Anastrozole monotherapy further improves near-adult height after the initial combined treatment with leuprorelin and anastrozole in early-maturing girls with compromised growth prediction: results from the second phase of the GAIL study.

Background: The first phase of the GAIL study ("Girls treated with an Aromatase Inhibitor and Leuprorelin," ISRCTN11469487) has shown that the combination of anastrozole and leuprorelin for 24 months is safe and effective in improving the predicted adult height (PAH) in girls with early puberty and compromised growth prediction by +1.21 standard deviation score (SDS; +7.51 cm) compared to inhibition of puberty alone, +0.31 SDS (+1.92 cm). Objectives and hypotheses: In the second phase of the GAIL study, we assessed the adult height (AH)/near-adult height (NAH) at the end of the first phase and, in addition, the efficacy of anastrozole monotherapy thereafter in further improving NAH. Methods: We measured the AH (age 16.5 years)/NAH [bone age (BA), 15 years] of the 40 girls included, divided into two matched groups: group A (20 girls on anastrozole + leuprorelin) and group B (20 girls on leuprorelin alone). Group A was further randomized into two subgroups: A1 and A2. Group A1 (n = 10), after completion of the combined therapy, received anastrozole 1 mg/day as monotherapy until BA 14 years, with a 6-month follow-up. Group A2 (n = 10) and group B (n = 20), who received only the combined treatment and leuprorelin alone, respectively, were recalled for evaluation of AH/NAH. Results: AH or NAH exceeded the PAH at the completion of the 2-year initial phase of the GAIL study in all groups, but the results were statistically significant only in group A1: NAH-PAH group A1, +3.85 cm (+0.62 SDS, p = 0.01); group A2, +1.6 cm (+0.26 SDS, p = 0.26); and group B, +1.7 cm (+0.3 SDS, p = 0.08). The gain in group A1 was significantly greater than that in group A2 (p = 0.04) and in group B (p = 0.03). Anastrozole was determined to be safe even as monotherapy in Group A1. Conclusions: In early-maturing girls with compromised growth potential, the combined treatment with leuprorelin and anastrozole for 2 years or until the age of 11 years resulted in a total gain in height of +9.7 cm when continuing anastrozole monotherapy until the attainment of NAH, as opposed to +7.4 cm if they do not continue with the anastrozole monotherapy and +3.6 cm when treated with leuprorelin alone. Thus, the combined intervention ends at the shortest distance from the target height if continued with anastrozole monotherapy until BA 14 years.

Multisystem inflammatory syndrome in children (MIS-C): A nationwide collaborative study in the Greek population.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe hyperinflammatory condition that may occur following SARS-CoV-2 infection. This retrospective, descriptive study of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) in 12 tertiary care centers from 3/11/2020 to 12/31/2021. Demographics, clinical and laboratory characteristics, treatment and outcomes are described. Among 145 patients (95 males, median age 8.2 years) included, 123 met the WHO criteria for MIS-C, while 112 (77%) had serological evidence of SARS-CoV-2 infection. Fever was present in 99%, gastrointestinal symptoms in 77%, mucocutaneous involvement in 68% and respiratory symptoms in 28%. Fifty-five patients (38%) developed myocarditis, 29 (20%) pericarditis and 19 (13%) coronary aneurysms. Among the above cases 11/55 (20%), 1/29 (3.4%) and 5/19 (26.3%), respectively, cardiac complications had not fully resolved at discharge. Underlying comorbidities were reported in 18%. Median CRP value was 155 mg/l, ferritin 535 ng/ml, PCT 1.6 ng/ml and WBC 14.2 × 109/mm3. Most patients had elevated troponin (41.3%) and/or NT-pro-BNP (49.6%). Intravenous immunoglobulin plus corticosteroids were used in 117/145 (80.6%), monotherapy with IVIG alone in 13/145 (8.9%) and with corticosteroids alone in 2/145 (1.3%). Anti-IL1 treatment was added in 15 patients (10.3%). Thirty-three patients (23%) were admitted to the PICU, 14% developed shock and 1 required ECMO. Mortality rate was 0.68%. The incidence of MIS-C was estimated at 0.69/1000 SARS-CoV-2 infections. Patients who presented with shock had higher levels of NT-pro-BNP compared to those who did not (p < 0.001). Acute kidney injury and/or myocarditis were associated with higher risk of developing shock. CONCLUSION: MIS-C is a novel, infrequent but serious disease entity. Cardiac manifestations included myocarditis and pericarditis, which resolved in most patients before discharge. Timely initiation of immunomodulatory therapy was shown to be effective. NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. Further research is required to elucidate the pathogenesis, risk factors and optimal management, and long-term outcomes of this clinical entity. WHAT IS KNOWN: • MIS-C is an infrequent but serious disease entity. • Patients with MIS-C present with multi-organ dysfunction, primarily involving the gastrointestinal and cardiovascular systems. WHAT IS NEW: • NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. • Acute kidney injury and/or myocarditis were associated with higher risk of developing shock.

Extrauterine Growth Restriction and Optimal Growth of Very Preterm Neonates: State of the Art.

Over the last few decades, there has been an ongoing debate over both the optimal feeding mode for very premature neonates (VPN) as well as what their optimal growth should be. Despite the American Academy of Pediatric declaring since 1997 that the growth of VPN should follow the trajectory of intrauterine fetal growth, differences of opinion persist, feeding policies keep changing, and the growth and development of VPN remains extremely variable not only between countries, but even between neighboring neonatal units. Even the appropriate terminology to express poor postnatal growth (extrauterine growth restriction (EGR) and postnatal growth failure (PGF)) remains a subject of ongoing discussion. A number of recent publications have shown that by implementing breast milk fortification and closely following growth and adjusting nutrition accordingly, as per the consensus guidelines of the major Neonatal Societies, we could achieve growth that closely follows birth centiles. A recent position paper from EPSGAN recommending targeted nutritional support to cover the energy and protein deficits sustained by VPN during periods of critical illness further strengthens the above findings. Conclusion: We can promote better growth of VPN by ensuring a stable administration of sufficient calories and protein, especially in the first 2 weeks of life, implementing breast milk fortification, covering energy and protein deficits due to critical illness, and increasing feeding volumes as per the latest guidelines. The adoption of universal protocol for nutrition and growth of VPN is essential and will enable better monitoring of long-term outcomes for this population.

Decreasing Incidence of the Multisystem Inflammatory Syndrome in Children Over 3 Pandemic Waves.

In this nationwide retrospective study, a substantial decline in the incidence of multisystem inflammatory syndrome in children over 3 successive pandemic waves characterized by different severe acute respiratory syndrome coronavirus 2 variants was documented-from 3.4 of 1000 to 1.1 of 1000 and finally to 0.25 of 1000 confirmed severe acute respiratory syndrome coronavirus 2 positive cases (P < 0.0001), respectively, whereas clinical findings and severity did not significantly vary.

Molecular surveillance of pneumococcal carriage following completion of immunization with the 13-valent pneumococcal conjugate vaccine administered in a 3 + 1 schedule.

In a cross-sectional study, with the use of molecular methods, we aimed to gain insight into oropharyngeal pneumococcal colonization over time in 1212 Greek children recruited in general pediatric settings throughout the country; they were fully vaccinated with PCV13 (3 + 1 schedule). A single sample was obtained from each child at a time interval of 26 days to 70 months after administration of the 4th (booster) PCV13 dose; sampling time was divided into six time intervals. Carriage of Streptococcus pneumoniae was detected by real-time PCR targeting the lytA gene and isolates were serotyped by singleplex real-time PCR assays. Multiple control procedures to avoid false-positive results were applied. We showed an overall S. pneumoniae carriage rate of 48.6%. Serotyping identified typeable isolates in 82% of the total lytA-positive samples. Non-PCV13 serotypes represented 83.8% of total isolates when excluding serogroups with mixed PCV13 and non-PCV13 serotypes. In multivariate analysis daycare/school attendance emerged as the main contributing factor. Notably, serotypes 19A and 3 were the only two PCV13 serotypes the colonization rate of which increased over time (χ2 for trend P < 0.001 and P = 0.012, respectively). The application of the SP2020 gene on lytA-positive serotyped samples showed pneumococcal colonization in 97% of cases, and the overall colonization profile over time closely resembled that of the lytA gene. With the provisions of the methodological approach and age group of our study, the use of the oropharynx emerges as a reliable alternative to the nasopharynx in estimating pneumococcal carriage in epidemiological studies.

"Aggressive" Feeding of Very Preterm Neonates and Body Mass Index at School Age.

INTRODUCTION: The effects of "aggressive" neonatal feeding policies of very preterm neonates (VPN) and the risk of metabolic syndrome later in life remain questionable. We aimed to evaluate the effect of our "aggressive" nutrition policies of VPN during hospitalisation on body mass index (BMI) at ages 2 and 8 years. MATERIALS AND METHODS: Eighty four VPN, who received "aggressive" nutrition during hospitalisation in an effort to minimise postnatal growth restriction (PGR) (group A), and 62 term neonates, as controls (group B), were enrolled in the study. Group A was further divided in four subgroups depending on the type (A1: fortified expressed breast milk and preterm formula; A2: exclusively preterm formula) and quantity of milk received (A3: maximum feeds 180-210 mL/kg/day; A4: maximum feeds 210 and up to 260 mL/kg/day). BMI was calculated at ages 2 and 8 years and plotted on the centile charts. RESULTS: There was no significant difference in BMI between groups A and B at 2 and 8 years, respectively, in both absolute BMI values and their centile chart distribution. There was no significant difference in BMI at 2 and 8 years either between subgroups A1 and A2 or between subgroups A3 and A4. CONCLUSIONS: "Aggressive" and individualised feeding policy for VPN did not affect the BMI and obesity rates at ages of 2 and 8 years in our study population. The type and quantity of milk feeds had no impact on their BMI at school age. Further larger studies are needed to confirm our results.

Val66Met polymorphism is associated with decreased likelihood for pediatric headache and migraine.

Background: Migraine is a complex multifactorial disorder and its pathogenesis still remains unclear. Evidence suggests the involvement of the activated trigeminovascular pathway, in which BDNF seems to play an important role. Therefore, BDNF polymorphisms are promising candidate susceptibility factors.Aim: BDNF rs6265 functional polymorphism was analyzed in order to determine its possible association with pediatric headache and migraine risk.Methods: The research included 120 consecutive pediatric patients who were diagnosed with headache and 120 healthy controls. The diagnosis was in compliance with the International Classification of Headache Disorders. Blood samples were collected from all participants and genotyped for rs6265.Results: BDNF rs6265 was significantly associated with decreased headache risk, particularly in the dominant model [Odds Ratio, OR (95% confidence interval, C.I.): 0.47 (0.26-0.85), p = 0.011] and the log-additive model [OR (95% C.I.): 0.48 (0.28-0.82), p = 0.0053]. During the sensitivity analysis, the associations were also maintained among patients with migraine.Conclusions: This is the first study to reveal a significant association of this BDNF variant with headache risk. Additionally, Val66Met was also for the first time related to decreased childhood migraine risk.

Gastric Volume Changes in Preterm Neonates during Intermittent and Continuous Feeding-GRV and Feeding Mode in Preterm Neonates.

Background: We aimed to evaluate gastric volume changes during intermittent milk feeds (IMF) and continuous milk feeds (CMF) in very premature neonates (VPN), with gastric residual volume (GRV) based on antral cross-sectional area (ACSA) measurements and to examine if there were differences in GRV between the two feeding methods. Methods: A randomized prospective clinical trial with crossover design was conducted in 31 preterm neonates (gestational age < 30 weeks). Gastric volume was assessed twice in each neonate (during IMF and CMF feeding), at 7 specific time points during a 2-h observation period by measuring ACSA changes via the ultrasound (U/S) method. Results: There was a significantly different pattern of gastric volume changes between the two feeding methods. GRV, expressed as the median percentage of ACSA measurement at 120 min relative to the higher ACSA measurement during IMF, was found to be 3% (range 0-25%) for IMF and 50% (range 15-80%) for CMF. Neonates fed with IMF had a shorter mean gastric emptying time compared to those fed with CMF (p = 0.0032). No signs of feeding intolerance were recorded in either group during the period of observation. Conclusions: Our results showed that gastric volume changes and gastric emptying time in VPN, based on ACSA measurement changes, depend on the milk feeding method. No gastrointestinal complications/adverse events were noted with GRV up to 80% with CMF.

Caffeine and Gastric Emptying Time in Very Preterm Neonates.

BACKGROUND: Caffeine has been commonly used for prevention and treatment of apnea-related symptoms in premature infants. However, its side effects have not been thoroughly studied. We investigated whether caffeine affects gastric motility in very-preterm (VP) neonates. METHODS: The study is a randomized crossover clinical trial. Twenty-two neonates with mean birth weight (BW) (standard deviation-SD) 1077 (229) g and mean gestational age (GA) (SD) 28.6 (2.1) weeks were recruited. Each neonate had its gastric emptying time checked twice with ultrasound assessment of changes in antral cross sectional area (ACSA). All neonates were sequentially allocated to the caffeine group (A) and the control group (B). Complications from the gastrointestinal tract were documented throughout the study. RESULTS: Statistically significant difference was found with regards to the gastric emptying time [median, (range)] between caffeine and control group (p = 0.040). Additionally, in the neonates with BW 1000-1500 g and GA ≥ 28 weeks, the gastric emptying time (minutes) was significantly longer during caffeine treatment [44.5 (36-68.2)] and [40 (34.5-66.5)] respectively, as compared to the gastric emptying time during no caffeine treatment [27 (24.2-30)] (p = 0.002) and [27 (24.5-30)] (p = 0.001). The incidence of gastrointestinal (GI) complications was significantly greater in neonates receiving caffeine [6 (27.%)] as compared with those without caffeine treatment [1 (4.6%)] (p = 0.039). CONCLUSIONS: During caffeine treatment, a significantly delayed gastric emptying time was noted in all study neonates, especially in these with BW 1000-1500 g and those with GA ≥ 28 weeks. Further larger studies are necessary in order to confirm this interesting finding.

emm Types and clusters and macrolide resistance of pediatric group A streptococcal isolates in Central Greece during 2011-2017.

BACKGROUND: The surveillance of emm types and macrolide susceptibility of group A streptococcus (GAS) in various areas and time periods enhances the understanding of the epidemiology of GAS infections and may guide treatment strategies and the formulation of type-specific vaccines. Greece has emerged as a country with high macrolide use. However, studies suggest a gradual reduction in macrolide consumption after 2007. METHODS: During a 7-year period (2011-2017), 604 GAS isolates were recovered from consecutive children presenting with pharyngeal or nonpharyngeal infections in Central Greece; 517 viable isolates underwent molecular analysis, including emm typing. RESULTS: Isolates belonged to 20 different emm types (in decreasing order of prevalence: 1, 89, 4, 12, 28, 3, 75 and 6, accounting for 88.2% of total isolates). The emm types comprised 10 emm clusters (five most common clusters: E4, A-C3, E1, A-C4 and A-C5). The emm89 isolates were acapsular ('new clade'). Overall macrolide resistance rate was 15.4%, and cMLSB emerged as the predominant resistance phenotype (56.4%). The lowest annual resistance rates occurred in 2014 (13.1%), 2016 (5.5%) and 2017(8.0%) (P for trend = 0.002). Consumption of macrolide/lincosamide/streptogramin B declined by 22.6% during 2011-2017. Macrolide resistance and emm28 and emm77 types were associated (both P<0.001). The most frequently identified genetic lineages of macrolide-resistant GAS included emm28/ST52, emm77/ST63, emm12/ST36, emm89/ST101 and emm4/ST39. We estimated that 98.8% of the isolates belonged to emm types incorporated into a novel 30-valent M protein vaccine. CONCLUSIONS: In Central Greece during 2011-2017, the acapsular emm89 isolates comprised the second most prevalent type. Susceptibility testing and molecular analyses revealed decreasing GAS macrolide resistance rates, which may be attributed to the reduction in the consumption of macrolides and/or the reduced circulation of macrolide-resistant clones in recent years. Such data may provide valuable baseline information in targeting therapeutic intervention and the formulation of type-specific GAS vaccines.

It is Time for a Universal Nutrition Policy in Very Preterm Neonates during the Neonatal Period? Comment on: "Applying Methods for Postnatal Growth Assessment in the Clinical Setting: Evaluation in a Longitudinal Cohort of Very Preterm Infants" Nutrients 2019, 11, 2772.

We have read the article entitled "Applying Methods for Postnatal Growth Assessment in the Clinical Setting: Evaluation in a Longitudinal Cohort of Very Preterm infants" by Montserrat Izquierdo Renau et al [...].

Very preterm neonates receiving "aggressive" nutrition and early nCPAP had similar long-term respiratory outcomes as term neonates.

BACKROUND: The impact of the consistent implementation of "aggressive" nutrition by means of intensive early neonatal nutritional support up to 40-44 weeks postmenstrual age and the use of nasal continuous positive airway pressure (nCPAP) within the first hour of life on the respiratory function of very premature neonates (VPN) at school age is unclear. METHOD: Respiratory function was evaluated in 108 VPN and 70 term controls. Growth, frequency of lower respiratory tract infections, re-hospitalization, and spirometry were recorded up to 8-10 years of age. Comparison was carried out between the two study groups. RESULTS: There was no significant difference in forced expiratory volume in 1 s and forced vital capacity at 8 years of age, and also in lower respiratory tract infections and re-hospitalization due to them, up to 8 years of age between preterm and term neonates. No significant difference was found in spirometry measurements neither between premature neonates with and without BPD nor between the two subgroups of preterms and term neonates. CONCLUSION: "Aggressive" nutrition, persistent nCPAP use, and their impact on early postnatal growth probably positively affect the respiratory function of our study population. These very encouraging results need to be confirmed by larger studies.

Daptomycin Use in Children: Experience With Various Types of Infection and Age Groups.

BACKGROUND: In Greece, there are high rates of methicillin (40%-60%) and clindamycin (15%-25%) resistance among community-acquired Staphylococcus aureus isolates. Therefore, we sought to identify other antimicrobial treatment options such as daptomycin. METHODS: We studied retrospectively all pediatric infections treated with daptomycin at the University General Hospital of Larissa, Greece, from January 1, 2007, to June 16, 2016. RESULTS: Of a total of 128 patients (median age: 2.8 years; range: 8 days to 14.5 years; 76.6% <7 years) treated with daptomycin, 45 (35.2%) had invasive infection, most frequently musculoskeletal, and 83 (64.8%) had noninvasive infection, that is, complicated skin and soft tissue infection. S. aureus was the most commonly recovered pathogen (n = 61) (63.9% methicillin-resistant isolates, 21.3% clindamycin-resistant). The average daily dose of daptomycin was 10 mg/kg qd, and the median duration of therapy was 10 days. Daptomycin was administered alone (n = 61) or in combination therapy (n = 67), most frequently with rifampin (n = 40) and/or a ß-lactam antibiotic (n = 33). Open or closed drainage was performed in 86 (67.2%) of the total number of patients. Of 128 treated patients, 123 (96.1%) achieved clinical success, 114 (89.1%) had complete remission, and 9 (7%) had improvement of their disease. There were no failures with daptomycin therapy. The adverse events were of no clinical significance. CONCLUSIONS: Daptomycin administered alone or in combination with other antimicrobial agents to children was efficacious and well tolerated in the treatment of complicated infections of suspected or proven staphylococcal etiology.

Pneumonia with empyema among children in the first five years of high coverage with 13-valent pneumococcal conjugate vaccine.

BACKGROUND: Parapneumonic effusions in children are usually associated with pneumococcal infections. In Greece, the 7-valent pneumococcal conjugate vaccine was replaced by higher-valent pneumococcal conjugate vaccines (PCVs); 10-valent was introduced in May 2009 and 13-valent (PCV13) in June 2010. Since July 2010, PCV13 has been the most commonly used PCV. In a study conducted at the University General Hospital of Larissa, Central Greece, from January 2012 to January 2016, 85.7% of children born after the implementation of PCV13 and aged 24-59 months had received the complete series (3 + 1 immunization schedule) of PCV13. METHODS: We studied all paediatric community-acquired pneumonia cases with empyema hospitalized at the University General Hospital of Larissa from January 2008 to January 2016. RESULTS: There were 30 cases of parapneumonic empyema. Among 27 empyema cases of known aetiology, 19 (70.4%) were due to Streptococcus pneumoniae (identifiable serotypes 3, 19A, 7F, and 9N/L). After September 2011, no more cases caused by serotypes 7F and 19A were observed, whereas serotype 3 emerged as the predominant pathogen of pneumococcal empyema (9 of 11 cases). Serotype 3 continued to cause empyema despite vaccination with PCV13 either fully with a 3 + 1 schedule (n = 3) or with one booster dose at the age of 21 months (n = 1). CONCLUSION: In Central Greece during the first five years of high coverage with PCV13, serotype 3 was the only PCV13 serotype that clearly persisted in children with empyema.

Kingella kingae sequence type-complex 14 arthritis in a 16-month-old child in Greece.

We describe the first case of Kingella kingae arthritis in a 16-month-old girl in Greece, which has been diagnosed by novel molecular techniques. A joint aspiration of her knee was performed before the initiation of antibiotics, as well as on the 5th and 14th day of empiric antimicrobial therapy. The synovial fluid white blood cell count decreased from 65,000 to 1500 cells/mm, but the percentage of neutrophils remained 90% in all 3 specimens. Molecular analysis of the synovial fluid specimens by real-time polymerase chain reaction and multilocus sequence typing enabled us to reveal the presence of K. kingae belonging to the international sequence type-complex 14, which persisted up to the fifth day of antibiotic therapy.

Dynamics of pneumococcal carriage among day-care center attendees during the transition from the 7-valent to the higher-valent pneumococcal conjugate vaccines in Greece.

BACKGROUND: In Greece recently, higher-valent pneumococcal conjugate vaccines (PCVs) replaced the 7-valent (PCV7); the 10-valent (PCV10) became available in May 2009 and the 13-valent (PCV13) in June 2010. METHODS: We investigated the nasopharyngeal colonization with Streptococcus pneumoniae in day-care center attendees in Athens and the prefecture of Viotia. Between December 2010 and June 2011, nasopharyngeal cultures were obtained 4 times, at enrollment and then every 6 to 8 weeks. RESULTS: Among the 233 children, 225 (96.6%) had been vaccinated with ≥1 dose of PCV7. One tenth of the PCV7 vaccinated attendees had also received ≥1 dose of PCV13 or PCV10. During the 4 samplings, 358 isolates were recovered from a total of 874 samples. Of the 233 children, 183 (78.5%) were found to carry S. pneumoniae at least once. The overall serotype distribution among carriers was similar regardless of the time lapsed since the last PCV7 dose. A high frequency of 19A (17.1%) coincided with a low frequency of 19F (1.4%). Non-PCV13 serotypes accounted for 73.1% of the isolates; 23B, 15B/C, 16F, 21, 11A, 15A, 6C, 10A, 22F and 23A were the most common. Among attendees aged 24-59 months (median age 42 months), prolonged carriage of a non-PCV13 serotype was relatively common, mainly for 21 and 16F. One out of 4 cases of colonization with the prevalent non-PCV13 serotypes was followed by persistent carriage for 5 to 14 weeks. CONCLUSIONS: During this period of transition to the higher-valent PCVs in the day-care center setting, non-PCV13 serotypes dominated and exhibited prolonged colonization. The frequency and the duration of prolonged carriage tends to be increased, if sampling frequency increases and the carriage time before and after positive cultures is taken into consideration. Further studies regarding the fitness of the colonizing non-PCV13 serotypes will likely to be seen in the future.

Vaccination against human papillomavirus among 865 female students from the health professions in central Greece: a questionnaire-based cross-sectional study.

BACKGROUND: There are still sparse data on vaccination coverage against human papillomavirus (HPV) among students in the health professions. The aim of this study was to investigate HPV vaccination coverage in female students from the health professions in Greece. METHODS: A self-administered, anonymous questionnaire was distributed to second-year and third-year female students pursuing degrees in medicine, nursing, and paramedical health disciplines in central Greece. RESULTS: Overall vaccination coverage was 44.3%. The major reason for lack of vaccination was fear about safety of the vaccine. Participants who had received information about safety of the vaccine from the mass media and paramedical students had lower vaccination coverage in comparison with students who had received information about vaccine safety from alternative sources. CONCLUSION: Further quantitative and qualitative research is needed to design educational activities targeting female students in the health professions in order to create a positive domino effect and improve HPV vaccination coverage levels in Greece.