Timing of antibiotics in febrile children meeting sepsis criteria at a paediatric emergency department.

OBJECTIVE: Delay in antibiotic administration in paediatric sepsis is associated with increased mortality and prolonged organ dysfunction. This pre-intervention study evaluated performance in paediatric sepsis management. METHODS: Retrospective cohort study of febrile children admitted through the ED at The Children's Hospital at Westmead, Sydney, between 1 May and 31 July 2017. Participants were children aged 29 days to 60 months excluding children with simple febrile seizures, neonates and children who had received intravenous antibiotics elsewhere. We assessed the timing of antibiotic administration in children meeting local sepsis guidelines. We conducted a survey of clinicians in ED in 2018 to describe contributing factors. RESULTS: There were 160 febrile children admitted and 144 presentations were included in the analysis. Male 53% (n = 76); median age 20.1 months (interquartile range [IQR] 3.9-37 months). Thirty-seven (26%) febrile children met local sepsis criteria. The median time from triage to first dose of intravenous antibiotic was 109 min (IQR 62-183 min). Delay (>60 min) occurred in 26 (76%) children. Reported reasons contributing to delay included high patient load, long waiting times, difficult intravenous access, delayed prescribing, inadequate staffing and difficulty distinguishing between a viral infection and serious bacterial infection. CONCLUSION: There was frequent delay in administering antibiotics in children meeting local sepsis criteria, more commonly in young infants. Reasons contributing to delay were specific to young children along with departmental factors that will require addressing through targeted quality improvement interventions.

Deep Learning Algorithm for Automated Cardiac Murmur Detection via a Digital Stethoscope Platform.

Background Clinicians vary markedly in their ability to detect murmurs during cardiac auscultation and identify the underlying pathological features. Deep learning approaches have shown promise in medicine by transforming collected data into clinically significant information. The objective of this research is to assess the performance of a deep learning algorithm to detect murmurs and clinically significant valvular heart disease using recordings from a commercial digital stethoscope platform. Methods and Results Using >34 hours of previously acquired and annotated heart sound recordings, we trained a deep neural network to detect murmurs. To test the algorithm, we enrolled 962 patients in a clinical study and collected recordings at the 4 primary auscultation locations. Ground truth was established using patient echocardiograms and annotations by 3 expert cardiologists. Algorithm performance for detecting murmurs has sensitivity and specificity of 76.3% and 91.4%, respectively. By omitting softer murmurs, those with grade 1 intensity, sensitivity increased to 90.0%. Application of the algorithm at the appropriate anatomic auscultation location detected moderate-to-severe or greater aortic stenosis, with sensitivity of 93.2% and specificity of 86.0%, and moderate-to-severe or greater mitral regurgitation, with sensitivity of 66.2% and specificity of 94.6%. Conclusions The deep learning algorithm's ability to detect murmurs and clinically significant aortic stenosis and mitral regurgitation is comparable to expert cardiologists based on the annotated subset of our database. The findings suggest that such algorithms would have utility as front-line clinical support tools to aid clinicians in screening for cardiac murmurs caused by valvular heart disease. Registration URL: https://clinicaltrials.gov; Unique Identifier: NCT03458806.

Does location of rapid influenza diagnostic testing influence treatment time and ancillary testing in a paediatric emergency department?

OBJECTIVE: Influenza causes a significant burden of disease. Our aim was to assess whether location of rapid influenza diagnostic testing (RIDT) for patients with influenza-like illness (ILI) has an impact on ED treatment time or ancillary testing. METHODS: This was a retrospective observational study in a tertiary paediatric ED during 2017 influenza season. All patients with ILI were included. Some had RIDT performed (ED bedside or at the laboratory). Primary outcome measure was the correlation of RIDT location to treatment time compared to patients with ILI with no RIDT. Secondary outcome measures were the correlation of RIDT location to ancillary testing and treatment with antibiotics. RESULTS: A total of 1451 patients with ILI were included. Eighty patients for whom RIDT was performed at the laboratory had a shorter treatment time in the ED when compared to the 215 patients for whom RIDT was performed bedside (2.8 and 3.4 h, respectively; P < 0.0001). However, treatment time was not statistically different when sub-analysed for admitted and discharged patients separately. Overall, patients with ILI and no RIDT had the shortest treatment time in the ED (1.7 h). There was no difference in ancillary testing and treatment with antibiotics between ILI patients for whom RIDT was performed bedside or at the laboratory regardless of admission. CONCLUSION: Location of RIDT may not have a significant impact on treatment time, ancillary testing and treatment with antibiotics. When RIDT was not performed, patients had the shortest treatment time.

Educational intervention does not reduce non-invasive urine contamination rates in children presenting to the emergency department.

AIM: Urinary tract infection is common in children with high contamination rates with non-invasive urine sampling (NIU). Our aims were to evaluate an educational tool for decreasing contamination rates and find factors associated with contamination. METHODS: This was a prospective cohort interventional study with a review of microbiology data and medical records of all NIU specimens collected at a large tertiary children's emergency department (ED) over a 1-year period. The intervention was the provision of a urine collection kit and educational pamphlet and education of staff. NIU contamination was calculated for 6 months pre-intervention and 6 months post-intervention. The association of factors with NIU contamination was evaluated for all cohorts (age, gender, presence of diarrhoea, season, time of day, time to incubation and activity of the ED). RESULTS: A total of 2104 NIU samples were included (median age 3 years, 52% females). There was no difference between periods in contamination rates (29.2% and 31.2%, respectively, P = 0.322). Collectively, high monthly activity of the department, age and female gender were associated with contamination. The highest contamination rates were among children aged 0-3 months and 12 years and older (38.1 and 48.9%, respectively). CONCLUSIONS: The urine collection kit and educational tool did not decrease NIU contamination rates in our ED. Contamination rates were correlated with the monthly activity of our department and female gender and were noticeably high among infants and adolescents. Given the high prevalence of urinary tract infection among these age groups, measures should be taken to reassess indications and methods for urine collection.

Quantitative analysis of spectral Doppler clicks in assessment of aortic stenosis.

OBJECTIVES: This study was performed to evaluate an additional echocardiographic spectral Doppler marker, which would identify severe aortic stenosis (AS). BACKGROUND: Echocardiography is most commonly utilized to assess AS and has been validated against invasive measurements. However, the data obtained are not always in agreement, leaving a conundrum regarding the true severity of AS and can lead to other diagnostic procedures. This highlights the importance of improved noninvasive diagnostic techniques. METHODS: Forty-eight indeterminate cases of calcific AS that had been previously evaluated by both echocardiography and cardiac catheterization were included in the study, using cardiac catheterization as the gold standard for calculation of aortic valve area (AVA). The intensity of opening and closing of the aortic valve, represented by bright vertical deflections on the CW spectral waveform, was quantified using ImageJ software to generate pixel intensity histograms to create opening and closing click (OC and CC) ratios. These ratios were compared with echocardiographic variables and catheterization AVA. RESULTS: Thirty-five patients were found to have severe AS and 13 patients were found to have nonsevere AS, as assessed by cardiac catheterization. CC ratio was found to be a significant predictor of severe AS with an OR 0.024 (95% CI: 0.002-0.378, P = .0079). Adding CC to a model using standard echocardiographic parameters resulted in significant improvement in the C-statistic (0.693 to 0.835, P = .0134). CONCLUSIONS: An additional Doppler marker measuring the aortic valve CC ratio has been found to improve detection of severe AS.

Global Coronary Flow Reserve Measured During Stress Cardiac Magnetic Resonance Imaging Is an Independent Predictor of Adverse Cardiovascular Events.

OBJECTIVES: The aim of this study was to evaluate the incremental prognostic value of global coronary flow reserve (CFR) in patients with known or suspected coronary artery disease who were undergoing stress cardiac magnetic resonance (CMR) imaging. BACKGROUND: Coronary microvascular dysfunction results in impaired global CFR and is implicated in the development of both atherosclerosis and heart failure. Although noninvasive assessment of CFR with positron emission tomography provides independent prognostic information, the incremental prognostic value of CMR-derived CFR remains unclear. METHODS: Consecutive patients undergoing stress perfusion CMR were prospectively enrolled (n = 507). Coronary sinus flow was measured using phase-contrast imaging at baseline (pre) and immediately after stress (peak) perfusion. CFR was calculated as the ratio of peak to pre-flow. Patients were followed for major adverse cardiac events (MACE): death, nonfatal myocardial infarction, heart failure hospitalization, sustained ventricular tachycardia, and late revascularization. Cox proportional hazards regression modeling was used to examine the association between CFR and MACE. The incremental prognostic value of CFR was assessed in nested models. RESULTS: Over a median follow-up of 2.1 years, 80 patients experienced MACE. By Kaplan-Meier analysis, the risk of MACE was significantly higher in patients with CFR lower than the median (2.2) (log-rank p < 0.001); this remained significant after adjustment for the presence of ischemia and late gadolinium enhancement (LGE) (log-rank p < 0.001). CFR was significantly associated with the risk of MACE after adjustment for clinical and imaging risk factors, including ischemia extent, ejection fraction, and LGE size (hazard ratio: 1.238; p = 0.018). Addition of CFR in this model resulted in significant improvement in the C-index (from 0.70 to 0.75; p = 0.0087) and a continuous net reclassification improvement of 0.198 (95% confidence interval: 0.120 to 0.288). CONCLUSIONS: CMR-derived CFR is an independent predictor of MACE in patients with known or suspected coronary artery disease, incremental to common clinical and CMR risk factors. These findings suggest a role for CMR-derived CFR in identifying patients at risk of adverse events following stress CMR, even in the absence of ischemia and LGE.

Feature-Tracking Global Longitudinal Strain Predicts Death in a Multicenter Population of Patients With Ischemic and Nonischemic Dilated Cardiomyopathy Incremental to Ejection Fraction and Late Gadolinium Enhancement.

OBJECTIVES: The aim of this study was to evaluate the prognostic value of cardiac magnetic resonance (CMR) feature-tracking-derived global longitudinal strain (GLS) in a large multicenter population of patients with ischemic and nonischemic dilated cardiomyopathy. BACKGROUND: Direct assessment of myocardial fiber deformation with GLS using echocardiography or CMR feature tracking has shown promise in providing prognostic information incremental to ejection fraction (EF) in single-center studies. Given the growing use of CMR for assessing persons with left ventricular (LV) dysfunction, we hypothesized that feature-tracking-derived GLS may provide independent prognostic information in a multicenter population of patients with ischemic and nonischemic dilated cardiomyopathy. METHODS: Consecutive patients at 4 U.S. medical centers undergoing CMR with EF <50% and ischemic or nonischemic dilated cardiomyopathy were included in this study. Feature-tracking GLS was calculated from 3 long-axis cine-views. The primary endpoint was all-cause death. Cox proportional hazards regression modeling was used to examine the association between GLS and death. Incremental prognostic value of GLS was assessed in nested models. RESULTS: Of the 1,012 patients in this study, 133 died during median follow-up of 4.4 years. By Kaplan-Meier analysis, the risk of death increased significantly with worsening GLS tertiles (log-rank p < 0.0001). Each 1% worsening in GLS was associated with an 89.1% increased risk of death after adjustment for clinical and imaging risk factors including EF and late gadolinium enhancement (LGE) (hazard ratio [HR]:1.891 per %; p < 0.001). Addition of GLS in this model resulted in significant improvement in the C-statistic (0.628 to 0.867; p < 0.0001). Continuous net reclassification improvement (NRI) was 1.148 (95% confidence interval: 0.996 to 1.318). GLS was independently associated with death after adjustment for clinical and imaging risk factors (including EF and late gadolinium enhancement) in both ischemic (HR: 1.942 per %; p < 0.001) and nonischemic dilated cardiomyopathy subgroups (HR: 2.101 per %; p < 0.001). CONCLUSIONS: CMR feature-tracking-derived GLS is a powerful independent predictor of mortality in a multicenter population of patients with ischemic or nonischemic dilated cardiomyopathy, incremental to common clinical and CMR risk factors including EF and LGE.

Intestinal Intussusception: Etiology, Diagnosis, and Treatment.

Intussusception is defined as the invagination of one segment of the bowel into an immediately adjacent segment of the bowel. Idiopathic ileocolic intussusception is the most common form in children and is typically managed with nonoperative reduction via pneumatic and/or hydrostatic enemas. In the adult population, intussusception is uncommon and occurs more often in the small intestine than in the colon. It is associated with lead point pathology in most symptomatic cases presenting as bowel obstruction. When lead point pathology is present in adult small bowel intussusception, it is usually benign, though when malignant it is most frequently due to diffuse metastatic disease, for example, melanoma. In contrast, adult ileocolic and colonic intussusception lead point pathology is most frequently primary adenocarcinoma when malignant. The diagnosis is typically made intraoperatively or by cross-sectional imaging. With increasingly frequent CT/MRI of the adult abdomen in the current era, transient and/or asymptomatic intussusceptions are increasingly found and may often be appropriately observed without intervention. When intervention in the adult population is warranted, usually oncologic bowel resection is performed due to the association with lead point pathology.

Pompe disease results in a Golgi-based glycosylation deficit in human induced pluripotent stem cell-derived cardiomyocytes.

Infantile-onset Pompe disease is an autosomal recessive disorder caused by the complete loss of lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA) activity, which results in lysosomal glycogen accumulation and prominent cardiac and skeletal muscle pathology. The mechanism by which loss of GAA activity causes cardiomyopathy is poorly understood. We reprogrammed fibroblasts from patients with infantile-onset Pompe disease to generate induced pluripotent stem (iPS) cells that were differentiated to cardiomyocytes (iPSC-CM). Pompe iPSC-CMs had undetectable GAA activity and pathognomonic glycogen-filled lysosomes. Nonetheless, Pompe and control iPSC-CMs exhibited comparable contractile properties in engineered cardiac tissue. Impaired autophagy has been implicated in Pompe skeletal muscle; however, control and Pompe iPSC-CMs had comparable clearance rates of LC3-II-detected autophagosomes. Unexpectedly, the lysosome-associated membrane proteins, LAMP1 and LAMP2, from Pompe iPSC-CMs demonstrated higher electrophoretic mobility compared with control iPSC-CMs. Brefeldin A induced disruption of the Golgi in control iPSC-CMs reproduced the higher mobility forms of the LAMPs, suggesting that Pompe iPSC-CMs produce LAMPs lacking appropriate glycosylation. Isoelectric focusing studies revealed that LAMP2 has a more alkaline pI in Pompe compared with control iPSC-CMs due largely to hyposialylation. MALDI-TOF-MS analysis of N-linked glycans demonstrated reduced diversity of multiantennary structures and the major presence of a trimannose complex glycan precursor in Pompe iPSC-CMs. These data suggest that Pompe cardiomyopathy has a glycan processing abnormality and thus shares features with hypertrophic cardiomyopathies observed in the congenital disorders of glycosylation.

Chemical-genomic dissection of the CTD code.

Sequential modifications of the RNA polymerase II (Pol II) C-terminal domain (CTD) coordinate the stage-specific association and release of cellular machines during transcription. Here we examine the genome-wide distributions of the 'early' (phospho-Ser5 (Ser5-P)), 'mid' (Ser7-P) and 'late' (Ser2-P) CTD marks. We identify gene class-specific patterns and find widespread co-occurrence of the CTD marks. Contrary to its role in 3'-processing of noncoding RNA, the Ser7-P marks are placed early and retained until transcription termination at all Pol II-dependent genes. Chemical-genomic analysis reveals that the promoter-distal Ser7-P marks are not remnants of early phosphorylation but are placed anew by the CTD kinase Bur1. Consistent with the ability of Bur1 to facilitate transcription elongation and suppress cryptic transcription, high levels of Ser7-P are observed at highly transcribed genes. We propose that Ser7-P could facilitate elongation and suppress cryptic transcription.

Specific gravity and creatinine as corrections for variation in urine concentration in humans, gorillas, and woolly monkeys.

Hormones excreted in the urine are widely used to assess the physiological and psychological condition of unrestrained animals. In order to control for variation in the water concentration of urine samples, the hormone concentration is often indexed to the concentration of creatinine. Because there are several problems with using creatinine, we have investigated the efficacy of specific gravity as an alternative basis for adjusting the hormone concentration in humans, gorillas, and woolly monkeys. In an experimental manipulation of human urine hydration, ten volunteers drank a water load proportional to body weight, and provided complete urine collection and saliva samples for four consecutive 20 min intervals. From the urine, we measured cortisol (radioimmunoassay), creatinine (colorimetric assay), and specific gravity (refractometer). Only cortisol was assayed from saliva. During 80 min following water ingestion, cortisol, creatinine, and specific gravity declined as urine became diluted; however, total cortisol excretion remained constant. Only cortisol concentration indexed to specific gravity accurately reflected the consistent cortisol excretion. Specific gravity and creatinine-corrected cortisol values were highly correlated but were significantly different. Salivary cortisol provided evidence for the relative stability of serum cortisol. To determine the utility of these corrections in other primates, we compared specific gravity- and creatinine-corrected cortisol in urine samples from captive gorillas (N=16) and woolly monkeys (N=8). As with the human study, the two corrections were strongly correlated in each species, but the means were different. Specific gravity correction was superior in revealing the circadian variation in cortisol.

Management of complex abdominal wall defects using acellular porcine dermal collagen.

Multiple techniques have been used for the repair of complex abdominal wall defects after recurrent incisional hernias with varying rates of success. Primary repair has been associated with high recurrence rates, and prosthetic mesh placement is contraindicated in contaminated surgical fields. The development of biologic prostheses has changed the approach to these difficult problems. This study evaluates the management of complex abdominal wall defects using acellular porcine dermal collagen. Between August 2006 and May 2007, 18 patients underwent abdominal wall reconstruction for complex defects with acellular porcine dermal collagen (CollaMend; Bard Inc., Warwick, RI). Patient demographics, preoperative risk factors, previous herniorrhaphy attempts, postoperative complications, recurrences, and long-term results were retrospectively reviewed. Records were reviewed at a mean follow up of 7.3 months; the recurrence rate was 44.4 per cent. A total of 38.9 per cent (seven of 18) developed a postoperative wound complications, including infection in 22.2 per cent (four of 18). All of the patients with infection required prosthesis removal as a result of encapsulation rather than incorporation of the biologic prosthesis. Acellular porcine dermal collagen has the potential for reconstruction of abdominal wall defects with postoperative wound occurrences comparable with other biologic materials. Encapsulation of the material was a major problem in cases with wound infection that required graft removal rather than local wound measures. Hernia recurrence and dehiscence of the graft were problems in noncompromised surgical fields.

Transoral technique for gastrojejunostomy in laparoscopic Roux-en-Y gastric bypass (LRYGBP) can accelerate learning curve and reduce cost.

BACKGROUND: The stapled gastrojejunostomy of the laparoscopic Roux-en-Y gastric bypass (LRYGBP) can be created by linear and circular stapling techniques. In the circular-stapled technique, the anvil of the stapler can be introduced into the gastric pouch transabdominally or pulled down the esophagus (transorally) by attachment to a modified gastric tube. The purpose of this study is to determine if the transoral technique to introduce the anvil will reduce operative time and cost compared with the transabdominal technique, which requires creating a new gastrotomy to insert the anvil and followed by its closure. METHODS: We compared 60 consecutive morbidly obese patients who underwent laparoscopic RYGBP. First 30 cases were performed by transabdominal anvil insertion, followed by 30 cases using transoral anvil insertion. All of the transabdominal cases were assisted by experienced fellows. The first ten transoral cases were assisted by experienced fellows and the remaining 20 by new fellows in order to evaluate if the transoral technique shortens the learning curve. Surgery duration and operative costs were compared. Complications (bleeding, leaks, anastomotic strictures, ulcers, wound infections) and length of stay were also evaluated. Data are expressed as mean +/- SD. RESULTS: Mean operative time was shorter in the transoral group compared with the transabdominal group (162.2 +/- 35.8 vs. 186 +/- 33.6 min respectively, p = 0.01), even though most of the transoral cases (n = 20) were assisted by new fellows and all of the transabdominal cases by experienced fellows. Operative times were not different between new and experienced fellows in the transoral technique. Supply costs per patient were higher in the transabdominal technique compared with the transoral technique (2,983.5 +/- 540.9 vs. 2,658.8 +/- 474.4 USD, respectively, p = 0.03). Perioperative complications and length of stay were not statistically different. CONCLUSION: The transoral introduction of the anvil of the circular stapler into the gastric pouch is a simple, safe, and efficient technique for creating the gastrojejunostomy in laparoscopic RYGBP. In addition, the transoral technique is less expensive and appears to accelerate the learning curve compared with the transabdominal technique.