12 months postpacemaker implantation, the LVEF was significantly lower while the A4C and QRS duration on electrocardiogram were significantly higher in the group A. While the LVEF and A4C became markedly abnormal in group A as early as 1 month, the A4C did not seem to demonstrate such marked abnormalities in group B. However, a sub-analysis of patients in the group A with preserved LVEF at 1 month demonstrated significant worsening in their A4C at that time. CONCLUSION: Myocardial deformation imaging may be a clinically useful tool for the prediction of a decline in LV systolic function following pacemaker implantation. Abnormalities in A4C seem to appear before LVEF decline and as soon as 1-month postpacemaker implantation.

Exercise stress echocardiography: Impact on clinical decision-making in pediatric patients.

BACKGROUND: The role of exercise stress echocardiography (ESE) in the pediatric population is less well defined as compared to adults. We aimed to determine the utility and impact of ESE on clinical decision-making in pediatric patients. METHODS: We identified patients who underwent an ESE at our center from 2011 to 2015. Test indications were categorized into symptoms with exercise; sports/activity clearance; hypertrophic cardiomyopathy (HCM) or suspected HCM; coronary anomalies; or abnormal electrocardiogram (EKG). Change in clinical management was assessed by comparing pre- and post-test activity restrictions, which were categorized into unrestricted from exercise or activity; restricted from exercise or activity; and surgical referral. RESULTS: During the study period, 353 ESEs met inclusion criteria. Of all ESEs performed, 263 (75%) were normal. Clinical management changed as a result of ESE in 144 (40%). Of the abnormal ESEs, 44 were restricted from activity, including 25 (56.8%) restricted from competitive or varsity athletics, 14 (31.8%) restricted from recreational sports, and 5 (11.4%) restricted from all activity. Surgical referrals included valve repair/replacement in 7 (50%), ICD placement in 5 (35.8%), coronary re-implantation in 1 (7.1%), and atrial septal defect repair in 1 (7.1%). CONCLUSION: Exercise stress echocardiography provides the pediatric cardiologist with useful information that impacts management in a wide variety of cardiac disorders. Clinical management changed in nearly half the patients that were subjected to an ESE at our center. This supports the value of ESE for informing clinical decision-making. Future studies should aim to refine patient selection and examine its impact on patient outcomes.

Convolutional neural network for single-sensor acoustic localization of a transiting broadband source in very shallow water.

When a broadband source of radiated noise transits past a fixed hydrophone, a Lloyd's mirror constructive/destructive interference pattern can be observed in the output spectrogram. By taking the spectrum of a (log) spectrum, the power cepstrum detects the periodic structure of the Lloyd's mirror fringe pattern by generating a sequence of pulses located at the fundamental quefrency and its multiples. The fundamental quefrency, which is the reciprocal of the frequency difference between adjacent destructive interference fringes, equates to the multipath delay time. An experiment is conducted where a motorboat transits past a hydrophone located about 1 m above the seafloor in very shallow water (20 m deep). The hydrophone has a frequency bandwidth of 90 kHz, and its output is sampled at 250 kHz. A cepstrogram database is compiled from multiple vessel transits, and its cepstrum-based feature vectors (along with ground-truth range data) form the input to train a convolutional neural network (CNN) so that it can predict the source range relative to the hydrophone for other ("unseen") vessel transits. The CNN provides an accurate prediction of the instantaneous source range even when the range estimate from conventional multipath passive ranging is biased, which occurs at low grazing angles (<12°).

High-precision acoustic localization of dolphin sonar click transmissions using a modified method of passive ranging by wavefront curvature.

When configured as a wide aperture array, only three hydrophones are required to localize dolphin sonar transmissions with unprecedented precision, even when the underwater sound scene of their natural habitat is complicated by many of them emitting echolocation "click" signals at the same time. Given the sensor position coordinates and speed of sound travel, the passive ranging by the wavefront curvature algorithm estimates the source range and bearing, using range difference measurements between signals, arriving at two adjacent pairs of widely spaced sensors. If the sensor positions are not strictly collinear, then the source range estimates are biased. This problem is overcome by modifying the input parameters to the basic passive ranging algorithm. The experimental results for the estimated source positions are found to agree with the predicted localization performance for a wide aperture array passive ranging sonar. The precision of the source bearing estimates is 0.005°, which is independent of the source range. The precision of the source range estimates degrades a hundredfold (from 2.5 cm to 2.6 m) for a tenfold increase in source range (33-318 m). A lower bound for the peak-to-peak source levels of Indo-Pacific bottlenose dolphins (Tursiops aduncus) is 183 ± 2 dB re 1 µPa for regular click pulses.

Simple lateral flow assays for microbial detection in stool.

Diarrheal diseases claim the lives of 1300 children daily, mostly in the developing world. We have developed a simple lateral flow assay capable of detecting E. coli and EPEC DNA and RNA rapidly (<15 minutes) at the point-of-need, directly from stool without nucleic acid extraction or molecular amplification. The limit of detection of the method is 1 nM using synthetic DNA target substrates spiked into stool. However, due to the endogenous amplification of the 23S rRNA targets, we were able to detect the endogenous EPEC in pea-sized (5 mg) stool without labor-intensive and time-consuming nucleic acid purification or target amplification using enzymes. The significance of this method is that it is rapid (<15 minutes) and simple (without nucleic acid purification or molecular amplification) and does not require instrumentation, or access to a laboratory, cold chain or electric power. Thus, it is well-suited for point-of-need use in remote and/or resource-limited settings in the developing world where the mortality due to diarrheal diseases is especially high. The rapid testing of stool pathogens in real time at the point-of-need will decrease the loss of patients to follow-up, and enable patients to be treated earlier with the appropriate therapeutics in both the developed and developing world settings.

Five-Year Retrospective Review of Blunt Renal Injuries at a Level I Trauma Center.

We report the experience of a Level I trauma center in the management of blunt renal injury during a 5-year period, with special attention to those treated using angiography with embolization. The institutional trauma registry was queried for all patients with blunt renal injury between September 1, 2009 and August 30, 2014. Each injury was graded using the American Association for the Surgery of Trauma guidelines. Patients that underwent angiography with embolization were reviewed for case-specific information including imaging findings, treatment, materials used, clinical course, and mortality. The registry identified 48 blunt renal injury patients. Median Injury Severity Score was higher and hospital length of stay was significantly longer in those with blunt renal injury when compared with those without blunt renal injury (P < 0.001). The majority of patients with blunt renal injury were managed nonoperatively. Mortality was three out of 48 patients (5%). Nine patients underwent exploratory laparotomy. These operations were always performed for reasons other than the renal trauma (e.g., splenic injury, free fluid, free air). No patient underwent invasive renal operation. Six patients were treated using angiography with embolization. Of the six, one patient died of pulmonary septic complications. We conclude that selective nonoperative management is the mainstay of treatment for blunt renal injury. Angiography with embolization is a useful modality for cases of ongoing bleeding, and is typically preferable to nephrectomy in our experience.

Preliminary Study of Acute Changes in Emotion Processing in Trauma Survivors with PTSD Symptoms.

Accumulating evidence suggests traumatic experience can rapidly alter brain activation associated with emotion processing. However, little is known about acute changes in emotion neurocircuits that underlie PTSD symptom development. To examine acute alterations in emotion circuit activation and structure that may be linked to PTSD symptoms, thirty-eight subjects performed a task of appraisal of emotional faces as their brains were functionally and structurally studied with MRI at both two weeks and three months after motor vehicle collision (MVC). As determined by symptoms reported in the PTSD Checklist at three months, sixteen survivors developed probable PTSD, whereas the remaining 22 did not meet criteria for PTSD diagnosis (non-PTSD). The probable PTSD group had greater activation than the non-PTSD group in dorsal and ventral medial prefrontal cortex (dmPFC and vmPFC) while appraising fearful faces within two weeks after MVC and in left insular cortex (IC) three months after MVC. dmPFC activation at two weeks significantly positively correlated with PTSD symptom severity at two weeks (R = 0.462, P = 0.006) and three months (R = 0.418, p = 0.012). Changes over time in dmPFC activation and in PTSD symptom severity were also significantly positively correlated in the probable PTSD group (R = 0.641, P = 0.018). A significant time by group interaction was found for volume changes in left superior frontal gyrus (SFG, F = 6.048, p = 0.019) that partially overlapped dmPFC active region. Between two weeks and three months, left SFG volume decreased in probable PTSD survivors. These findings identify alterations in frontal cortical activity and structure during the early post-trauma period that appear to be associated with development of PTSD symptoms.

Concurrent Case Review and Retrospective Review Using the Matrix Method Are Complementary Methods for Tracking and Improving Timeliness of Care in a Level I Trauma Center.

Ensuring timely care for patients with moderate-to-severe traumatic injury has been shown to significantly reduce the rate of injury-related mortality. Using concurrent case review and the matrix method described in the 2014 version of Resources for Optimal Care of the Injured Patient, we sought to reduce direct admissions and undertriage at our institution. We believed this would optimize outcomes for patients who may have been significantly impacted otherwise. Several process improvement initiatives were implemented throughout the study period and we calculated direct admission, overtriage, and undertriage rates bimonthly for evaluation of effectiveness and to intervene, if needed. Direct admission and undertriage rates significantly declined the last six months of our study when compared to baseline (July 2014 to December 2014; 0.80% vs 6.46%, P < 0.001 and 3.72% vs 6.71%, P = 0.002, respectively). In addition, a significant increase was observed in the overtriage rate (64.36% vs 74.20%, P = 0.002).We conclude that when implemented properly, continuous tracking of adherence to triage criteria and retrospective review of fallout cases leads to significant decline in both direct admissions and undertriage, as well as concomitant increase in overtriage.

The microbiome of the oral mucosa in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a poorly understood disorder characterized by persistent symptoms, including visceral pain. Studies have demonstrated oral microbiome differences in inflammatory bowel diseases suggesting the potential of the oral microbiome in the study of non-oral conditions. In this exploratory study we examine whether differences exist in the oral microbiome of IBS participants and healthy controls, and whether the oral microbiome relates to symptom severity. The oral buccal mucosal microbiome of 38 participants was characterized using PhyloChip microarrays. The severity of visceral pain was assessed by orally administering a gastrointestinal test solution. Participants self-reported their induced visceral pain. Pain severity was highest in IBS participants (P = 0.0002), particularly IBS-overweight participants (P = 0.02), and was robustly correlated to the abundance of 60 OTUs, 4 genera, 5 families and 4 orders of bacteria (r2 > 0.4, P < 0.001). IBS-overweight participants showed decreased richness in the phylum Bacteroidetes (P = 0.007) and the genus Bacillus (P = 0.008). Analysis of ß-diversity found significant separation of the IBS-overweight group (P < 0.05). Our oral microbial results are concordant with described fecal and colonic microbiome-IBS and -weight associations. Having IBS and being overweight, rather than IBS-subtypes, was the most important factor in describing the severity of visceral pain and variation in the microbiome. Pain severity was strongly correlated to the abundance of many taxa, suggesting the potential of the oral microbiome in diagnosis and patient phenotyping. The oral microbiome has potential as a source of microbial information in IBS.

Inter-rater Variability Interferes with Reproducibility of Splenic Injury Grades Reported to the American College of Surgeons Committee on Trauma.

The objective of this study was to determine reproducibility of our splenic injury grading data, previously reported to the American College of Surgeons Committee on Trauma for our most recent site visit. The institutional registry of a Level I trauma center was queried to identify adult patients presenting with blunt splenic injury between January 1, 2013 and December 31, 2013. Original CT scans were scanned into the picture archiving and communication system and subsequently reviewed by four trauma surgeons and two radiologists for clinical impressions of splenic injury grade. Grades assigned by the clinician and the grade recorded in the registry were compared for inter-rater reliability using the intraclass correlation coefficient, as a means of assessing variance of ordinal data. The intraclass correlation coefficient in our model was 0.77, which indicates that 77 per cent of the observed variance was due to true variance and 23 per cent of the variance was due to error. Variability in grading may, in some cases, underestimate injury severity and compromise the clinician's expectation of clinical outcome, both in real-time, as well as during retrospective review processes such as those used during the trauma center reverification process.

Results of Primary Repair Versus Shunt Palliation in Ductal Dependent Infants With Pulmonary Atresia and Ventricular Septal Defect.

BACKGROUND: The 2 management strategies of neonates born with ductal-dependent pulmonary atresia and ventricular septal defect (PAVSD) include single stage primary biventricular repair (BVR) or staged palliation with modified Blalock-Taussig shunt (BTS) followed by second stage repair. Each approach is associated with specific benefits and drawbacks. We report outcomes of those 2 different strategies. METHODS: Between 2002 and 2012, 86 neonates with ductal-dependent PAVSD underwent surgery using primary repair (BVR group: n = 28, 33%) or shunt palliation (BTS group: n = 58, 67%). Early and late results were compared between the 2 groups. RESULTS: Median age was 6 days (interquartile range [IQR] 3-17) and median weight was 2.8 kg (IQR 2.5-3.3) with 27 patients (31%) 2.5 kg or less. Associated risk factors such as prematurity 36 weeks or less and genetic or extra-cardiac malformations were present in 30% and 40% of patients, respectively. Hospital mortality occurred in 5 (5.8%) patients (1 [3.6%] for BVR versus 4 [6.9%] for BTS, p = 1.00). Overall 8-year survival was 76.5% (85.5% for BVR versus 72.2% for BTS, p = 0.189). On multivariable analysis, risk factors for mortality were genetic or extra-cardiac malformations (hazard ratio [HR], 2.8 (95% confidence interval [CI] 1.7% to 16.0%), p = 0.036) and postoperative extracorporeal membrane oxygenation (ECMO) (HR, 4.0 [95% CI, 1.1% to 14.4), p = 0.039). Freedom from right ventricular outflow tract reoperation after achievement of repair was 63.2% at 8 years (52.4% for BVR versus 70.2% for BTS, p = 0.170). On multivariable analysis, risk factors for reoperation were the use of conduit (HR, 8.7 [95% CI, 1.1% to 65.8%], p = 0.037) and prematurity (HR, 2.8 [95% CI, 1.1% to 7.2%], p = 0.028). CONCLUSIONS: Primary BVR of neonates with ductal-dependent PAVSD is associated with a trend for improved survival due to hospital and interstage mortality with the staged approach. Genetic or extra-cardiac malformations are common and are associated with worse survival.

Plasma fluoride level as a predictor of voriconazole-induced periostitis in patients with skeletal pain.

BACKGROUND: Voriconazole is a triazole antifungal medication used for prophylaxis or to treat invasive fungal infections. Inflammation of the periosteum resulting in skeletal pain, known as periostitis, is a reported side effect of long-term voriconazole therapy. The trifluorinated molecular structure of voriconazole suggests a possible link between excess fluoride and periostitis, as elevated blood fluoride has been reported among patients with periostitis who received voriconazole. METHODS: Two hundred sixty-four patients from Michigan were impacted by the multistate outbreak of fungal infections as a result of contaminated methylprednisolone injections. A retrospective study was conducted among 195 patients who received voriconazole therapy at St Joseph Mercy Hospital during this outbreak. Twenty-eight patients who received both bone scan and plasma fluoride measurements for skeletal pain were included in the statistical analyses. Increased tracer uptake on bone scan was considered positive for periostitis. The primary outcome measure was the correlation between plasma fluoride and bone scan results. RESULTS: Blood fluoride (P < .001), alkaline phosphatase (P = .020), daily voriconazole dose (P < .001), and cumulative voriconazole dose (P = .027) were significantly elevated in patients who had periostitis compared with those who did not. Discontinuation or dose reduction of voriconazole resulted in improvement of pain in 89% of patients. CONCLUSIONS: High plasma fluoride levels coupled with skeletal pain among patients who are on long-term voriconazole therapy is highly suggestive of periostitis. Initial measurement of fluoride may be considered when bone scan is not readily available. Early detection should be sought, as discontinuation of voriconazole is effective at reversing the disease.