Developing COVID-19 vaccine recommendations during the pandemic: The experience of Serbia's Expert Committee on Immunization.

A National Immunization Technical Advisory Group (NITAG) is a multi-disciplinary body of national experts that provide evidence-based recommendations to policy-makers to assist them in making informed immunization policy and programme decisions. During the COVID-19 pandemic, NITAGs faced many challenges in making evidence-based recommendations for COVID-19 vaccines due to the rapidly evolving situation with new vaccine products available in a short time period and limited data on vaccine effectiveness. The authors reviewed the process used by Serbia's NITAG, which is called the Serbian Expert Committee on Immunization, to develop COVID-19 vaccine recommendations during the pandemic. The article examines the challenges and successes faced by the committee. Serbia's expert committee used the best available evidence to develop over forty recommendations on all aspects of COVID-19 vaccination. These expert committee recommendations facilitated the early procurement and successful roll-out of COVID-19 vaccines, guidance for vaccination of individuals at the highest risk, and high COVID-19 vaccination coverage in the country. The availability of five COVID-19 vaccines in Serbia was an advantage for the successful roll-out but posed challenges for the expert committee. Serbia's expert committee plans to use the experience and best practices developed during the pandemic to improve and expand its work moving forward.

Cardiac findings in pediatric patients with spinal muscular atrophy types 2 and 3.

BACKGROUND: It is unclear whether the heart is affected in pediatric patients with milder forms of spinal muscular atrophy (SMA). Therefore, we aimed to determine the presence of any cardiac abnormalities in these patients. METHODS: We conducted a cross-sectional study of children and adolescents with SMA types 2 and 3 between July 2018 and July 2019. All patients underwent a comprehensive cardiac evaluation, including history-taking, physical examination, electrocardiography, echocardiography, measurement of cardiac biomarkers (cardiac troponin T [cTnT] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), and 24-hour Holter monitoring. RESULTS: In total, 42 patients were enrolled (27 and 15 with SMA type 2 and 3, respectively). No patient had structural heart disease, except for one with mitral valve prolapse. None had signs of ventricular dysfunction on echocardiography. Both cTnT and NT-proBNP levels were normal in all patients. Electrocardiography showed sinus tachycardia in seven patients (16.7%), and prolonged P-R interval in one (2.4%). Holter monitoring detected benign ventricular arrhythmias in two patients (4.8%), and rare supraventricular premature beats in one. The mean 24-hour heart rate was elevated in six patients (14.3%), whereas both the minimum 24-hour heart rate and the maximum R-R interval were increased in 23 (54.8%). DISCUSSION: The prevalence of cardiac disease in pediatric patients with SMA types 2 and 3 is low; however, these patients may have increased resting heart rates. A complete cardiac history and physical examination are a useful screen. Additional cardiac investigations may be performed as needed.

Multi-purpose ECG telemetry system.

BACKGROUND: The Electrocardiogram ECG is one of the most important non-invasive tools for cardiac diseases diagnosis. Taking advantage of the developed telecommunication infrastructure, several approaches that address the development of telemetry cardiac devices were introduced recently. Telemetry ECG devices allow easy and fast ECG monitoring of patients with suspected cardiac issues. Choosing the right device with the desired working mode, signal quality, and the device cost are still the main obstacles to massive usage of these devices. METHODS: In this paper, we introduce design, implementation, and validation of a multi-purpose telemetry system for recording, transmission, and interpretation of ECG signals in different recording modes. The system consists of an ECG device, a cloud-based analysis pipeline, and accompanied mobile applications for physicians and patients. The proposed ECG device's mechanical design allows laypersons to easily record post-event short-term ECG signals, using dry electrodes without any preparation. Moreover, patients can use the device to record long-term signals in loop and holter modes, using wet electrodes. In order to overcome the problem of signal quality fluctuation due to using different electrodes types and different placements on subject's chest, customized ECG signal processing and interpretation pipeline is presented for each working mode. RESULTS: We present the evaluation of the novel short-term recorder design. Recording of an ECG signal was performed for 391 patients using a standard 12-leads golden standard ECG and the proposed patient-activated short-term post-event recorder. In the validation phase, a sample of validation signals followed peer review process wherein two experts annotated the signals in terms of signal acceptability for diagnosis.We found that 96% of signals allow detecting arrhythmia and other signal's abnormal changes. Additionally, we compared and presented the correlation coefficient and the automatic QRS delineation results of both short-term post-event recorder and 12-leads golden standard ECG recorder. CONCLUSIONS: The proposed multi-purpose ECG device allows physicians to choose the working mode of the same device according to the patient status. The proposed device was designed to allow patients to manage the technical requirements of both working modes. Post-event short-term ECG recording using the proposed design provide physicians reliable three ECG leads with direct symptom-rhythm correlation.

Oral propranolol for infantile hemangiomas: a prospective study on the role of 48-hour Holter monitoring in additional safety assessment.

PURPOSE: Oral propranolol has been recently approved for infantile hemangiomas (IHs), but potential side effects stay a challenge. We sought to make an additional assessment on oral propranolol safety for this indication. MATERIALS AND METHODS: Prospective study included 108 infants consecutively treated for IHs at the University Children's Hospital Tirsova, Belgrade from January 2010 to December 2013. Propranolol was administered orally at a daily dose of 0.5 mg/kg and doubled every 48 hours in the absence of side effects until reaching the maximum dose of 2 mg/kg daily. Systolic and diastolic blood pressure and heart rate were measured every 48 hours with clinical observation. Heart rate was monitored by standard electrocardiogram (ECG) and 48-hour Holter ECG. RESULTS: Statistically significant, but asymptomatic decreases in systolic blood pressure and heart rate recorded by Holter ECG were observed during the first doubling of dose and then remained stable. Arrhythmias were not detected. Despite mild sleep disturbance observed in 31% of infants in the hospital milieu, Holter monitoring indicated circadian rhythm maintenance. CONCLUSIONS: Oral propranolol for IHs does not remarkably affect heart rhythm including circadian variations throughout hospital initiation. Therefore, there is no necessity for Holter monitoring in additional safety assessment.

[The Role of Two-Dimensional Echocardiography in Diagnostics of Coarctation of the Aorta in Newborns].

INTRODUCTION: Diagnosis of neonatal coarctation of the aorta (CoA) still presents a challenge in routine practice because of absence of reliable morphologic and functional parameters for early detection of this congenital heart defect in newborns. OBJECTIVE: The aim of this study is to identify easy obtainable two-dimensional echocardiographic parameters for detection of the CoA in newborns. METHODS: Echocardiographic evaluation was performed in 30 newborns with CoA and 20 healthy neonates (control group). Measurements of the proximal transverse arch (PTA), distal transverse arch (DTA), isthmus, distance between the left common carotid artery (LCCA) at the origin of the left subclavian artery (LSA), were obtained by two-dimensional echocardiography. Aortic arch hypoplasia was defined using Mouleart, Karl and Mee criteria, and Z-value. Index 1 was calculated as a ratio of DTA and distance between origins LCCA-LSA, Index 2 was calculated as a ratio of the ascending aorta and the distance between LCCA-LSA origins, and Index 3 was calculated as a ratio of PTA and distance between LCCA-LSA origins. RESULTS: Index 1 was significantly lower in patients with CoA in comparison with control group (0.50 vs. 1.39; p≤0.01). A cut-off point at 0.39, for Index 1, showed a sensitivity of 92% and specificity of 99% for the diagnosis of neonatal CoA, while cut off points at 0.69 and 0.44, for Index 2 and Index 3, showed the highest sensitivity and specificity for the diagnosis of CoA in newborns. CONCLUSION: By using these echo indexes, two-dimensional echocardiographic aortic arch measurement becomes a simple, reliable noninvasive method for the evaluation of aortic coarctation in newborns and may lead to earlier diagnosis and subsequent surgical correction.

Prenatal growth retardation, microcephaly, and eye coloboma in infant with multiple congenital anomalies: further delineation of presumed new dysmorphic syndrome.

BACKGROUND: Ten years ago an unusual association of prenatal growth retardation, microcephaly, coloboma of the iris/eye anomalies, congenital heart defects, and urogenital anomalies was reported for the first time in three siblings. Autosomal recessive inheritance was presumed. This finding has been included in London Winter-Baraitser Dysmorphology Database as a separate entity, but still has not been classified as a distinct syndrome. CASE: We report an infant with an association of prenatal growth retardation, microcephaly, facial dysmorphism, eye anomalies, congenital heart defects, and testis retention. Mild craniofacial dysmorphism consists of sloped forehead, bulbous nose tip, and micrognathia. Eye anomalies include coloboma of the iris, choroidea, and optic nerve as well as lens dislocation. The patient also presents with ventricular and atrial septal defects, hypoplastic mitral valve, persistent left superior vena cava, accessory spleen, and club foot. CONCLUSIONS: To the best of our knowledge, this is the second family and the fourth case with this pattern of birth defects reported worldwide so far. We presume that this combination of multiple congenital anomalies and growth retardation constitutes a newly recognized syndrome of likely autosomal recessive inheritance. So far no data suggest etiological impact of consanguinity, parental age, or environmental factors.

[The influence of respiratory pattern on heart rate variability analysis in heart failure].

INTRODUCTION: Autonomic dysfunction is present early in the course of heart failure, and has a direct role on deterioration of cardiac function and prognosis. Heart rate variability (HRV) estimates sympathovagal control of heart frequency. The influence of respiratory pattern on HRV is clinically important. Breathing disorders are common in heart failure and highly affect HRV and autonomic evaluation. It was previously shown that slow and deep breathing increased parasympathetic tone, but effects of this respiratory pattern on HRV were not evaluated. OBJECTIVE: The aim of the study was to estimate effects of slow and deep breathing (SDB) on HRV in heart failure patients. METHOD: In 55 patients with heart failure (78% male, mean age 57.18 +/- 10.8 yrs, mean EF = 34.12 +/- 10.01%) and 14 healthy controls (57.1% male, mean age 53.1 +/- 8.2 yrs), short term HRV spectral analysis was performed (Cardiovit AT 60, Schiller). VLF, LF, HF and LF/HF were determined during spontaneous and deep and slow breathing at 0.1 Hz (SDB). RESULTS: LF, HF and LF/HF significantly increased during SDB compared with spontaneous breathing both in controls (LF 50.71 +/- 61.55 vs. 551.14 +/- 698.01 ms2, p < 0.001; HF 31.42 +/- 29.98 vs. 188.78 +/- 142.74 ms2, p < 0.001 and LF/HF 1.46 +/- 0.61 vs. 4.21 +/- 3.23, p = 0.025) and heart failure patients (LF 27.37 +/- 36.04 vs. 94.50 +/- 96.13 ms2, p < 0.001; HF 12.13 +/- 19.75 vs. 41.58 +/- 64.02 ms2, p < 0.001 and LF/HF 3.77 +/- 3.79 vs. 6.38 +/- 5.98, p = 0.031). Increments of LF and HF induced by SDB were significantly lower in patients than healthy controls. Heart failure patients had lower HRV compared to healthy controls both during spontaneous breathing and SDB. During spontaneous breathing, only HF was significantly lower between healthy controls and patients (p = 0.002). During SDB VLF (p = 0.022), LF (p < 0.001) and HF (p < 0.001) were significantly lower in heart failure patients compared to controls. CONCLUSION: These data suggest that SDB increases HRV both in healthy and heart failure patients; the highest increment is in LF range. Differences in spectral profile of HRV between healthy controls and heart failure patients become more profound during SDB. Controlled respiration during HRV analysis might increase sensitivity and reliability in detection of autonomic dysfunction in heart failure patients.

Heart rate variability in children with idiopathic ventricular tachycardia.

Idiopathic ventricular tachycardia (IVT) is a rare arrhythmia in children. A great deal of uncertainty and numerous questions still remain regarding the extent of investigation, therapy, and long-term prognosis for children with IVT. The existence of subclinical cardiac disease, as well as of autonomic dysfunction in patients with ventricular arrhythmias, has been well documented. A number of experimental and clinical studies have suggested that imbalances within the cardiac autonomic system's activity may be crucial in the generation of ventricular tachycardia, irrespective of the presence of cardiovascular pathological substrate. Heart rate variability (HRV) analysis provides a useful method for measuring the autonomic activity. This study evaluates HRV in children with IVT. The study included 31 children with ventricular arrhythmia who were divided into two groups: (1) patients with frequent ventricular extrasystoles (VES) and (2) patients with IVT. The control group comprised 23 healthy children without pathological findings on 24-h ECG Holter. Twenty-four-hour ambulatory electrocardiography recordings were obtained, and the time-domain variables were calculated. HRV was compared to age-related normal values. It was observed that the overall heart rate variability is diminished in children with IVT. We recommend HRV analysis of any child with IVT. Quantification of the autonomic nervous system activity using time domain analyses may be a helpful diagnostic tool in the clinical assessment and initial evaluation of these children.

[Influence of heart failure severity on heart rate variability].

INTRODUCTION: Autonomic regulation of cardiovascular functions in congestive heart failure is characterised by enhanced sympathetic and diminished parasympathetic activity. The long term predominance of sympathetic tone is a significant factor in arrhythmogenesis, sudden cardiac death, and progressive pump failure. Heart rate variability (HRV) is a noninvasive method for estimating the sympatho vagal balance in cardiovascular control. AIM: The aim of this study was to analyse the influence of heart failure severity on HRV. METHOD: HRV was estimated through the spectral analysis of short term ECG (Cardiovit AT 60, Schiller, CH) in 63 patients (78% male, mean age 56.9 +/- 10.9 years) and 14 healthy volunteers (57.1% male, mean age 53.1 +/- 8.2 years). The following spectral components were measured: VLF (very low frequency), LF (low frequency), HF (high frequency), and total power (Tot Power). RESULTS: All spectral componentswere statistically, significantly lower in patients with heart failure in comparison to healthy controls (VLF: 159.89 +/- 147.02 vs. 285.50 +/- 202.77 ms2; p = 0.023, LF: 161.48 +/- 204.01 vs. 474.57 +/- 362.93 ms2; p < 0.001, HF: 88.58 +/- 102.47 vs. 362.71+/- 318.28 ms2; p < 0.001), as well as total power (Tot Power: 723.39 +/- 644.52 vs. 1807.29 +/- 1204.74 ms2; p < 0.001). A significant, negative correlation between HRV parameters and NYHA class was detected in heart failure patients (VLF: r = -0.391; p = 0.002, LF: r = -0.401; p = 0.001, and Tot Power r = -0.372; p = 0.003). Ejection fraction proved to be in significant, positive correlation to VLF (r = 0.541; p = 0.002), LF (r = 0.531; p = 0.003), HF (r = 0.418; p = 0.020), and Tot Power (r = 0.457; p = 0.013). CONCLUSION: Significant HRV reduction is a precursor to incipient heart failure (NYHA I). In heart failure progression, total power as well as the power of all spectral components is progressively reduced. LF and Tot Power are the most prominent parameters for discriminating between the different stages of heart failure. These results could promote HRV as an important decision-making tool in heart failure treatment as well as in monitoring the results of that treatment.

[Results of treatment of cyanotic heart defects in children]. / Rezultati lecenja cijanogenih mana srca kod dece.

Cyanotic heart diseases are relatively rare, but they are severe and heterogeneous congenital heart diseases, which require complex surgery. Development of different advanced surgical procedures, such as arterial switch operation (ASO), Fontan and its modifications, Norwood etc. operations, as well as better perioperative care significantly improved survival rate and quality of life of these children. The study group included 308 children treated for cyanotic heart disease in Yugoslavia, in the period January 2000 to July 2004. Some of them (239, 77.6%) were treated at the University Children's Hospital in Belgrade, and others (69, 22.4%) in different institutions abroad. The age of the operated patients varied between 1 day and 19 years (median 12 months). The patients (pts) were divided into four groups, according to the disease and type of the operation. In the whole group of 308 patients treated due to cyanotic heart disease, there were 232 (75.3%) cases with open heart surgery and 76 (24.7%) with closed procedures. The mortality rate was significantly different between disease/operation groups, and age groups. Average mortality rates differed from 11.8% for palliative procedures to 12.5% for complete corrections. Mortality rate and achieved surgical results in treatment of children with cyanotic heart diseases were significantly worse than those published by leading cardiac surgery centers in the world. However, there is a clear tendency in introducing new surgical procedures, lowering the age at which the operation is done and decreasing the mortality rates.

[Surgery for coarctation of the aorta in infants younger than three months]. / Hirursko lecenje koarktacije aorte kod odojceta uzrasta do tri meseca.

INTRODUCTION: Recurrent coarctation is a complication which is seen at a consistent rate following repair for coarctation of the aorta in young infants. OBJECTIVE: This retrospective analysis was carried out to compare the results between resection with end-to-end anastomosis (ETE), and resection with extended end-to-end anastomosis (E-ETE), in this age group during late follow-up period. The role of ductus arteriosus is not clearly defined and the second objective of this study was to analyze intimal thickening in aortic coarctation. MATERIAL AND METHODS: From 1999 to 2003, 45 patients less than 3 months of age underwent repair of aortic coarctation. Mean age was 24 days (2-89 days), average weight was 3.5 +/- 0.6 kg (2.4-5.2 kg). The method of repair was ETE in 14 (31.1%) patients, E-ETE in 29 (64.4%) patients and other techniques were applied in 2 cases. Demographic, morphometric, clinical and operative variables were analyzed for correlation with recurrent arch obstruction. In order to characterize the components of intimal thickening in coarctation, narrowed segments of aorta resected from 16 neonates during surgery were examined immunocytochemically and by electron microscopy. For light microscopy, the specimens were dehydrated in graded ethanol (70-100%), cleared in xylol and embedded in paraffin. Immunocytochemical staining was performed in 5 microm sections from formaldehyde-fixed paraffin-embedded blocks, using a labeled streptavidin-biotin method with an LSAB kit (Dako). RESULTS: Early mortality was 6.7% (CI 95%, 2.9%-10.4%). All early deaths (3 patients) occurred in infants with associated ventricular septal defects (p<0.05). The mean follow-up for all patients was 30 +/- 21 months (range 1.5-63 months). During mean follow-up of 2 months, recurrent arch obstruction was diagnosed in 9 patients (21.4%). Two patients with associated complex heart defects died before re-intervention, one had mild gradient on catheterization (20 mm Hg) and one is waiting for catheterization. Five patients were reoperated and the mean time to re-intervention was 4 months (range 2.6-6 months). Kaplan-Meier freedom from recoarctation was 78.1 +/- 6.4% at 5 years in the whole group. Freedom from recoarctation was 60.6 +/- 15.4% at 25 months in ETE group and 86.2 +/- 6.4% at 60 months in E-ETE group (p=0.062). Factors associated with recoarctation, obtained by univariable Cox regression, included abnormal right subclavian artery (p=0.003), hypoplastic proximal transverse aortic arch (Z < or = -2, p=0.025) and weight at operation < or = 3 kg (p=0.02). Abnormal origin of the right subclavian artery was the only independent predictor of recoarctation obtained by multivariable Cox regression analysis. DISCUSSION: All examined specimens had intimal thickening of the posterior aortic wall, with accumulation of smooth muscle cells (SMC) with alpha smooth muscle actin (alpha-SMA) and vimentin-immunoreactivity (but not desmin and MHC) and also expressed PCNA and S-100. In the inner media of the anteromedial wall of the aorta, all specimens had large number of SMC expressing desmin and MHC. SMC in the inner media exhibit contractile phenotype and their origin could be ductal. CONCLUSION: Both procedures are effective for coarctation repair in young infants. Risk of recoarctation is a function of the complex anatomy of the arch, while residual ductal tissue may play a significant role.