Newborn Screening for High-Risk Congenital Heart Disease by Dried Blood Spot Biomarker Analysis.

Importance: Congenital heart disease (CHD) is the most common human organ malformation, affecting approximately 1 of 125 newborns globally. Objectives: Assessing the performance of 2 diagnostic tests using minimal amounts of dried blood spots (DBS) to identify high-risk CHD compared with controls in a Swedish cohort of neonates. Design, Setting, and Participants: This diagnostic study took place in Sweden between 2019 and 2023 and enrolled full-term babies born between 2005 and 2023. All cases were identified through centralized pediatric cardiothoracic surgical services in Lund and Gothenburg, Sweden. Controls were followed up for 1 year to ensure no late presentations of high-risk CHD occurred. Cases were verified through surgical records and echocardiography. Exposure: High-risk CHD, defined as cases requiring cardiac surgical management during infancy due to evolving signs of heart failure or types in which the postnatal circulation depends on patency of the arterial duct. Using 3-µL DBS samples, automated quantitative tests for NT-proBNP and interleukin 1 receptor-like 1 (IL-1 RL1; formerly known as soluble ST2) were compared against established CHD screening methods. Main Outcomes and Measures: Performance of DBS tests to detect high-risk CHD using receiver operating characteristic curves; Bland-Altman and Pearson correlation analyses to compare IL-1 RL1 DBS with plasma blood levels. Results: A total of 313 newborns were included (mean [SD] gestational age, 39.4 [1.3] weeks; 181 [57.8%] male). Mean (SD) birthweight was 3495 (483) grams. Analyzed DBS samples included 217 CHD cases and 96 controls. Among the CHD cases, 188 participants (89.3%) were high-risk types, of which 73 (38.8%) were suspected prenatally. Of the 188 high-risk cases, 94 (50.0%) passed pulse oximetry screening and 36 (19.1%) were initially discharged after birth without diagnoses. Combining NT-proBNP and IL-1 RL1 tests performed well in comparison with existing screening methods and enabled additional identification of asymptomatic babies with receiver operating characteristic area under the curve 0.95 (95% CI, 0.93-0.98). Conclusions and relevance: In this diagnostic study, NT-proBNP and IL-1 RL1 DBS assays identified high-risk CHD in a timely manner, including in asymptomatic newborns, and improved overall screening performance in this cohort from Sweden. Prospective evaluation of this novel approach is warranted.

Left Ventricular Diastolic Function in Children with Atrial Septal Defects Improves After Closure by Means of Increased Hydraulic Force.

Hydraulic force aids diastolic filling of the left ventricle (LV) by facilitating basal movement of the atrioventricular plane. The short-axis atrioventricular area difference (AVAD) determines direction and magnitude of this force. Patients with atrial septal defect (ASD) have reduced LV filling due to the left-to-right shunt across the atrial septum and thus potentially altered hydraulic force. The aims were therefore to use cardiac magnetic resonance images to assess whether AVAD and thus the hydraulic force differ in children with ASD compared to healthy children, and if it improves after ASD closure. Twenty-two children with ASD underwent cardiac magnetic resonance before ASD closure. Of these 22 children, 17 of them repeated their examination also after ASD closure. Twelve controls were included. Left atrial and ventricular areas were delineated in short-axis images, and AVAD was defined as the largest ventricular area minus the largest atrial area at each time frame and normalized to body height (AVADi). At end diastole AVADi was positive in all participants, suggesting a force acting towards the atrium assisting the diastolic movement of the atrioventricular plane; however, lower in children both before (6.3 cm2/m [5.2-8.0]; p < 0.0001) and after ASD closure (8.7 cm2/m [6.6-8.5]; p = 0.0003) compared to controls (12.2 cm2/m [11.3-13.9]). Left ventricular diastolic function improves after ASD closure in children by means of improved hydraulic force assessed by AVAD. Although AVADi improved after ASD closure, it was still lower than in controls, indicating diastolic abnormality even after ASD closure. In patients where AVADi is low, ASD closure may help avoid diastolic function deterioration and improve outcome. This could likely be important also in patients with small shunt volumes, especially if they are younger, who currently do not undergo ASD closure. Changes in clinical routine may be considered pending larger outcome studies.

Treatment-Relevant Findings in Transesophageal Echocardiography After Stroke: A Prospective Multicenter Cohort Study.

BACKGROUND AND PURPOSE: Cardiac ultrasound to identify sources of cardioembolism is part of the diagnostic workup of acute ischemic stroke. Recommendations on whether transesophageal echocardiography (TEE) should be performed in addition to transthoracic echocardiography (TTE) are controversial. We aimed to determine the incremental diagnostic yield of TEE in addition to TTE in patients with acute ischemic stroke with undetermined cause. METHODS: In a prospective, observational, pragmatic multicenter cohort study, patients with acute ischemic stroke or transient ischemic attack with undetermined cause before cardiac ultrasound were studied by TTE and TEE. The primary outcome was the rate of treatment-relevant findings in TTE and TEE as defined by a panel of experts based on current evidence. Further outcomes included the rate of changes in the assessment of stroke cause after TEE. RESULTS: Between July 1, 2017, and June 30, 2019, we enrolled 494 patients, of whom 492 (99.6%) received TTE and 454 (91.9%) received TEE. Mean age was 64.7 years, and 204 (41.3%) were women. TEE showed a higher rate of treatment-relevant findings than TTE (86 [18.9%] versus 64 [14.1%], P<0.001). TEE in addition to TTE resulted in 29 (6.4%) additional patients with treatment-relevant findings. Among 191 patients ≤60 years additional treatment-relevant findings by TEE were observed in 27 (14.1%) patients. Classification of stroke cause changed after TEE in 52 of 453 patients (11.5%), resulting in a significant difference in the distribution of stroke cause before and after TEE (P<0.001). CONCLUSIONS: In patients with undetermined cause of stroke, TEE yielded a higher number of treatment-relevant findings than TTE. TEE appears especially useful in younger patients with stroke, with treatment-relevant findings in one out of seven patients ≤60 years. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03411642.

Evaluation of Circulating Cardiovascular Biomarker Levels for Early Detection of Congenital Heart Disease in Newborns in Sweden.

Importance: Congenital heart disease (CHD) is the most common congenital malformation in humans worldwide. Circulating cardiovascular biomarkers could potentially improve the early detection of CHD, even in asymptomatic newborns. Objectives: To assess the performance of a dried blood spot (DBS) test to measure the cardiovascular biomarker amino terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) levels in newborns and to compare DBS with standard EDTA analysis in control newborns during the first week of life. Design, Setting, and Participants: This diagnostic study was conducted in a single regional pediatric service in southern Sweden. Healthy, term neonates born between July 1, 2018, and May 31, 2019, were prospectively enrolled and compared against retrospectively identified newborns with CHD born between September 1, 2003, and September 30, 2019. Neonates who required inpatient treatment beyond the standard postnatal care were excluded. Exposure: New DBS test for NT-proBNP quantification in newborns that used 3 µL of blood vs the current screening standard. Main Outcomes and Measures: Performance of the new test and when combined with pulse oximetry screening was measured by receiver operating characteristic curve analysis. Performance of the new test and EDTA screening was compared using Pearson linear correlation analysis. Results: The DBS samples of 115 neonates (81 control newborns and 34 newborns with CHD, of whom 63 were boys [55%] and the mean [SD] gestational age was 39.6 [1.4] weeks) were analyzed. The new NT-proBNP test alone identified 71% (n = 24 of 34) of all CHD cases and 68% (n = 13 of 19) of critical CHD cases as soon as 2 days after birth. Detection of any CHD type improved to 82% (n = 28 of 34 newborns) and detection of critical CHD improved to 89% (n = 17 of 19 newborns) when combined pulse oximetry screening and NT-proBNP test results were used. Performance of the NT-proBNP test was excellent when control newborns were matched to newborns with CHD born between July 1, 2018, and May 31, 2019 (area under the curve, 0.96; SE, 0.027; 95% CI, 0.908-1.0; asymptotic P < .05). Conclusions and Relevance: This study found that NT-proBNP assay using minimal DBS samples appears to be timely and accurate in detecting CHD in newborns and to discriminate well between healthy newborns and newborns with various types of CHD. This finding warrants further studies in larger cohorts and highlights the potential of NT-proBNP to improve neonatal CHD screening.

Developing person-centred analysis of harm in a paediatric hospital: a quality improvement report.

The provision of safe care is complex and difficult to achieve. Awareness of what happens in real time is one of the ways to develop a safe system within a culture of safety. At Great Ormond Street Hospital, we developed and tested a tool specifically designed for patients and families to report harm, with the aim of raising awareness and opportunities for staff to continually improve and provide safe care. Over a 10-month period, we developed processes to report harm. We used the Model for Improvement and multiple Plan, Do, Study, Act cycles for testing. We measured changes using culture surveys as well as analysis of the reports. The tool was tested in different formats and moved from a provider centric to a person-centred tool analysed in real time. An independent person working with the families was best placed to support reporting. Immediate feedback to families was managed by senior staff, and provided the opportunity for clarification, transparency and apologies. Feedback to staff provided learning opportunities. Improvements in culture climate and staff reporting were noted in the short term. The integration of patient involvement in safety monitoring systems is essential to achieve safety. The high number of newly identified 'near-misses' and 'critical incidents' by families demonstrated an underestimation of potentially harmful events. This testing and introduction of a self-reporting, real-time bedside tool has led to active engagement with families and patients and raised situation awareness. We believe that this will lead to improved and safer care in the longer term.

Electrical storm in children.

Electrical storm (ES) presents a difficult management problem that has predominantly been described in adults and there are limited published data relating to children. We set out to characterize ES in children to assist management based on published literature and own institutional experience. We retrospectively analyzed the records of children presenting with ES to our institution between July 2001 and July 2011 and conducted a systematic literature review. Four children were identified (median age: 5.7 years, range: 3.3-9.6 years, one male). Each ES was of different character and different management strategies were used. All patients were alive at a median follow-up of 5.7 years and all had received implantable cardioverter-defibrillators. Two patients were felt to have catecholaminergic polymorphic ventricular tachycardia, one possible long QT syndrome and one the "short-coupled" variant of torsades de pointes. At least three of our four patients had possible iatrogenic contribution to their ES. Forty-seven cases of ES in children with variable management strategies were identified from the published literature. ES is a rare medical emergency in children with multiple etiologies requiring individualized management.

Kawasaki disease: always straight to the heart?

Kawasaki disease is an important differential diagnosis when evaluating prolonged fever in childhood. Although the aetiology of this vasculitic disease process remains obscure, prompt recognition and treatment significantly reduces vascular complications such as coronary artery aneurysms. Patients presenting with atypical or incomplete diagnostic features remain a challenge. Here the authors describe the atypical features of Kawasaki disease that led to profound acute hearing loss in a 6-year-old boy with complex congenital heart disease. Coronary changes were not seen on early follow-up, but the patient required bilateral hearing aids. Considering Kawasaki disease early, even in the possibly confusing context of complex congenital heart disease and atypical symptomatology, is crucial to avoid long-term sequelae.

Paediatric arrhythmias in the emergency department.

OBJECTIVE: Emergency department (ED) staff need to rapidly establish accurate diagnosis and management for children with arrhythmias. Limited data are available on the presenting features, epidemiology and management of arrhythmias encountered in the ED. The aim of this study was to characterise the incidence, presenting features, management and outcomes of arrhythmias at a large tertiary children's hospital ED. PATIENTS AND METHODS: Retrospective review of medical records identified via the ED electronic database using ICD-10 codes for arrhythmias including cardiac arrests over a 6-year period (2002-2008). Patients <18 years were analysed using predefined criteria. RESULTS: There were a total of 444 non-arrest arrhythmias with an incidence of 11.5:10 000 presentations. Median age of patients at presentation was 10.4 years; 45% were male. Supraventricular arrhythmias (SVTs) represented the largest subgroup (n=250, 56%). Conduction disorders (n=18), ventricular tachycardia (n=17) and atrial flutter/fibrillation (n=7) were rare. There were 19 cardiac arrests. Fifty-seven (13%) patients had underlying congenital heart disease. For ongoing SVT (n=135), vagal manoeuvres were used in 74%, and antiarrhythmic drugs in 64%. In five patients with SVT, drugs other than adenosine were used. Defibrillators were used only on 2 occasions for arrthymias and 6 times for cardiac arrests. 18 of 19 children in cardiac arrest died. CONCLUSION: In this largest paediatric series outside the intensive care and postoperative setting, arrhythmias were uncommon, defibrillator use was very rare, and observed mortality was low.

Bluetongue disease in Germany (2007-2008): monitoring of entomological aspects.

In the summer of 2006, a bluetongue epidemic started in the border area of Belgium, The Netherlands, and Germany, spread within 2 years over large areas of Western and Central Europe, and caused substantial losses in farm ruminants. Especially sheep and cattle were severely affected, leading to a case-fatality ratio of nearly 40% in sheep (Conraths et al., Emerg Inf Dis 15(3):433-435, 2009). The German federal ministry of food, agriculture, and consumer protection (BMELV) established a countrywide monitoring on the occurrence of the vectors of this virus, i.e., midges (family Ceratopogonidae) of the genus Culicoides. The monitoring was done on 91 sites, most of which were localized in the 150-km restriction zone that existed in December 2006. A grid consisting of 45 x 45 km(2) cells was formed that covered the monitoring area. As a rule, one trap was placed into each grid cell. The monitoring program started at the end of March 2007 and lasted until May 2008. It included the catching of midges by ultraviolet light traps-done each month from days 1 until 8, the selection of midges of the Culicoides obsoletus, Culicoides pulicaris group, and other Culicoides spp., the testing of midges for bluetongue virus (BTV) by polymerase chain reaction (PCR), and the daily registration of weather data at each trap site for the whole monitoring period. The following main results were obtained: (1) Members of the C. obsoletus group were most commonly found in the traps, reaching often 3/4 of the catches. The African and South European vector of BTV-the species Culicoides imicola-was never found. (2) Members of the C. obsoletus group were most frequently found infected with BTV besides a few cases in the C. pulicaris group and other species. (3) Members of the C. obsoletus group were also found in winter. Their numbers were reduced, however, and they were caught mostly close to stables. Therefore, a true midge-free period does not exist during the year in Germany. (4) The amounts of midges caught daily depended on the weather conditions. If it was cold and/or windy, the traps contained only a few specimens. Since the months from January to May 2008 were considerably colder (at all farms) than their correspondents in 2007, the growing of the population of midges started 2-3 months later in 2008 than in 2007. (5) The highest populations of midges occurred in both years (2007 and 2008) during the months September and October. This corresponded significantly to the finding of highest numbers of infected midges and to the number of diseased cattle and sheep during these 2 months. (6) It is noteworthy that in general, the first virus-positive midges of the species C. obsoletus were found about 1 1/2 months later than the first clinical cases had occurred or later than the first PCR-proven virus-positive sentinel animals had been documented. In 2007, the first BTV-positive cattle were detected in May in North Rhine-Westphalia, while the first positive Culicoides specimens were only found in August on the same farm. Evaluating these main results of the entomological monitoring and the fact that many wild ruminants have also been infected with BTV, it becomes evident that bluetongue disease has become endemic in Central Europe, and that only constant effort including vaccination and perhaps also insecticidal protection of cattle and sheep will keep the economical losses at a reasonable level. The following papers (1-10) in this journal will contribute more details obtained from this worldwide unique entomological monitoring: Bartsch et al. 2009; Bauer et al. 2009; Stephan et al. 2009; Clausen et al. 2009; Hörbrand and Geier 2009; Kiehl et al. 2009; Mehlhorn et al. 2009; Kiel et al. 2009; Vorsprach et al. 2009; Balczun et al. 2009.

Determination of microvessel density by quantitative real-time PCR in esophageal cancer: correlation with histologic methods, angiogenic growth factor expression, and lymph node metastasis.

PURPOSE: Angiogenesis and lymphangiogenesis are important steps in tumor growth and dissemination and are of prognostic importance in solid tumors. The determination of microvessel density (MVD) by immunohistology is subject to considerable variability between different laboratories and observers. We compared MVD determination by immunohistology and quantitative real-time PCR and correlated the results with clinical variables. EXPERIMENTAL DESIGN: The expression of endothelial antigens vascular endothelial cadherin (CD144), P1H12 (CD146), tie-2, and VEGFR-2, and lymphatic endothelial markers VEGFR-3, Prox, and LYVE was assessed by quantitative PCR (qPCR) in primary surgical samples. The expression of angiogenetic growth factors VEGF-A, VEGF-C, VEGF-D, angiopoietin-1, and angiopoietin-2 was quantified by PCR and correlated with MVD and clinical variables. RESULTS: The expression of endothelial antigens vascular endothelial cadherin (CD144), P1H12 (CD146), tie-2, and VEGFR-2 correlated with each other in 54 samples of primary esophageal cancer (P < 0.0001 for all comparisons). MVD determined immunohistologically by CD31 staining in a subgroup of 35 patients correlated significantly with the qPCR method. The expression of angiogenetic growth factors VEGF-A, VEGF-C, VEGF-D, angiopoietin-1, and angiopoietin-2 was significantly associated with MVD (P < 0.0001 for all comparisons). Analysis of the expression of lymphendothelial markers VEGFR-3, Prox, and LYVE revealed concordant results, indicating that quantification of lymphendothelial cells is possible by qPCR. The presence of lymph node metastasis on surgical specimens was significantly correlated with MVD (P < 0.003), VEGFR-2 (P < 0.048), and VEGF-C (P < 0.042) expression. CONCLUSIONS: These results indicate that quantification of MVD by qPCR in surgical samples of esophageal carcinoma yields similar results with immunohistology. Interestingly, the extent of angiogenesis and lymphangiogenesis was not related in individual tumor samples. Lymph node metastases could be predicted by MVD and VEGF-C expression.