The Relationship between Depression Symptoms and Physical Activity in Children with Idiopathic Ventricular Extrasystoles.

Background and Objectives: Depression in childhood often co-occurs with anxiety disorders and a range of somatic symptoms. Recent studies have identified physical activity as a target for preventing the onset of depression. However, idiopathic ventricular extrasystoles (VEs) in children are sometimes associated with somatic symptoms and limitations in physical activity. The occurrence of arrhythmia can also be distressing for children and their parents. This study was conducted to determine the relationship between symptoms of depression, physical activity, and somatic symptoms in children with idiopathic VE. Materials and Methods: This study of children with structurally normal hearts and VE was approved by the local ethics committee (no. 2021/10-1383-859(1). The authors designed a questionnaire to assess symptoms, physical activity, and general well-being. As part of that, symptoms of depression were evaluated with a modified pediatric PHQ-9 (MP-PHQ-9) questionnaire, with scores ≤4 for no, 5-9 for mild, 10-14 for moderate, and ≥15 for severe depression. Children aged ≥12 years and parents who assessed their children's condition completed the questionnaires. All children also underwent 24-h electrocardiography and echocardiography to evaluate arrhythmia frequency and cardiac condition. Results: Questionnaires were completed by 60 children's parents and 39 children (≥12 years old). The median children's age was 13 years. Palpitations were experienced by 26 (43.3%), chest pain by 13 (21.7%), and exercise intolerance by 15 (25%) children. All patients had normal ventricular function and hemodynamically normal hearts. The median score of the MP-PHQ-9 completed by parents was 2, and by children was 4. The median VE frequency was 4.77 (0.1-32.77) % per 24 h. We found that 31 (51.7%) children engaged in extra-sports participation with a median time of 3.75 h per week. Eleven of the children were suspended from sports. There was no significant difference between VE frequency and MP-PHQ-9 scores. Higher MP-PHQ-9 scores were noted for symptomatic children who engaged in <5 h per week of physical activity. Conclusions: Higher depression scores were found for children with somatic symptoms than those without symptoms. Children who were physically active for less than 5 h per week also had higher depression risk scores than those who were more active. Our research has shown that parents underestimate the signs of depression in their children.

Primary child health care services in Lithuania: Does it meet the needs of the children?

BACKGROUND: Primary health care is the foundation of a health system and has a strong influence on the efficiency of the health system as a whole. For children in Europe, it is defined by three primary health care models: paediatric; mixed paediatrician and family physician; and family physician. There is much debate in Europe about which model is most appropriate for children. The Lithuanian model is mixed, although health policy is geared towards the promotion of family physicians, with a decline in the number of primary paediatricians in clinical practice. OBJECTIVES: To review the children's primary health care system in Lithuania, compare the indicators of primary care by family physicians and paediatricians in Lithuania, and identify parents' perceptions of the primary health care model for children. METHODS: A retrospective longitudinal study was performed of children's primary health care indicators for quantity and quality in 2014-2018. A representative opinion survey of 1000 adult respondents was conducted. RESULTS: A total of 3.5 million children's visits to primary care physicians (6.7 ± 3 visits for each child) were registered in Lithuania in 2018. During a recent 5-year period (2014-2018), the number of visits did not change significantly. Visits to paediatricians accounted for 41% of all children's visits to primary care physicians in 2018. Visits to Emergency Departments increased by 20%. The results of the survey showed that 72.3% of the respondents would prefer their children be treated by a primary care paediatrician. CONCLUSION: The mixed paediatrician and family physician health care model gives parents the right to choose. The results showed a decreased number of paediatricians in primary care; paediatric primary care is more frequent than family physician care; and parents tend to trust paediatricians more. The study also showed differences in the models of service used and patterns between regions in Lithuania.

Ultrasonic cardiac output monitor provides effective non-invasive bedside measurements of neonatal cardiac output.

This study determined the accuracy and validity for the haemodynamic parameters of haemodynamically stable neonates after postnatal circulatory adaptation using the ultrasonic cardiac output monitor (USCOM) in comparison with echocardiography. We conducted a prospective, observational study of neonates born at 23-41 weeks of gestation. They all underwent both echocardiography and USCOM assessments for comparison purposes. The 127 neonates were examined at the median of postmenstrual age of 35 weeks and there was a very high correlation between the cardiac output measurements provided by both methods. The mean difference in cardiac output was - 12 ± 25 ml/kg/min, with percentage error of 8.3 ± 6.9%. A larger bias was observed in cases with higher left ventricular output. Bland-Altman analysis confirmed no significant bias, with acceptable limits of agreement between these two methods. There was a very good correlation between the USCOM and echocardiographic methods when we used them to measure cardiac output in neonates.

A Randomized Phase 4 Study of Immunogenicity and Safety After Monovalent Oral Type 2 Sabin Poliovirus Vaccine Challenge in Children Vaccinated with Inactivated Poliovirus Vaccine in Lithuania.

BACKGROUND: Understanding immunogenicity and safety of monovalent type 2 oral poliovirus vaccine (mOPV2) in inactivated poliovirus vaccine (IPV)-immunized children is of major importance in informing global policy to control circulating vaccine-derived poliovirus outbreaks. METHODS: In this open-label, phase 4 study (NCT02582255) in 100 IPV-vaccinated Lithuanian 1-5-year-olds, we measured humoral and intestinal type 2 polio neutralizing antibodies before and 28 days after 1 or 2 mOPV2 doses given 28 days apart and measured stool viral shedding after each dose. Parents recorded solicited adverse events (AEs) for 7 days after each dose and unsolicited AEs for 6 weeks after vaccination. RESULTS: After 1 mOPV2 challenge, the type 2 seroprotection rate increased from 98% to 100%. Approximately 28 days after mOPV2 challenge 34 of 68 children (50%; 95% confidence interval, 38%-62%) were shedding virus; 9 of 37 (24%; 12%-41%) were shedding 28 days after a second challenge. Before challenge, type 2 intestinal immunity was undetectable in IPV-primed children, but 28 of 87 (32%) had intestinal neutralizing titers ≥32 after 1 mOPV2 dose. No vaccine-related serious or severe AEs were reported. CONCLUSIONS: High viral excretion after mOPV2 among exclusively IPV-vaccinated children was substantially lower after a subsequent dose, indicating induction of intestinal immunity against type 2 poliovirus.

A questionnaire-based study to assess knowledge and attitudes to meningococcal disease and prevention among parents of children up to two years in Lithuania.

OBJECTIVES: In July 2018, vaccine against meningococcal B infection in Lithuania was added to the national vaccination calendar. However, vaccination rates were low. The aim of the study was to identify parents' attitudes towards meningococcal disease and vaccination. METHODS: In the period from February to March 2019, a questionnaire survey was conducted; 483 parents of children aged up to 2 years participated. In the validated questionnaire respondents provided data on their gender, education, age and answered questions that helped to estimate knowledge and attitudes towards meningococcal disease and vaccination. RESULTS: Parents with higher education are more likely to believe that meningococcal infection can be prevented; 316 (65.4%) parents are concerned that their child is at high risk of infection and evaluated the level of anxiety M = 7.39, SD = 2.29 out of 10 points; 309 (64.0%) believe that the vaccine is effective (M = 8.41; SD = 1.15 out of 10 points). One third of parents will not vaccinate their children because they believe that the MenB vaccine is not safe (71.2%); 370 (76.6%) have heard negative information about this vaccine, the majority (83.2%) from the Internet. The negative information received is positively correlated with the belief that the vaccine is not effective (r = 0.18, p = 0.031) and not safe (r = 0.35, p < 0.001); 49.3% of parents report side effects after vaccination; 326 (67.5%) parents believe that they need more evidence-based information on MenB vaccination and 90.8% would like to get it from a healthcare professional. CONCLUSIONS: Due to high level of mistrust of vaccines and the lack of evidence-based information, parents decide not to vaccinate their children against meningococcal B infection. There is a great need for parents' education and the dissemination of evidence-based information among them.

Clinical and laboratory features of children with community-acquired pneumonia are associated with distinct radiographic presentations.

Chest radiographs from children with community-acquired pneumonia (CAP) were categorized into three distinct presentations and each presentation was correlated to clinical and laboratory findings. Children < 59 months with CAP presenting to pediatric emergency rooms during two years were enrolled prospectively in eight centers across Europe. Clinical and laboratory data were documented and radiographs obtained from patients. Of the 1107 enrolled patients, radiographs were characterized as 74.9% alveolar CAP, 8.9% non-alveolar CAP, and 16.3% clinical CAP. Alveolar CAP patients had significantly higher rates of fever (90.7%), vomiting (27.6%), and abdominal pain (18.6%), while non-alveolar CAP patients presented more with cough (96.9%). A model using independent parameters that characterize alveolar, non-alveolar, and clinical CAP demonstrated that alveolar CAP patients were significantly older (OR = 1.02) and had significantly lower oxygen saturation than non-alveolar CAP patients (OR = 0.54). Alveolar CAP patients had significantly higher mean WBC (17,760 ± 8539.68 cells/mm3) and ANC (11.5 ± 7.5 cells/mm3) than patients categorized as non-alveolar CAP (WBC 15,160 ± 5996 cells/mm3, ANC 9.2 ± 5.1 cells/mm3) and clinical CAP (WBC 13,180 ± 5892, ANC 7.3 ± 4.7). CONCLUSION: Alveolar CAP, non-alveolar CAP, and clinical CAP are distinct entities differing not only by chest radiographic appearance but also in clinical and laboratory characteristics. Alveolar CAP has unique characteristics, which suggest association with bacterial etiology. TRIAL REGISTRATION: Trial number 3075 (Soroka Hospital, Israel) What is Known: • Community-acquired pneumonia in children is diagnosed based on clinical and radiological definitions. • Radiological criteria were standardized by WHO-SICR and have been utilized in vaccine studies. What is New: • Correlation between the WHO-SICR radiological definitions and clinical and laboratory parameters has not been studied. • Using the WHO-SICR radiological definitions for alveolar community-acquired pneumonia (CAP) and non-alveolar CAP and the study definition for clinical CAP, it was found that the groups are distinct, differing clinically and in laboratory parameters.

Factors Determining Parents' Decisions to Bring Their Children to the Pediatric Emergency Department for a Minor Illness.

BACKGROUND The number of children visiting Emergency Departments (EDs) is increasing in Lithuania; therefore, the aim of this study was to determine the factors influencing the parental decision to bring their child to the ED for a minor illness that could be managed in a primary healthcare setting, and to compare parents' and medical professionals' attitudes toward a child's health status and need for urgent care. MATERIAL AND METHODS A prospective observational study was performed at the tertiary-level teaching Children's Hospital in Vilnius. A total of 381 patients' parents were interviewed using an original questionnaire based on Andersen's behavioral model of healthcare utilization; in addition, the medical records of patients were reviewed to identify factors that might have an impact on parental decisions to bring their child to the ED for a minor health problem. The study participants were enrolled from October 1, 2013 to August 31, 2014. The urgency of medical care needed to be provided to the patients was evaluated by a tertiary-level triage system. RESULTS Based on the assessment of the triage nurses, the need for emergency care to patients was distributed as follows: 298 patients (78.2%) needed non-urgent care and 83 patients (21.8%) needed urgent care. More than one-third (38.8%) of the parents reported that they came to the ED due to their child's urgent care need and worsened child's health; however, the opinion of ED professionals indicated only a fifth of patients required urgent care. Parents who brought their children to the ED without physician referral were five times more likely to visit the ED during evening hours and on weekends (OR=5.416; 95% CI, 3.259-8.99; p<0.001). The decision to come to the ED without visiting a primary care physician was made more often by parents with a higher income (OR=2.153; 95% CI, 1.167-3.97) and those who came due to children having rash (OR=4.303; 95% CI, 1.089-16.995) or fever (OR=3.463; 95% CI, 1.01-11.876). Older parents were 2.07 (95% CI, 1.1224-3.506) times more likely to evaluate their child's health unfavorably than younger parents. CONCLUSIONS We identified predisposing, enabling, and need factors that influenced the parents' decision to bring their child to the ED for minor health problems that could be managed by a primary care physician. Parents assessed their child's condition more critically and thought that their child required urgent medical aid more frequently than healthcare professionals.

Unscheduled return visits to a pediatric emergency department.

BACKGROUND AND OBJECTIVE: Return visits (RVs) to a pediatric emergency department (ED) within a short period after discharge have an influence on overcrowding of the ED and reveal some weaknesses of the health care system. The aim of this study was to determine the rate of RVs and factors related to RVs to the pediatric ED in Lithuania. MATERIALS AND METHODS: A retrospective study in an urban, tertiary-level teaching hospital was carried out. Electronic medical records of all patients (n=44097) visiting the ED of this hospital between 1 January and 31 December 2013 were analyzed. Demographic and clinical characteristics of patients who return to the ED within 72h and those who had not visited the ED were compared. Factors associated with RVs were determined by multivariable logistic regression. RESULTS: Of the overall ED population, 33889 patients were discharged home after the initial assessment. A total of 1015 patients returned to the ED within 72h, giving a RV rate of 3.0%. Being a 0-7-year old, visiting the ED during weekdays, having a GP referral, receiving of laboratory tests and ultrasound on the initial visit were associated with greater likelihoods of returning to the ED. Patients who arrived to the ED from 8:01a.m. to 4:00p.m. and underwent radiological test were less likely to return to the ED within 72h. Diseases such as gastrointestinal disorders or respiratory tract/earth-nose-throat (ENT) diseases and symptoms such as fever or pain were significantly associated with returning to the ED. The initial diagnosis corresponded to the diagnosis made on the second visit for only 44.1% of the patients, and the highest rate of the congruity in diagnosis was for injuries/poisoning, surgical pathologies (77.2%) and respiratory tract diseases (76.9%). CONCLUSIONS: RVs accounted for only a small proportion of visits to the ED. RVs were more prevalent among younger patients and patients with a GP referral as well as performed more often after discharging from the ED in the evening and at night.

Antibiotic resistance of Streptococcus pneumoniae, isolated from nasopharynx of preschool children with acute respiratory tract infection in Lithuania.

BACKGROUND: Increasing pneumococcal resistance to commonly used antibiotics and multidrug resistance is a serious public health concern. Data on distribution of resistant Streptococcus pneumoniae (SPn) strains among children in Lithuania are limited. We evaluated the circulation of SPn serotypes and antimicrobial susceptibility among preschool children in Lithuania before the introduction of universal infant pneumococcal vaccination. METHODS: A prospective study was carried out from February 2012 to March 2013 in five cities of Lithuania. A total of 900 children under six years of age who presented to primary care centre or a hospital emergency department with acute respiratory tract infection were enrolled in the study. Nasopharyngeal swabs were obtained and cultured for SPn. Positive samples (n = 367) were serotyped and tested for antimicrobial susceptibility. Associations of pneumococcal non-susceptibility with study site, season, age, sex, attendance of day care centre and treatment with antimicrobials (between one and six months prior the study) were evaluated. RESULTS: About a half (56.7 %) of SPn strains were susceptible to all the antibiotics tested. Pneumococcal non-susceptibility to penicillin, erythromycin, clindamycin and trimethoprim-sulphamethoxazole was 15.8, 21.3, 16.9 and 27.3 %, respectively. None of the tested isolates was resistant to norfloxacin or vancomycin. We found a geographical variation of pneumococcal resistance within the cities of the country. Age, sex, the attendance of day care centre and treatment with antimicrobials prior the study was not significantly associated with a carriage of non-susceptible SPn strains. Among non-susceptible SPn serotypes 67.9 %-82.4 % were present in currently available pneumococcal conjugate vaccines. CONCLUSIONS: The rates of nasopharyngeal SPn susceptibility to penicillin and macrolides are still high among preschool children in Lithuania, however they are lower compared with previous studies. A strict policy with respect to antibiotic prescription together with widespread use of vaccination could potentially reduce the carriage rate of antibiotic-resistant pneumococci in our country.

Incidence of acute otitis media in children below 6 years of age seen in medical practices in five East European countries.

BACKGROUND: Although acute otitis media (AOM) remains a major public health problem worldwide and brings economic burden on health care system and caregivers, little information is available about its epidemiology in Eastern Europe. METHODS: We conducted an epidemiological, prospective, observational, multi-centre cohort study (NCT01365390) in five East European countries (Estonia, Lithuania, Poland, Romania and Slovenia) between June 2011 and January 2013 to determine the incidence and clinical characteristics of AOM among children aged < 6 years during 1 year. RESULTS: AOM incidence was 160.7 cases (95 % confidence interval [CI]: 144.7-177.9) per 1000 person-years (PY) being the lowest in the < 1 year age group (92.3 cases [95 % CI: 59.7-136.2] per 1000 PY) and the highest in the 3- < 4 years age group (208.9 cases [95 % CI: 165.1-260.7] per 1000 PY). AOM incidence was similar across the countries, with the exception of Slovenia (340.3 cases [95 % CI: 278.3-412.0] per 1000 PY). There was a lower risk in breastfed children and a higher risk in those attending school/childcare or with allergies. AOM required 521 visits to the doctor. Antibiotics were prescribed for 276 (74.8 %) episodes with the lowest prescription rate in Estonia (51.4 %) and the highest in Romania (83.7 %). Complications were rare and hospitalisations occurred in 2 % of the cases. CONCLUSIONS: The disease burden of AOM in Eastern Europe is relevant and public health initiatives to reduce it should be considered. TRIAL REGISTRATION: ClinicalTrial.gov NCT01365390 .

Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial.

BACKGROUND: Rates of varicella have decreased substantially in countries implementing routine varicella vaccination. Immunisation is possible with monovalent varicella vaccine or a combined measles-mumps-rubella-varicella vaccine (MMRV). We assessed protection against varicella in naive children administered one dose of varicella vaccine or two doses of MMRV. METHODS: This study was done in ten European countries with endemic varicella. Healthy children aged 12-22 months were randomised (3:3:1 ratio, by computer-generated randomisation list, with block size seven) to receive 42 days apart (1) two doses of MMRV (MMRV group), or (2) MMR at dose one and monovalent varicella vaccine at dose two (MMR+V group), or (3) two doses of MMR (MMR group; control). Participants and their parents or guardians, individuals involved in assessment of any outcome, and sponsor staff involved in review or analysis of data were masked to treatment assignment. The primary efficacy endpoint was occurrence of confirmed varicella (by detection of varicella zoster virus DNA or epidemiological link) from 42 days after the second vaccine dose to the end of the first phase of the trial. Cases were graded for severity. Efficacy analyses were per protocol. Safety analyses included all participants who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, number NCT00226499. FINDINGS: Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. In the efficacy cohort of 5285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8·8), in the MMR+V group was 36 months (8·5) and in the MMR group was 35 months (8·9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94·9% (97·5% CI 92·4-96·6), and against moderate to severe varicella was 99·5% (97·5-99·9). Efficacy of one-dose varicella vaccine against all varicella was 65·4% (57·2-72·1), and against moderate to severe varicella (post hoc) was 90·7% (85·9-93·9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57·4% (95% CI 53·9-60·9) of participants in the MMRV group reported fever of 38°C or more, by contrast with 44·5% (41·0-48·1) with MMR+V, and 39·8% (33·8-46·1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period. INTERPRETATION: These results support the implementation of two-dose varicella vaccination on a short course, to ensure optimum protection from all forms of varicella disease. FUNDING: GlaxoSmithKline Vaccines.

The influence of Streptococcus pneumoniae nasopharyngeal colonization on the clinical outcome of the respiratory tract infections in preschool children.

BACKGROUND: Streptococcus pneumoniae (SPn) is an important pathogen causing a variety of clinical manifestations. The effects of SPn nasopharyngeal colonization on respiratory tract infections are poorly studied. We evaluated the association of SPn colonization with features of respiratory tract infections. METHODS: Children under the age of 6 years who visited a primary care physician because of respiratory tract infections were enrolled in the study. History was taken, children were clinically assessed by the physician, and nasopharyngeal swabs were obtained and cultured for SPn. Positive samples were serotyped. Associations of SPn colonization with clinical signs and symptoms, recovery duration, absence from day care centre, frequencies of specific diagnoses, and treatment with antimicrobials were evaluated. RESULTS: In total 900 children were enrolled. The prevalence of SPn colonization was 40.8 % (n = 367). There were minor differences between male and female subjects (199 of 492, 40.4 % vs 168 of 408, 41.2 %, p = 0.825). Children with and without siblings had similar colonization rates (145 of 334, 43.4 % vs 219 of 562, 39.0 %, p = 0.187). Clinical signs and symptoms were not associated with SPn colonization. Children colonized with SPn had longer recovery duration compared to non-colonized children (114 of 367, 31.1 % vs 98 of 533, 18.4 %, p < 0.001) and were longer absent from day care (270 of 608, 44.4 % vs 94 of 284, 33.1 %, p = 0.001). Pneumonia, sinusitis, and acute otitis media were more frequently diagnosed in children colonized with SPn. Children attending day care centres had significantly higher prevalence of SPn colonization (270 of 367, 44.4 % vs 338 of 533, 33.1 %, p = 0.001). Children with pneumonia, sinusitis and acute otitis media were more frequently treated with antimicrobials than children with other diagnoses. CONCLUSIONS: SPn nasopharyngeal colonization has a negative impact on the course of respiratory tract infection, likely because of SPn being the cause of the disease or a complicating factor. It is also associated with and may be responsible for higher frequencies of bronchitis, pneumonia, acute otitis media, sinusitis and the need of antimicrobial treatment.

Current management of late onset neonatal bacterial sepsis in five European countries.

UNLABELLED: Late onset neonatal sepsis (LOS) has a high mortality and the optimal management is poorly defined. We aimed to evaluate new expert panel-derived criteria to define LOS and characterize the current management and antibiotic susceptibility of LOS-causing organisms in Europe. A prospective observational study enrolled infants aged 4 to 90 days in five European countries. Clinical and laboratory findings as well as empiric treatment were recorded and patients were followed until the end of antibiotic therapy. Failure was defined as a change of primary antibiotic, no resolution of clinical signs, appearance of new signs/pathogens or death. Antibiotic therapy was considered appropriate if the organism was susceptible to at least one empiric antibiotic. 113 infants (median age 14 days, 62 % ≤1500 g) were recruited; 61 % were culture proven cases (28 CoNS, 24 Enterobacteriaceae, 11 other Gram-positives and 6 Gram-negative non-fermentative organisms). The predictive value of the expert-panel criteria to identify patients with a culture proven LOS was 61 % (95 % CI 52 % to 70 %). Around one third of Enterobacteriaceae were resistant to ampicillin + or cefotaxime + gentamicin but only 10 % to meropenem. Empiric treatment contained a total of 43 different antibiotic regimens. All-cause mortality was 8 % with an additional 45 % classified as failure of empiric therapy, mainly due to change of primary antibiotics (42/60). CONCLUSIONS: The expert panel-derived diagnostic criteria performed well identifying a high rate of culture proven sepsis. Current management of LOS in Europe is extremely variable suggesting an urgent need of evidence-based guidelines.

Complete genome sequence of a novel human enterovirus C (HEV-C117) identified in a child with community-acquired pneumonia.

The new enterovirus C-117 strain belongs to the human enterovirus C species in the Picornaviridae family. We describe the characterization of the complete genome of this strain identified in a respiratory specimen of a child enrolled in the Community-Acquired Pneumonia Pediatric Research Initiative (CAP-PRI) study evaluating the etiology of community-acquired pneumonia (CAP).

Rotavirus vaccination in central Europe.

Each year, rotavirus (RV) infection is the leading cause of acute gastroenteritis requiring hospitalisation and of nosocomially transmitted diseases in children younger than 5 years across Central European Vaccination Awareness Group (CEVAG) countries; however, inadequate surveillance systems and lack of routine RV testing still exist in most CEVAG countries, making it difficult to accurately assess the present burden of acute RV gastroenteritis in the younger population. Furthermore, routine immunisation of infants with RV vaccines has not been implemented, and no official and uniform recommendations exist in most of the countries in these territories. The present study provides CEVAG country-specific estimates of the disease burden of RV gastroenteritis among the youngest population and presents evidence-based advice on the use of RV vaccines in the region, while providing a framework for vaccination at the national level.

Correlation of protection against varicella in a randomized Phase III varicella-containing vaccine efficacy trial in healthy infants.

BACKGROUND: Varicella vaccination confers high and long-lasting protection against chickenpox and induces robust immune responses, but an absolute correlate of protection (CoP) against varicella has not been established. This study models the relationship between varicella humoral response and protection against varicella. METHODS: This was a post-hoc analysis of data from a Phase IIIb, multicenter, randomized trial (NCT00226499) conducted in ten varicella-endemic European countries. Healthy children aged 12-22 months were randomized 3:3:1 to receive one dose of measles-mumps-rubella and one dose of varicella vaccine (one-dose group) or two doses of measles-mumps-rubella-varicella vaccine (two-dose group) or two doses of measles-mumps-rubella vaccine (control group) six weeks apart. The study remained observer-blind until completion, except in countries with obligatory additional immunizations. The objective was to correlate varicella-specific antibody concentrations with protection against varicella and probability of varicella breakthrough, using Cox proportional hazards and Dunning and accelerated failure time statistical models. The analysis was guided by the Prentice framework to explore a CoP against varicella. RESULTS: The trial included 5803 participants, 5289 in the efficacy (2266: one-dose group, 2279: two-dose group and 744: control group) and 5235 (2248, 2245 and 742 in the same groups) in the immunogenicity cohort. The trial ended in 2016 with a median follow-up time of 9.8 years. Six weeks after vaccination with one- or two-dose varicella-containing vaccine, more than 93.0% of vaccinees were seropositive for varicella-specific antibodies. Estimated vaccine efficacy correlated positively with antibody concentrations. The fourth Prentice CoP criterion was not met, due to predicted positive vaccine efficacy in seronegative participants. Further modelling showed decreased probability of moderate to severe varicella breakthrough with increasing varicella-specific antibody concentrations (ten-year probability <0.1 for antibody concentrations ≥2-fold above the seropositivity cut-off). CONCLUSIONS: Varicella-specific antibody concentrations are a good predictor of protection, given their inverse correlation with varicella occurrence. CLINICAL TRIAL: NCT00226499.

Ten-year follow-up on efficacy, immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: Results from five East European countries.

BACKGROUND: We assessed the 10-year efficacy, immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine (MMRV) or one dose of a monovalent varicella vaccine (V) in children from Czech Republic, Lithuania, Poland, Romania and Slovakia. METHODS: This was a phase IIIB follow-up of an observer-blind, randomized, controlled trial (NCT00226499). In phase A, healthy children aged 12-22 months from 10 European countries were randomized in a 3:3:1 ratio to receive two doses of MMRV (MMRV group), one dose of MMR followed by one dose of V (MMR + V group), or two doses of MMR (MMR; control group), 42 days apart. Vaccine efficacy (VE) against varicella (confirmed by viral DNA detection or epidemiological link and clinical assessment) was calculated with 95% confidence intervals using Cox proportional hazards regression model. Immunogenicity was assessed as seropositivity rates and geometric mean concentrations (GMCs). Solicited and unsolicited adverse events (AEs) and serious AEs (SAEs) were recorded. RESULTS: A total of 3705 children were vaccinated (1590, MMRV group; 1586, MMR + V group; 529, MMR group). There were 663 confirmed varicella cases (47, MMRV group; 349, MMR + V group; 267, MMR group). VE ranged between 95.4% (Lithuania) and 97.4% (Slovakia) in the MMRV group and between 59.3% (Lithuania) and 74% (Slovakia) in the MMR + V group. At year 10, seropositivity rates were 99.5%-100% in the MMRV group, 98%-100% in the MMR + V group and 50%-100% in the MMR control group, and the anti-VZV antibody GMCs were comparable between MMRV and MMR + V groups. The occurrence of solicited and unsolicited AEs was similar across groups and no SAE was considered as vaccination-related. No new safety concerns were identified. CONCLUSIONS: Our results indicated that two doses of varicella zoster virus-containing vaccine provided better protection than one dose against varicella and induced antibody responses that persisted 10 years post-vaccination.

Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for influenza vaccination in children.

BACKGROUND: Influenza vaccination in infants and children with existing health complications is current practice in many countries, but healthy children are also susceptible to influenza, sometimes with complications. The under-recognised burden of disease in young children is greater than in elderly populations and the number of paediatric influenza cases reported does not reflect the actual frequency of influenza. DISCUSSION: Vaccination of healthy children is not widespread in Europe despite clear demonstration of the benefits of vaccination in reducing the large health and economic burden of influenza. Universal vaccination of infants and children also provides indirect protection in other high-risk groups in the community. This paper contains the Central European Vaccination Advisory Group (CEVAG) guidance statement on recommendations for the vaccination of infants and children against influenza. The aim of CEVAG is to encourage the efficient and safe use of vaccines to prevent and control infectious diseases. SUMMARY: CEVAG recommends the introduction of universal influenza vaccination for all children from the age of 6 months. Special attention is needed for children up to 60 months of age as they are at greatest risk. Individual countries should decide on how best to implement this recommendation based on their circumstances.

The Effect of Prolonged Freezing and Holder Pasteurization on the Macronutrient and Bioactive Protein Compositions of Human Milk.

Introduction: Human donor milk is widely used to feed premature and sick newborns when the milk of their own mothers is insufficient. All treatment processes involving human milk affect its composition. The aim of this study was to assess changes in the macronutrients and bioactive protein (lactoferrin and lysozyme) content in human milk caused by freezing and Holder pasteurization. Materials and Methods: Milk samples were collected from 42 mothers 14-16 days after delivery. Each sample was divided into two parts and tested twice for macronutrient content, once upon being freshly collected and again after freezing at -40°C, thawing and Holder pasteurization. The lysozyme and lactoferrin concentrations were first determined in the unpasteurized thawed human milk after it was stored frozen at -80°C for up to 10 months and again after Holder pasteurization. The macronutrient concentrations were determined by midinfrared spectrophotometry, and enzyme-linked immunosorbent assay was used to measure the lysozyme and lactoferrin concentrations. Results: Freezing and Holder pasteurization had no significant effects on the macronutrient concentrations. The mean lactoferrin content before and after pasteurization was 2.5 ± 1.07 and 0.03 ± 0.03 mg/mL, respectively (p < 0.001), and the lysozyme content was 19.57 ± 20.11 and 12.62 ± 14.14 µg/mL, respectively (p = 0.007). Conclusions: Freezing and Holder pasteurization did not decrease the nutritional value of human milk but caused considerable loss of lactoferrin and lysozyme. New methods for treating human milk are needed that ensure the destruction of pathogenic microorganisms while retaining the biological and nutritional value of the milk. The Clinical Trial Registration number: NCT04382989.

Circadian changes in the composition of human milk macronutrients depending on pregnancy duration: a cross-sectional study.

BACKGROUND: The purpose of this study was to evaluate the circadian variation of human milk macronutrients and energy content depending upon pregnancy duration. METHODS: One hundred eighty fresh human milk samples from 45 mothers (27 of preterm and 18 of full-term newborns) were collected on a single day chosen between the 14th to 16th day after delivery. The samples were taken four times per day at 12 PM, 6 PM, 12 AM and 6 AM. Only lactating women, who could not breastfeed their hospitalized newborns and expressed milk by breast pump, were enrolled in the study. Human milk macronutrient composition and energy count were evaluated by mid-infrared spectrophotometry. RESULTS: Significant differences in macronutrient content were observed between 6 AM and 12 PM for mean protein content (t = - 4.62, df = 44, p < 0.001), for mean fat content (t = - 2.10, df = 44, p = 0.04) and for mean energy content (t = - 2.24, df = 44, p = 0.03); between 6 AM and 6 PM for mean protein content (t = - 2.41, df = 43, p = 0.02), for mean fat content (t = - 3.76, df = 43, p = 0.001) and for mean energy content (t = - 3.85, df = 43, p < 0.001); between 12 PM and 12 AM for mean protein content (Wilcoxon test V = 75.5, p = 0.001), for mean fat content (t = 2.50, df = 44, p = 0.02) and for mean energy content (t = 2.74, df = 44, p = 0.01); between 6 PM and 12 AM for mean protein content (V = 229, p = 0.02), for mean fat content (t = 4.39, df = 43, p < 0.001) and for mean energy content (t = - 4.57, df = 43, p < 0.001). The average content of carbohydrates did not change significantly during the 24 h. The samples of preterm newborns' mothers had more apparent diurnal fluctuations in macronutrient content. CONCLUSIONS: Our study revealed significant diurnal variations in protein and fat in human milk, and these circadian fluctuations were more apparent in the milk of mothers of preterm infants.