Interviewing children: the impact of the COVID-19 quarantine on children's perceived psychological distress and changes in routine.

BACKGROUND: The COVID-19 outbreak has resulted in governments implementing disease containment measures such as school closures, social distancing, and home quarantine. To date, only a few studies have drawn attention to the psychological impact of lockdown on Italian children's mental health. The present study aimed to investigate the psychological distress (anxiety and mood symptoms) and perceived changes in routine among Italian primary and middle school students during the COVID-19 quarantine. METHODS: This interview study was performed between the 18th of May and 7th of June 2020: it involved a sample of 82 children and adolescents living in Milan (Italy), attending primary and middle school (aged 6 to 14 years), and their parents. RESULTS: Almost 30 % of the subjects reported having struggled to adjust to home learning. 36 responders completely changed their dietary habits during the lockdown: they were not eating the same amount of food and were consuming more junk food. Sleep habits were also affected by the lockdown measures: 28 % of the sample had difficulties sleeping and wished to sleep in their parents' bed. Concerning psychological distress, 64 (78 %) children and adolescents had anxiety symptoms; 43.9 % of the students reported significant mood symptoms. CONCLUSIONS: Children are not indifferent to the dramatic impact of the COVID-19 epidemic: our data confirm their difficulties in adapting to the quarantine measures. The effects of stress exposure may not manifest later on during the children's development, and, for this reason, it would be interesting to follow up on these participants to improve our understanding of how long these outcomes may last.

International trends in clozapine use: a study in 17 countries.

OBJECTIVE: There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis. METHOD: A repeated cross-sectional design was applied to data extracts (2005-2014) from 17 countries worldwide. RESULTS: In 2014, overall clozapine use prevalence was greatest in Finland (189.2/100 000 persons) and in New Zealand (116.3/100 000), and lowest in the Japanese cohort (0.6/100 000), and in the privately insured US cohort (14.0/100 000). From 2005 to 2014, clozapine use increased in almost all studied countries (relative increase: 7.8-197.2%). In most countries, clozapine use was highest in 40-59-year-olds (range: 0.6/100 000 (Japan) to 344.8/100 000 (Finland)). In youths (10-19 years), clozapine use was highest in Finland (24.7/100 000) and in the publicly insured US cohort (15.5/100 000). CONCLUSION: While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation.

Drugs Delivery by Charities: A Possible Epidemiologic Indicator in Children of Undocumented Migrants.

Describing the health status of a population is difficult, especially in the case of irregular migrants who are now a growing population in western Countries. Data for children of these families are almost inexistent. In the absence of databases on this peculiar pediatric population, we analyzed drugs dispensation by a major Charity to have an insight into their health needs. This observational retrospective study was carried out during the entire 2015 and enrolled 628 undocumented children. A cohort of 8438 adult patients belonging to the same ethnic groups was used for comparison. Respiratory drugs were those most commonly prescribed, followed by those for skin and ocular diseases and by those for gastrointestinal disorders. Also in adults respiratory medications were the most dispensed, but almost in equal measure than cardiovascular drugs.To our knowledge this is the first study on the health needs of undocumented children residing in a western Country. The method we used seems to be a useful method for epidemiological analysis. As could be expected, respiratory and skin diseases ranked first, possibly owing to environmental factors.

Reducing the costs of paediatric antibiotic prescribing in the community by implementing guideline recommendations.

WHAT IS KNOWN AND OBJECTIVE: Italian children receive a high number of antibiotic prescriptions, and the use of second-choice antibiotics is common. A few studies in other countries have demonstrated that the implementation of international guidelines for the most common paediatric diseases may reduce the associated costs. A cost analysis of the expenditure for antibiotic prescriptions in outpatient children in the Lombardy region (Italy) and for each of the region's local health units (LHUs) was performed using a pharmacoepidemiological approach. The safety and cost impact associated with a quali-quantitative improvement in antibiotic prescribing was estimated. METHODS: The data source was the Lombardy region's prescription database (year 2008) for outpatient children <14 years old. The average total expenditure for each package, and per capita, was calculated for each active substance considered and for each LHU. An estimate of the possible cost reduction was elaborated using, as a reference, the prescription profile of a group of paediatricians that has been involved in initiatives concerning care for years. The hospital admission rates for acute respiratory infections (ARI) and their major complications were evaluated at the regional level and in the group of children followed by the reference paediatricians. RESULTS AND DISCUSSION: The cost reduction estimate reveals a possible decrease in antibiotic expenditure of about 3·6 million euros (-19·5%) in the Lombardy region. Large variability was observed between different LHUs (-33·3 to +9·2% of difference). The hospital admission rate was not different when comparing the group of children followed by the reference paediatricians to the rest of the study population, but the hospital admission rate for ARI was lower in the reference group (χ(2) = 16·4, P < 0·001). WHAT IS NEW AND CONCLUSION: This is the first Italian study to evaluate the costs related to a specific prescription profile, which already exists in the real setting, hypothesizing its application in a large outpatient child population of the same geographical area. The results show that by improving prescribing appropriateness, it is possible to reduce the expenditure associated with antibiotic prescriptions to outpatient children in the Lombardy region by about one-fifth. The lower rate of hospital admissions for ARI suggests that the adopted profile is also beneficial to children's health.

Differences in outpatient antibiotic prescription in Italy's Lombardy region.

OBJECTIVES: We assessed the antibiotic patterns of use and geographical distribution of prevalence and consumption by age in 15 Local Health Units (LHUs) of Italy's Lombardy region. METHODS: A retrospective analysis of reimbursement data for the community-dwelling population in 2005 was performed. Prescriptions reimbursed by the National Health System and consumption as defined daily doses (DDD) per 1,000 inhabitants per day (DID) were analyzed. A logistic regression was performed to evaluate the association between antibiotic drug prescription and age, gender, and LHU of residence of the population. RESULTS: During 2005, a total of 3,120,851 people (34% of the population) received at least one antibiotic drug prescription. The highest prescription prevalence was observed in the 0-17 and 80 or more years age ranges (41.6 and 41.9%, respectively). Large differences were found in the prevalence rates between different LHUs (ranging from 28.7% in Milan to 39.4% in Brescia) and in DID (ranging from 12.6 DID in Sondrio to 18.9 DID in Brescia). The age and residence of the population were the main determinants of drug exposure. In particular, patients aged <18 years (odds ratio [OR] = 1.73; 95% confidence interval [CI] 1.73, 1.74), aged 65 years or older (OR = 1.64; 95% CI 1.63, 1.65), and those that live in Brescia (OR = 1.66; 95% CI 1.65, 1.66) had a statistically significant higher risk of antibiotic drug exposure. CONCLUSIONS: The observed intra-regional differences underline the need for a careful monitoring with the aim to reduce antibiotic resistance and improve the rational use of drugs.

Pain management in the paediatric population: the regulatory situation in Europe.

This study compared the availability and the licensing status of analgesic drugs marketed in three European countries (Italy, France and the UK) and evaluated the evidence on safety and efficacy in the paediatric population of the drugs reported in the European Medicines Evaluation (EMA) document "Assessment of Pediatric Needs: Pain" (2005). Ten of 17 drugs reported in the EMA document were marketed with a paediatric licence in all three countries but with wide differences concerning age groups. In all, 594 randomised controlled trials (RCTs) concerning the 17 drugs in the EMA list were found through biomedical literature databases. Bupivacaine was the drug with the most trials retrieved (171 RCTs, 29%); 32 (5%) RCTs concerned clonidine not licensed for pain control, and 51 (9%) concerned ketamine licensed for paediatric use only in the UK. Access to, and the rational use, of drugs to prevent or control pain and its functional consequences pose a considerable challenge. There is a pressing need for further research and clinical development in the assessment and management of pain in children.

Drug prescribing by Italian family paediatricians: an exception?

AIMS: To identify which drugs are considered 'essential' by Italian family paediatricians based on their prescriptions. METHODS: Prescriptions reimbursed by the National Health System, involving 923,177 children < 14 years old, and dispensed during 2005 by the retail pharmacies of 15 local health units (LHUs) in the Lombardy Region, were analysed. The percentage of family paediatricians prescribing each single drug was calculated. A percentage > or =75% was considered as a high degree of agreement. RESULTS: In all, 746 different drugs were prescribed to 486,405 children (52.7%). The median number of drugs prescribed by each paediatrician was 60 (interquartile range 51-71). A total of 22 drugs were prescribed by at least 75% of paediatricians and six were prescribed by all the paediatricians. In all, 95% of the paediatricians prescribed four or more cephalosporins and 92% prescribed four inhaled steroids. Only eight of the 22 most frequent drugs are included in the World Health Organization Essential Medicines for children list. CONCLUSION: Despite the huge number of drugs prescribed, only for 22 there was a concordance between family paediatricians. Initiatives to evaluate and promote a more rational use of drugs in Italian children are necessary.

Adverse drug reactions in childhood: a review of prospective studies and safety alerts.

OBJECTIVE: To assess the incidence of adverse drug reactions (ADRs) in the paediatric population and the safety alerts concerning children and adolescents issued by international drug regulatory agencies since 2001. METHODS: A bibliographic search was performed in the Medline and Embase databases for prospective studies published between January 2001 and December 2007 evaluating the ADR incidence in the paediatric population. Data were analysed by a random effect model. Moreover, the websites of nine international drug regulatory agencies were searched to collect information on safety alerts concerning the paediatric population. RESULTS: A total of eight prospective studies were evaluated, six of which concerned the ADR incidence in hospitalised children. The overall incidence of ADRs was 10.9% (95% CI 4.8 to 17.0) in hospitalised children and 1.0% (95% CI 0.3 to 1.7) in outpatient children. The rate of hospital admission due to ADRs was 1.8% (95% CI 0.4 to 3.2). The skin and gastrointestinal system were the organs most commonly affected and antibiotics were the drugs most commonly associated with ADRs. Safety alerts in the paediatric population were retrieved for 28 drugs, five of which were for psychotropic drugs and most of which were issued by the Food and Drug Administration (20 drugs). For 12 drugs, warnings were published in the 2006-2007 period. Antidepressants were the only drugs for which alerts were issued by all the drug regulatory agencies. CONCLUSIONS: To ensure safe and effective medicines for children, efforts are needed at different levels (governments, drug regulatory agencies, pharmaceutical industries, health care professionals, and parents). Collaborative regulatory initiatives, such as the use of common warnings, can also contribute to a more rational use of drugs for children.

Neonatal outcome following pregnancy exposure to antidepressants: a prospective controlled cohort study.

OBJECTIVE: To determine the incidence of early adverse effects associated with antidepressant drug use during pregnancy. DESIGN: Prospective, controlled cohort study. SETTING: A Drug and Health Information Centre in Milan, Italy. POPULATION: A total of 200 neonates exposed to antidepressants in utero and 1200 controls. METHODS: Women who took antidepressants during pregnancy and delivered liveborn children between 1995 and 2003 were selected. Each case was matched for maternal age and gravidity to six randomly selected controls (not exposed to teratogenic drugs or drugs known to cause neonatal side effects). Odds ratio was estimated for attributable risks. MAIN OUTCOME MEASURES: Neonatal adverse events and Special Care Unit admission rate, assessed through an interview with the mothers. RESULTS: Of the 200 neonates exposed to antidepressants in utero, 14 had adverse events and 3 required Special Care Unit admission. Jaundice (n = 5), agitation (n = 3) and respiratory distress (n = 2) were the most common symptoms. In the control group, 50 newborns had side effects and no statistically significant differences in the prevalence rate compared to the exposed group were found, even after stratification for drugs and pregnancy period of exposure. Only the prematurity rate was significantly higher in exposed compared to non-exposed newborns (OR = 2.31; 95% CI 1.14-4.63). CONCLUSIONS: These results do not support an association between antidepressant exposure and unsafe fetal and neonatal outcomes in newborns. However, a collaborative international multicentre epidemiological monitoring of the use of psychotropic drugs during pregnancy is needed in order to guarantee pregnant women and their children safe and effective treatments, both at brief and long time from exposure.

The epidemiology of psychotropic drug use in children and adolescents.

Despite the scarcity of evidence on the safety and efficacy of psychotropic drugs in the paediatric population, especially in the long-term, several epidemiological studies have reported an increase in their prescription rates. This increase is especially evident for stimulants and selective serotonin reuptake inhibitors. An analysis of the epidemiological data suggests that the risk of inappropriate use or abuse of these drugs is high. In such a context, not only is additional, independent and transparent research necessary, but also children with mental disorders (and their parents) must be guaranteed appropriate care.

An animal evaluation of a paste of chitosan glutamate and hydroxyapatite as a synthetic bone graft material.

The objective of this study was to develop a synthetic bone graft in a paste form. Reported here are the results of the evaluation of a paste of chitosan glutamate (Protosan) and hydroxyapatite (referred to as a paste) used in a critical size defect model in rats. Eight-millimeter--diameter cranial defects were made in rat calvaria following a protocol approved by the animal review committee. Five groups were studied: (1) empty control, (2) defect filled with paste only, (3) defect filled with the paste containing bone-marrow aspirate, (4) defect filled with paste containing BMP-2, and (5) defect filled with paste containing osteoblasts cultured from bone-marrow aspirate. The sacrifice intervals were 9 and 18 weeks. Calvaria containing the defect were harvested, and the bone mineral density (BMD) was determined by dual energy X-ray absorptiometry. Push-out strength measurements were also performed. The BMD values of empty control were significantly lower than those of other groups at both 9 and 18 weeks. The mechanical properties, that is, push-out strengths and area under the push-out load and displacement were not significantly different between the samples. Histological examination of Goldner-trichromestained undecalcified sections showed the presence of mineralized bone spicules in the defect areas that were more prominent in those filled with paste and osteoblasts cultured from bone-marrow aspirate. Hence, this study demonstrated that the paste of chitosan glutamate and hydroxyapatite-containing osteoblasts cultured from bone-marrow aspirate would be an effective material to repair bone defects.

Interleukin-6 affects scopolamine-induced amnesia, but not brain amino acid levels in mice.

We have previously shown that, after peripheral administration, different cytokines affect cognitive functions in mice. In this study, we evaluated the effects of mouse interleukin-6 (IL-6) on the classical behavioural test of scopolamine-induced amnesia for a passive avoidance response in the mouse. Pretraining i.p. administration of this cytokine (0.125 and 0.5 microgram/mouse) significantly reduced the amnesic action of the muscarinic receptor antagonist. As it is well known that brain amino acids are deeply involved in the modulation of cognitive processes we measured the levels of glutamine, aspartic acid, glutamic acid and GABA in the hippocampus and hypothalamus of mice treated with IL-6. At both doses which affected the cognitive functions, this cytokine had no effect on brain levels of measured amino acids. Neither nociceptive thresholds to a thermal stimulus, nor spontaneous locomotor activity were modified by the acute administration of IL-6 (0.5 microgram/mouse). Our data confirm previous observations indicating that peripheral administration of cytokines affects some, but not other brain functions and suggest the involvement of IL-6 in the central modifications induced by the immune activation.

GM-CSF affects hypothalamic neurotransmitter levels in mice: involvement of interleukin-1.

We studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) on the brain levels of several neurotransmitters in mice. Administration of GM-CSF (5.0 and 10 microg, i.p.) significantly reduced the hypothalamic levels of glutamine, glutamic acid, GABA and aspartic acid. GM-CSF (5.0 microg, i.p.) also induced a significant reduction of norepinephrine and serotonin levels in the hypothalamus, without affecting dopamine levels. The hippocampal levels of neurotransmitters were not modified by GM-CSF administration. The peripheral administration of a specific interleukin-1 receptor antagonist (IL-1ra, 50 microg, i.p.) blocked the effects of GM-CSF. These results confirm our previous behavioural data suggesting that GM-CSF is able to exert neuromodulatory actions.

Changes in the serotonergic system during the sleep-wake cycle: simultaneous polygraphic and voltammetric recordings in hypothalamus using a telemetry system.

Changes in the serotonergic system in the posterior hypothalamus of freely moving rats were related to sleep and wakefulness using in vivo voltammetry (with carbon fiber microelectrodes) and polygraphic recordings. By using an optoelectronic telemetry system for the voltammetric signals, electrical cross-talk between the two settings was avoided and simultaneous neurochemical and electro-physiological recordings could be made so that a detailed time course of events could be obtained. Extracellular levels of the serotonin metabolite, 5-hydroxy-indoleacetic acid, measured every 2 min, increased with wakefulness and decreased with sleep: levels were significantly lower during desynchronized sleep than slow wave sleep. In vivo voltammetry associated with the optoelectronic telemetry system appears to be a useful tool for studying the relationship between neurochemical changes and electrophysiological events.

Serotonin uptake inhibition: in vivo effect of sertraline in rats.

Sertraline, a potent and selective serotonin uptake inhibitor, was used to analyze the changes occurring in the serotonin system after uptake inhibition in vivo. Sertraline (11 mg/kg) lowered extracellular 5-hydroxyindolacetic acid (5-HIAA), measured in rat hippocampus by in vivo voltammetry, for about 3 h. The interaction between sertraline and drugs known to interfere with the release or uptake of serotonin (L-5-hydroxytryptophan (5-HTP), d-norfenfluramine and tianeptine) was then studied. The sertraline-induced decrease in extracellular 5-HIAA was related to the inhibition of uptake.

In vivo studies on the enhancement of serotonin reuptake by tianeptine.

The present study investigates the in vivo effects of the serotonin uptake enhancer tianeptine. The serotonin metabolite, 5-hydroxy-indolacetic acid (5-HIAA) was measured by in vivo voltammetry and carbon fiber electrodes chronically implanted in different brain areas of freely moving rats. Tianeptine (10 mg/kg i.p.) increased extracellular 5-HIAA in the hippocampus and hypothalamus. The interaction between tianeptine and drugs known to interfere with the uptake or release of serotonin (sertraline, buspirone, D-norfenfluramine) was then studied and, to ascertain the in vivo pharmacological relevance of tianeptine's effects, its ability to reduce the serotoninergic syndrome was evaluated. Both the biochemical and behavioral data indicate that in vivo tianeptine's effects on the serotoninergic system are likely to be due to serotonin uptake enhancement.