Performance in Behavioral Testing in an Animal Model of Post-Surgical Hypoparathyroidism.

BACKGROUND: Hypoparathyroidism (HypoPT) is characterized by hypocalcemia and undetectable/inappropriately low PTH. Post-surgical HypoPT (PS-HypoPT) is the most common cause. Patients with PS-HypoPT present neuropsychological symptoms, probably due to the PTH deprivation in the central nervous system (CNS). However, these mechanisms are still not elucidated. The aim of this study was to evaluate the effects of PTH deprivation on CNS in an animal model of PS-HypoPT via a cognitive/behavioral assessment approach. METHODS: A surgical rat model of PS-HypoPT was obtained and treated with calcium to maintain normocalcemia. Twenty PS-HypoPT rats and twenty sham-operated controls (Crl) underwent behavioral testing in a Morris Water Maze (MWM), Open Field (OF), and Elevated Plus Maze (EPM). RESULTS: In the MWM, PTx rats showed a higher Escape Latency Time compared to Crl rats (p < 0.05); we observed a statistically significant improvement in the performance (day 1 to 8 p < 0.001), which was less pronounced in PTx group. In the OF test, the time and distance spent in the zone of interest were significantly lower in the PTx group compared with the Crl (p < 0.01 and p < 0.01). In the EPM experiment, the time spent in the close arm was significantly higher in the PTx group compared with the Crl (p < 0.01). CONCLUSIONS: This animal model of PS-HypoPT shows an impairment in spatial memory, which improved after training, and a marked anxiety-like behavior, resembling the condition of patients with PS-HypoPT. Further studies are needed to elucidate mechanisms.

Non-prescribed pharmaceutical stimulants use among adolescents: A way to self-care or peer success?

BACKGROUND: the use of pharmaceutical stimulants without a medical prescription (PSWMP) among adolescents is considered an established public health issue. The present study aimed to investigate the potential links between different patterns of non-medical use of pharmaceutical stimulants, psycho-social factors, and other risky behaviours (e.g. psychoactive substance use). METHODS: For this purpose, data from a sample of 14,685 adolescents aged 15-19 participating in the ESPAD®Italia 2019 study were analysed by conducting descriptive analyses and multinomial logistic regressions. RESULTS: The findings highlight the key role of psycho-social factors and engagement in other risky behaviours in either reducing or promoting the risk of PSWMP use. Particularly, being satisfied with peer relationships and with oneself is significantly associated with lower use of PSWMP. Conversely, the consumption of other psychoactive substances (both legal and illegal) and engagement in other risky behaviours (e.g., gambling and cyberbullying) may increase this phenomenon. CONCLUSIONS: Considering their representativeness, the results of the present study could be used as groundwork for the development of effective and targeted prevention programs and interventions.

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study.

AIMS: To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months. METHODS: The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years. RESULTS: Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and,  of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes. CONCLUSIONS: The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.

Echocardiographic Parameters for Risk Prediction in Borderline Right Ventricle: Review with Special Emphasis on Pulmonary Atresia with Intact Ventricular Septum and Critical Pulmonary Stenosis.

The aim of the present review is to highlight the strengths and limitations of echocardiographic parameters and scores employed to predict favorable outcome in complex congenital heart diseases (CHDs) with borderline right ventricle (RV), with a focus on pulmonary atresia with intact ventricular septum and critical pulmonary stenosis (PAIVS/CPS). A systematic search in the National Library of Medicine using Medical Subject Headings and free-text terms including echocardiography, CHD, and scores, was performed. The search was refined by adding keywords "PAIVS/CPS", Ebstein's anomaly, and unbalanced atrioventricular septal defect with left dominance. A total of 22 studies were selected for final analysis; 12 of them were focused on parameters to predict biventricular repair (BVR)/pulmonary blood flow augmentation in PAIVS/CPS. All of these studies presented numerical (the limited sample size) and methodological limitations (retrospective design, poor definition of inclusion/exclusion criteria, variability in the definition of outcomes, differences in adopted surgical and interventional strategies). There was heterogeneity in the echocardiographic parameters employed and cut-off values proposed, with difficultly in establishing which one should be recommended. Easy scores such as TV/MV (tricuspid/mitral valve) and RV/LV (right/left ventricle) ratios were proven to have a good prognostic accuracy; however, the data were very limited (only two studies with <40 subjects). In larger studies, RV end-diastolic area and a higher degree of tricuspid regurgitation were also proven as accurate predictors of successful BVR. These measures, however, may be either operator and/or load/pressure dependent. TV Z-scores have been proposed by several authors, but old and heterogenous nomograms sources have been employed, thus producing discordant results. In summary, we provide a review of the currently available echocardiographic parameters for risk prediction in CHDs with a diminutive RV that may serve as a guide for use in clinical practice.

Clinical Asthma Remission Obtained with Biologics in Real Life: Patients' Prevalence and Characteristics.

BACKGROUND: The prevalence of clinical asthma remission with biologics in severe asthma has not been well understood yet. We do not even know whether there might be characteristics that identify subjects prone to remission of the disease. MATERIALS AND METHODS: Retrospectively, four groups of severe asthmatics already treated with Omalizumab, Mepolizumab, Benralizumab and Dupilumab (302, 55, 95 and 34 patients, respectively) for at least 12 months were considered. The number of individuals with clinical asthma remission was sought in each group. This was considered when patients, after a treatment of at least 1 year with one of the aforesaid biologics, showed the disappearance of asthma symptoms (ACT ≥ 20), zero exacerbations, suspension of oral corticosteroids and a FEV1% ≥ 80%. Baseline characteristics of patients with and without remission were also taken into account. RESULTS: The prevalence of asthma remission after a mean of 37.8 ± 19.2, 13.5 ± 1.7, 15.4 ± 5.5 and 12 ± 0 months of Omalizumab, Mepolizumab, Benralizumab and Dupilumab treatments was 21.8%, 23.6%, 35.8% and 23.5%, respectively. For each biologic, different baseline characteristics, seem to be associated with failure to achieve clinical asthma remission. Older age, higher BMI, a later age of asthma onset, rhinitis/sinusitis/nasal polyposis, comorbidities and a greater asthma severity may be the characteristics of a suboptimal response to biologic treatments. CONCLUSION: All biologics have the potential to induce disease remission in severe asthmatics. For each biologic, there may be several markers that can identify the patients who will not achieve asthma remission. It would be important to detect them (by carrying out targeted studies) as they would allow us to select the best biologic that may induce clinical asthma remission on a larger number of patients.

Parathyroid Hormone (PTH)-Related Peptides Family: An Intriguing Role in the Central Nervous System.

Parathyroid Hormone (PTH) plays a crucial role in the maintenance of calcium homeostasis directly acting on bone and kidneys and indirectly on the intestine. However, a large family of PTH-related peptides exists that exerts other physiological effects on different tissues and organs, such as the Central Nervous System (CNS). In humans, PTH-related peptides are Parathyroid Hormone (PTH), PTH-like hormones (PTHrP and PTHLH), and tuberoinfundibular peptide of 39 (TIP39 or PTH2). With different affinities, these ligands can bind parathyroid receptor type 1 (PTH1R) and type 2 (PTH2R), which are part of the type II G-protein-coupled-receptors (GPCRs) family. The PTH/PTHrP/PTH1R system has been found to be expressed in many areas of the brain (hippocampus, amygdala, hypothalamus, caudate nucleus, corpus callosum, subthalamic nucleus, thalamus, substantia nigra, cerebellum), and literature data suggest the system exercises a protective action against neuroinflammation and neurodegeneration, with positive effects on memory and hyperalgesia. TIP39 is a small peptide belonging to the PTH-related family with a high affinity for PTH2R in the CNS. The TIP39/PTH2R system has been proposed to mediate many regulatory and functional roles in the brain and to modulate auditory, nociceptive, and sexual maturation functions. This review aims to summarize the knowledge of PTH-related peptides distribution and functions in the CNS and to highlight the gaps that still need to be filled.

Characterization of Aortic Flow Patterns by High-Frame-Rate Blood Speckle Tracking Echocardiography in Children.

Background Blood speckle tracking echocardiography allows for direct quantification of interventricular and aortic flow profiles, principally in children. Here, we sought to demonstrate the feasibility and reproducibility of blood speckle tracking echocardiography in the aortas of healthy children. Methods and Results One hundred healthy White children evaluated for the screening of congenital heart disease were prospectively enrolled. Echocardiographic examinations were performed using a Vivid E 95 ultrasound system, with blood speckle tracking from a focused and zoomed view of the aortic root and the ascending aorta. Vortex position, height (mm), width (mm), sphericity index, and area (cm2) were measured and indexed by body surface area. Median (interquartile range) age was 8.2 (5.6-11.0) years, median (interquartile range) weight was 28 (19-35) kg, and median (interquartile range) body surface area was 1.01 (0.79-1.16) m2. Vortices were visualized in only a single phase of the cardiac cycle in 25 subjects-14 (56.0%) were evident in early diastole and 11 (44.0%) in late systole. Vortices visualized in diastole had a mean area of 0.27±0.1 cm2/m2, while those in systole had a mean area of 0.34±0.12 cm2/m2. In a subset of 20 patients, inter- and intraobserver coefficient of variation and intraclass correlation coefficients were determined and showed good reproducibility. Conclusions We demonstrate feasibility and reproducibility of blood speckle tracking and identified vortical flow patterns in the aortic root and ascending aorta in healthy children. These data may serve as a baseline for evaluating aortic flow patterns in children with congenital and acquired heart disease.

COVID-19 severity appears to be reduced in spring/summer.

BACKGROUND: because of different human behaviours, SARS-CoV-2 spread may be lower in spring/summer. On the contrary, it is not clearly known whether the clinical course/severity of hospitalized patients infected by SARS-CoV-2 can be different in the various seasons.. OBJECTIVES: to understand whether there were differences in severity of COVID-19 in patients who had contracted the infection in winter versus those infected in spring/summer. DESIGN: observational retrospective cohort study. SETTING AND PARTICIPANTS: from the administrative database of the SARS-CoV-2 surveillance system and that of hospital discharge, a cohort of patients (8,221, 653 of which were hospitalized) who tested positive to the RT-PCR test for SARS-CoV-2 between 01.12.2020 and 31.07.2021 in the Grosseto province (Tuscany Region, Central Italy) was selected and analysed. MAIN OUTCOME MEASURES: hospitalization rate and length, continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) use, Intensive Care Unite (ICU) admissions, intra-hospital mortality and PaO2/FiO2 values were measured and compared between subjects infected in winter and those who developed COVID-19 in spring/summer. Viral load (cycle threshold, Ct), vitamin D, serum ferritin, IL-6, procalcitonin, D-dimer, and C-reactive protein measured in the two periods were also compared. RESULTS: in the considered months, the hospitalization rate among 8,221 patients with COVID-19 was 8%: 370 (8.5%) individuals were hospitalized in winter and 283 (7,3%; p=0.31) in spring/summer; 62 (16.8%), 88 (23.8%), and 63 (17%) in winter and 28 (9.9%), 40 (14.1%), and 36 (12.7%) in spring/summer were admitted in ICU (p=0.01), used CPAP/NIV (p=0.002) and died (p=0.13), respectively. Hospitalization days were 14.5±11.6 in winter and 10.3±8.84 in spring/summer (p=0.001), while minimum PaO2/FiO2, measured during hospital stays was 123.2±38.6 in spring/summer and 112.6±40.8 in winter (p=0.054). Multivariate analysis (adjusted for all confounding factors) also confirmed reduced risks of having ICU admissions (0.53; 95%CI 0.32;0.88; p=0.01) and of using CPAP/NIV (0.48; 95%CI 0.32;0.75; p=0.001) in spring/summer when compared to winter. Hospitalization days and minimum PaO2/FiO2 were also lower in spring/summer (ß= -3.9; 95%CI -5.5;-2.2; p=0.001) and winter (ß= -17; 95%CI -0.93;35; p=0.06), respectively. The adjusted hazard ratio of mortality in winter, obtained with a Cox model, was higher of about 38% compared to spring/summer. No Ct values (viral load) differences were found either in winter (19.45±6.18) or spring/summer (20.3±6.7; p=0.343). IL-6, ferritin, procalcitonin, D-dimer were similar. Conversely, CRP was lower whereas vitamin D was higher in the warmer seasons. CONCLUSIONS: COVID-19 may be less severe during spring/summer in hospitalized patients. This does not seem to be influenced by different SARS-CoV-2 viral load in the different periods considered. C-reactive protein was found to be lower whereas vitamin D higher in the warmer months. It can be hypothesized that higher levels of vitamin D in spring/summer, compared to winter, may be associated to a positive modulation of COVID-19 induced inflammation with a possible disease severity reduction during spring/summer.

Alcohol versus combined alcohol and energy drinks consumption: Risk behaviors and consumption patterns among European students.

INTRODUCTION: Recent research found that drinking alcohol mixed with energy drinks (AmED) could be riskier than drinking alcohol alone. Our aim was to compare rates of risk behaviors in consumers of AmED versus exclusive alcohol drinkers, matching them based on their drinking frequency. METHODS: Data about 16-year-old students who reported the number of occasions on which they had drunk AmED or alcohol only in the preceding 12 months (n = 32,848) were drawn from the 2019 ESPAD study. After matching for consumption frequency, the sample consisted of 22,370 students (11,185 AmED consumers and 11,185 exclusive alcohol drinkers). Key predictors comprised substance use, other individual risk behaviors, and family characteristics (parental regulation, monitoring, and caring). RESULTS: The multivariate analysis showed significantly higher odds of being AmED consumers compared to being exclusive alcohol drinkers in the majority of the investigated risk behaviors, including: daily tobacco smoking, illicit drug use, heavy episodic drinking, truancy at school, engaging in physical fights and serious arguments, having troubles with the police, and having unprotected sexual intercourse. Instead, lower odds were found for reporting high parents' educational level, medium and low family economic status, perceived possibility to freely talk about problems to family members, spending free time reading books or other hobbies. CONCLUSIONS: Our study shows that, given the same consumption frequency in the past year, AmED consumers typically reported higher associations with risk-taking behaviors compared to exclusive alcohol drinkers. These findings advance past research that failed to control for the frequency of AmED use versus exclusive alcohol consumption.

Adolescents' Psychoactive Substance Use During the First COVID-19 Lockdown: A Cross Sectional Study in Italy.

Background: Italy was one of the first European countries to be affected by Covid-19. Due to the severity of the pandemic, the Italian government imposed a nationwide lockdown which had a great impact on the population, especially adolescents. Distance-learning, moving restrictions and pandemic-related concerns, resulted in a particularly stressful situation. Objective: This cross-sectional study aims to analyse substance consumption and its associated factors during the Covid-19 lockdown imposed by the Italian government. Methods: ESPAD is a questionnaire that is administered yearly in Italian high schools. In 2020, it was administered online during dedicated hours of distance learning, collecting data from 6027 Italian students (52.4% were male) aged 15-19. Data collected from the 2020 questionnaire was matched with that collected in 2019, in order to make them comparable. Results: The prevalence of consumption of each substance decreased during the restriction period, and the most used substance during the lockdown period was alcohol (43.1%). There were some changes in factors associated with psychoactive substance use, especially painkillers and non-prescription drugs. For instance, unlike what was observed in the 2019 model, in 2020 spending money without parental control was associated with painkillers and non-prescription drug use while risk perception was not. Conclusions: The restrictions and the increased difficulties in obtaining psychoactive substances did not prevent their consumption, and students with particular risk factors continued to use them, possibly changing the substance type of substance. This information is useful in order to better understand adolescents' substance use during the ongoing pandemic.

Sex differences in excessive oral corticosteroid exposure in poor adherent adult asthmatics overusing short-acting ß-2 agonists.

BACKGROUND: We know that excessive short-acting ß2-agonists (SABA) use in asthma may be associated to high exacerbation risks. We studied whether such excessive SABA consumption is connected with different higher oral corticosteroid (OC) prescriptions in the two sexes. METHODS: In our prescribing database, we searched subjects aged 18-40 years that were prescribed at least one SABA package/year and/or at least two ICS or two ICS/LABA boxes/year to identify asthmatics. Their OC prescriptions/year were also examined. Subjects were divided into 4 groups according to SABA packages/year prescribed (0, 1-2,3-6 and ≥7), considering sexes separately. RESULTS: Individuals recruited were 9,102. Subjects with at least one OC prescription were higher in each group and were females (P<0.001). The OC packages/year number was also more elevated in women especially those with >7 SABA prescriptions/year (0.96 in males vs. 2.64 in females, P<0.001). 94.7%/93.6% males/females, who never used SABA, took at least one ICS/LABA (mean 5.84/5.48 packages/year), while the subject percentage adhering to ICS/LABA dropped to 28-47% (mean 0.94-3.82 packages/year) in those who used SABA (P<0.001). Higher SABA prescriptions were associated with an increasing OC dispensation (ß=0.057, P<0.0001). We observed also a greater risk of using >3 OC packages/year in subjects with 3-6 (OR: 2.98 [95% CI: 2.19-4.06], P<0.001) and ≥7 (OR: 3.49 [95% CI: 2.39-5.10], P<0.001) SABA prescriptions compared to those that never used SABA. Besides, we found that using ICS (OR:0.51 [95% CI: 0.35-0.75], P<0.001) or ICS/LABA (OR:0.07 [95% CI: 0.05-0.09], P<0.001) may significantly reduce SABA prescriptions. CONCLUSIONS: Poor adherence to maintenance treatment appears to associated with excessive SABA prescriptions that may lead to a higher OC consumption particularly noticeable in women.

E-cigarette use and conventional cigarette smoking among European students: findings from the 2019 ESPAD survey.

BACKGROUND AND AIMS: Representative data on e-cigarette use among European adolescents are scant. This study reports current vaping and tobacco smoking individual and country-specific correlates among European students. DESIGN: Cross-sectional survey: 2019 European School Survey Project on Alcohol and Other Drugs (ESPAD) collecting data on risk behaviours on a representative sample of 16-year-old students. SETTING: A total of 35 European countries, 25-30 with Tobacco Control Scale (TCS) and TCS components PARTICIPANTS: A total of 99 648 students (49.1% males) turning 16 years in the survey year. MEASUREMENTS: Data on current cigarette and e-cigarette use were gathered through a self-administered questionnaire which also collected socio-demographics and individual and family characteristics. ESPAD data were integrated with country-level data on TCS and selected TCS parameters to assess their association with the prevalence of current cigarette and e-cigarette use. FINDINGS: Of the 99 648 participating students, 12.4% were current e-cigarette users, from 5.5% in Serbia to 41.4% in Monaco; 19.3% current smokers, from 5.1% in Iceland to 32.4% in Italy. Compared with non-users, current e-cigarette users less frequently came from an average well-off family [odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.80-0.90] and lived in countries with higher cigarette prices (OR = 0.71, 95% CI = 0.50-0.99), restrictive measures on tobacco advertising and promotion (OR = 0.79, 95% CI = 0.63-0.99) and intermediate implementation of tobacco control measures (OR = 0.57, 95% CI = 0.38-0.85). Current vapers were more frequently life ever smokers (OR = 7.31, 95% CI = 6.47-8.25), were early smokers (OR = 4.35, 95% CI = 3.66-5.17), males (OR = 1.61, 95% CI = 1.55-1.67), from non-traditional families (OR = 1.43, 95% CI = 1.34-1.53), with relatively low parental education (OR = 1.15, 95% CI = 1.10-1.20). Compared with non-smokers, current smokers had similar family characteristics to vapers, and were less likely to live in countries with higher cigarette prices (OR = 0.70, 95% CI = 0.49-0.99) and higher spending on public anti-tobacco media campaigns (OR = 0.23, 95% CI = 0.10-0.50). CONCLUSIONS: E-cigarette use among European adolescents is associated with weaker tobacco control measures, particularly on tobacco price, advertising and promotion. Besides preventing tobacco smoking, the adoption of governmental tobacco control policies in European countries also seems to contribute to the prevention of vaping among adolescents.

Atrial Function Impairments after Pediatric Cardiac Surgery Evaluated by STE Analysis.

Background: Applications of atrial speckle tracking echocardiography (STE) strain (ε) analysis in pediatric cardiac surgery have been limited. This study aims to evaluate the feasibility of atrial STE ε analysis and the progression of atrial ε values as a function of post-operative time in children after pediatric cardiac surgery. Methods: 131 children (mean 1.69 ± 2.98; range 0.01−15.16 years) undergoing cardiac surgery were prospectively enrolled. Echocardiographic examinations were performed pre-operatively and at 3 different post-operative intervals: Time 1 (24−36 h), Time 2 (3−5 days), Time 3 (>5 days, before discharging). The right and left atrium longitudinal systolic contractile (Ct), Conduit (Cd), and Reservoir (R) ε were evaluated with a novel atrial specific software with both P- and R-Gating methods. One hundred and thirty-one age-matched normal subjects (mean 1.7 ± 3.2 years) were included as controls. Results: In all, 309 examinations were performed over the post-operative times. For each post-operative interval, all STE atrial ε parameters assessed were significantly lower compared to controls (all p < 0.0001). The lowest atrial ε values were found at Time 1, with only partial recovery thereafter (p from 0.02 to 0.04). All atrial ε values at discharge were decreased compared to the controls (all p < 0.0001). Significant correlations of the atrial ε values with cardio-pulmonary-bypass time, left and right ventricular ε values (p < 0.05), and ejection fraction (p < 0.05) were demonstrated. Conclusions: Atrial ε is highly reduced after surgery with only partial post-operative recovery in the near term. Our study additionally demonstrates that post-surgical atrial and ventricular ε responses correlated with each other.

A pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients.

To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5-0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5-1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.

Normal Values and Patterns of Normality and Physiological Variability of Mitral and Tricuspid Inflow Pulsed Doppler in Healthy Children.

BACKGROUND: While mitral (MV) and tricuspid valve (TV) pulsed Doppler velocities and derived gradients are commonly evaluated, data on normal pediatric values are limited. This study aimed to evaluate the normal values and physiological variability for MV and TV Doppler velocities and derived gradients in a large cohort of prospectively enrolled healthy children. METHODS: The echocardiographic measurements included pulsed Doppler MV and TV E and A velocities, E deceleration times (EDT), maximal and mean gradients, and velocity time integral (VTI). RESULTS: A total of 544 healthy subjects (median age 6.4 years, range 1 day-17.68 years) were included. MV and TV E velocity, E/A ratio, and E and A wave duration increased, while A velocity decreased with age (p < 0.001). Along with an increase in VTI, there occurred a progressive increase in maximum velocity and gradients and a decrease in mean velocities and gradients. E/A inversions were common, especially at the TV in neonates and infants. For MV, inversion in either one, two, or three consecutive beats occurred in 51.9% of neonates and 18.3% of infants, while it was rare at older ages (all p < 0.001). For TV, inversions in three consecutive beats occurred in 71.4% of neonates, while inversions in only one or two beats were more common in infants (27.3%). For TV, inversion in one or more beats, however, was not infrequent at all ages. CONCLUSIONS: We report normal values and patterns of normality and physiological variability for MV and TV inflow Doppler from a large population of healthy children.

Should a prescription database be used to search uncontrolled severe asthmatics?

INTRODUCTION: Many uncontrolled severe asthmatics are not on biologic therapy. We hypothesized that using a prescription database could help us identify them. MATERIAL AND METHODS: 3,309 patients who received at least one Montelukast prescription in 2019 were extracted from our prescription database. Number of packages/year, types and dosages of ICS, LABA, ICS/LABA, LAMA and monoclonal antibodies were considered for each patient. In our analysis, for subjects that took > 7 packages of ICS/LABA + LTRA +/- LAMA (high adherent) the number of oral corticosteroids (OC) packets prescribed for each of them was also looked upon. RESULTS: Patients that took ICS/LABA or ICS/LABA + LAMA continuously with high ICS doses were 188 (25.6%) and 117 (39.3%) respectively (total: 305 - 29.5%). Among them, 58 (30.9%) and 53 (45.3%) (total: 111 - 36.4%) were prescribed more than 2 OC packages. Whereas, 21 (11.2%) and 24 (20.5%) patients (total: 45 - 14.75%) received at least 4 OC package prescriptions. CONCLUSION: Approximately 36% of patients in continuous step-4/5 of GINA guidelines treatment may have severe uncontrolled asthma (overusing OC) which needed biologic treatment. In our opinion, a prescription archiving database may be a tool that can help us identify such uncontrolled asthma patients.

Locus Coeruleus magnetic resonance imaging in cognitively intact elderly subjects.

The locus coeruleus is the main noradrenergic nucleus of the brain and is often affected in neurodegenerative diseases. Recently, magnetic resonance imaging with specific T1-weighted sequences for neuromelanin has been used to evaluate locus coeruleus integrity in patients with these conditions. In some of these studies, abnormalities in locus coeruleus signal have also been found in healthy controls and related to ageing. However, this would be at variance with recent post-mortem studies showing that the nucleus is not affected during normal ageing. The present study aimed at evaluating locus coeruleus features in a well-defined cohort of cognitively healthy subjects who remained cognitively intact on a one-year follow-up. An ad-hoc semiautomatic analysis of locus coeruleus magnetic resonance was applied. Sixty-two cognitively intact subjects aged 60-80 years, without significant comorbidities, underwent 3 T magnetic resonance with specific sequences for locus coeruleus. A semi-automatic tool was used to estimate the number of voxels belonging to locus coeruleus and its intensity was obtained for each subject. Each subject underwent extensive neuropsychological testing at baseline and 12 months after magnetic resonance scan. Based on neuropsychological testing 53 subjects were cognitively normal at baseline and follow up. No significant age-related differences in locus coeruleus parameters were found in this cohort. In line with recent post-mortem studies, our in vivo study confirms that locus coeruleus magnetic resonance features are not statistically significantly affected by age between 60 and 80 years, the age range usually evaluated in studies on neurodegenerative diseases. A significant alteration of locus coeruleus features in a cognitively intact elderly subject might be an early sign of pathology.

Pediatric ranges of normality for 2D speckle-tracking echocardiography atrial strain: differences between p- and r-gating and among new (Atrial Designed) and conventional (Ventricular Specific) software's.

BACKGROUND: 2D speckle tracking echocardiography (STE) atrial strain (ε) analysis in children is gaining interest; however, pediatric nomograms remain limited. Comparison among conventional software's (designed for left ventricle and adapted to atria and using R-gating analysis) and new software's (designed for atria and allowing for both R- and P-gating) are lacking. The present study aims to establish pediatric nomograms for atrial ε using an atrial dedicated software and to compare values obtained by (a) R- and P-gating and, (b) R-gating with new and conventional software. METHODS: Echocardiographic measurements included STE left (LA) and right (RA) atrial longitudinal reservoir, conduit and contractile ε. Age/weigh/height/heart rate, and body surface area (BSA) were used as independent variables in the statistical analysis. RESULTS: In all, 580 healthy subjects (age range, 31 days-18 years; mean age 7.5 years; median age 7.1 years; inter-quartile range, 4.3-10.7 months; 45.5% female) were included. Feasibility of atrial ε measurements was high (98.9-96.8%). At lower age, atrial conduit ε was lower (p<0.001) while contractile ε was higher (p<0.001). All atrial ε values calculated with P-gating method were lower-than R-gating values (p<0.001). R-gated LA ε reservoir values generated with the new software were lower, and R-gated RA contractile ε higher than with the conventional software (p<0.011). CONCLUSION: We report pediatric atrial ε values from a dedicated atrial software. Maturational changes in STE atrial ε values were demonstrated. Significant differences were observed among ε values obtained with P- and R-gating and with different software's.

Left Ventricular Systolic Impairment after Pediatric Cardiac Surgery Assessed by STE Analysis.

BACKGROUND: Speckle-tracking echocardiography (STE) has gained increasing value in the evaluation of congenital heart diseases (CHD); however, its use in pediatric cardiac surgery is limited. AIM: To evaluate left ventricular (LV) systolic impairment after biventricular pediatric cardiac surgery by STE strain (ε) analysis. METHODS: We prospectively enrolled 117 children undergoing cardiac surgery for CHD. Echocardiography was performed at four different times: pre-operatively, 12-36 h (Time 1), 3-5 days (Time 2), and 6-8 days (Time 3). Images were obtained in the 4-2-and 3 apical chamber's views to derive LV global and regional (basal/mid/apical) ε values. RESULTS: At different postoperative times, we performed 320 examinations in 117 children (mean age: 2.4 ± 3.9, range: 0-16 years); 117 age-matched healthy children served as controls. All global, basal, and mid LVε values decreased after surgery; the lowest values being at Time 1 (p < 0.0001), which increased thereafter. At discharge, all global, basal, and mid LVε values remained lower than in pre-operative and healthy children (p < 0.05). Instead, apical segments (lowest at baseline) increased after surgery (p < 0.0001) but remained lower compared to controls. LV ejection fraction (LVEF) decreased at Time 1 (p = 0.0004) but promptly recovered to Time 2 and normalized at Time 3. CONCLUSIONS: STE ε analysis revealed a significant LV systolic impairment after surgery with amelioration thereafter but incomplete normalization at discharge. Base-apex differences emerged with apical segments that, contrary to all the other regions, showed relative hypercontractility after surgery. The slower recovery of LVε values compared to LVEF suggests that STE ε analysis may be more accurate for the follow-up of mild LV post-surgical impairment.