Molecular characterization of SARS-CoV-2 Omicron clade and clinical presentation in children.

Since its emergence, SARS-CoV-2 Omicron clade has shown a marked degree of variability and different clinical presentation compared with previous clades. Here we demonstrate that at least four Omicron lineages circulated in children since December 2021, and studied until November 2022: BA.1 (33.6%), BA.2 (40.6%), BA.5 (23.7%) and BQ.1 (2.1%). At least 70% of infections concerned children under 1 year, most of them being infected with BA.2 lineages (n = 201, 75.6%). Looking at SARS-CoV-2 genetic variability, 69 SNPs were found to be significantly associated in pairs, (phi < - 0.3 or > 0.3 and p-value < 0.001). 16 SNPs were involved in 4 distinct clusters (bootstrap > 0.75). One of these clusters (A23040G, A27259C, T23617G, T23620G) was also positively associated with moderate/severe COVID-19 presentation (AOR [95% CI] 2.49 [1.26-4.89] p-value: 0.008) together with comorbidities (AOR [95% CI] 2.67 [1.36-5.24] p-value: 0.004). Overall, these results highlight the extensive SARS-CoV-2 Omicron circulation in children, mostly aged < 1 year, and provide insights on viral diversification even considering low-abundant SNPs, finally suggesting the potential contribution of viral diversification in affecting disease severity.

The pediatric gut bacteriome and virome in response to SARS-CoV-2 infection.

Introduction: Since the beginning of the SARS-CoV-2 pandemic in early 2020, it has been apparent that children were partially protected from both infection and the more severe forms of the disease. Many different mechanisms have been proposed to explain this phenomenon, including children's frequent exposure to other upper respiratory infections and vaccines, and which inflammatory cytokines they are more likely to produce in response to infection. Furthermore, given the presence of SARS-CoV-2 in the intestine and its ability to infect enterocytes, combined with the well described immunomodulatory capabilities of the microbiome, another potential contributing factor may be the presence of certain protective microbial members of the gut microbiota (GM). Methods: We performed shotgun metagenomic sequencing and profiled both the bacteriome and virome of the GM of pediatric SARS-CoV-2 patients compared to healthy, age-matched subjects. Results: We found that, while pediatric patients do share some pro-inflammatory microbial signatures with adult patients, they also possess a distinct microbial signature of protective bacteria previously found to be negatively correlated with SARS-CoV-2 infectivity and COVID-19 severity. COVID-19 was also associated with higher fecal Cytomegalovirus load, and with shifts in the relative abundances of bacteriophages in the GM. Furthermore, we address how the preventative treatment of COVID-19 patients with antibiotics, a common practice especially in the early days of the pandemic, affected the bacteriome and virome, as well as the abundances of antimicrobial resistance and virulence genes in these patients. Discussion: To our knowledge, this is the first study to address the bacteriome, virome, and resistome of pediatric patients in response to COVID-19 and to preventative antibiotics use.

Outcomes of MIS-C patients treated with anakinra: a retrospective multicenter national study.

Background: The treatment of multisystem inflammatory syndrome in children unresponsive to first-line therapies (IVIG and/or steroids) is challenging. The effectiveness of IL-1 receptor antagonist, anakinra, is debated. Patients and methods: We conducted an anonymous retrospective multicenter study on MIS-C patients treated with anakinra in Italy from January 2020 to February 2021. Our study outcomes included the percentage of patients who required further therapeutic step-up, the percentage of patients who experienced fever resolution within 24 h and a reduction of CRP by half within 48 h, and the percentage of patients who developed Coronary Artery Anomalies (CAA) during follow-up. Results: 35 cases of MIS-C were treated in 10 hospitals. Of these, 13 patients started anakinra while in the ICU, and 22 patients started anakinra in other wards. 25 patients (71.4%) were treated with corticosteroids at a starting dose 2-30 mg/Kg/day plus IVIG (2 g/Kg), 10 patients (28.6%) received only corticosteroids without IVIG. Anakinra was administered intravenously to all patients in Group A (mean dose 8 mg/Kg/day), and subcutaneously in Group B (mean dose 4 mg/Kg/day). Only two patients required further treatment step-up and no patients developed CAA after receiving anakinra. The most commonly observed side effect was an increase in ALT, occurring in 17.1% of patients. Conclusions: In this retrospective cohort of severe MIS-C patients treated with anakinra we report favorable clinical outcomes with a low incidence of side effects. The simultaneous use of steroids ± IVIG in these patients hinders definitive conclusions regarding the need of IL-1 inhibition in MIS-C treatment.

A Neuropsychiatric Assessment of Children with Previous SARS-CoV-2 Infection.

AIM: Concerns have been raised about possible neuropsychiatric sequelae of COVID-19. The objective of this study was to examine the plausibility of long-term mental health consequences of COVID-19 by assessing a sample of children after the resolution of the acute SARS-CoV-2 infection. METHOD: As part of a systematic follow-up assessment of pediatric patients with COVID-19 conducted at two university children's hospitals, 50 children (56% males) aged 8 to 17 years (median 11.5), 26% with previous multisystem inflammatory syndrome in children (MIS-C), without a prior history of neuropsychiatric disorders, received a battery of clinical neuropsychiatric and neuropsychological rating scales that included the Pediatric Migraine Disability Assessment (PedMIDAS), Sleep Disturbance Scale for Children (SDSC), Multidimensional Anxiety Scale for Children (MASC-2), Child Depression Inventory (CDI-2), Child Behavior Checklist (CBCL), and the NEPSY II (Neuropsychological Assessment, Second Edition). The assessments were conducted between 1 and 18 months (median 8 months) after the acute infection. RESULTS: The CBCL internalizing symptoms score was in the clinical range for 40% of the participants (vs. a population expected rate of about 10%, p < 0.001). A sleep disturbance was detected in 28%, clinically significant anxiety in 48%, and depressive symptoms in 16%. The NEPSY II scores showed impairment in attention and other executive functions in 52%, and memory deficits in 40% of the children. CONCLUSIONS: These data from direct assessment of a sample of children who had SARS-CoV-2 infection show higher than expected rates of neuropsychiatric symptoms, thus supporting the possibility that COVID-19 may have mental health sequelae long after the resolution of the acute infection.

Italian good practice recommendations on management of persons with Long-COVID.

A significant number of people, following acute SARS-CoV-2 infection, report persistent symptoms or new symptoms that are sustained over time, often affecting different body systems. This condition, commonly referred to as Long-COVID, requires a complex clinical management. In Italy new health facilities specifically dedicated to the diagnosis and care of Long-COVID were implemented. However, the activity of these clinical centers is highly heterogeneous, with wide variation in the type of services provided, specialistic expertise and, ultimately, in the clinical care provided. Recommendations for a uniform management of Long-COVID were therefore needed. Professionals from different disciplines (including general practitioners, specialists in respiratory diseases, infectious diseases, internal medicine, geriatrics, cardiology, neurology, pediatrics, and odontostomatology) were invited to participate, together with a patient representative, in a multidisciplinary Panel appointed to draft Good Practices on clinical management of Long-COVID. The Panel, after extensive literature review, issued recommendations on 3 thematic areas: access to Long-COVID services, clinical evaluation, and organization of the services. The Panel highlighted the importance of providing integrated multidisciplinary care in the management of patients after SARS-CoV-2 infection, and agreed that a multidisciplinary service, one-stop clinic approach could avoid multiple referrals and reduce the number of appointments. In areas where multidisciplinary services are not available, services may be provided through integrated and coordinated primary, community, rehabilitation and mental health services. Management should be adapted according to the patient's needs and should promptly address possible life-threatening complications. The present recommendations could provide guidance and support in standardizing the care provided to Long-COVID patients.

The burden of central line-associated bloodstream infections in children with medical complexity.

BACKGROUND: Central line-associated bloodstream infections (CLABSI) are significant cause of complications in pediatric intensive care units (PICUs). An emerging challenge are CLABSIs in children with medical complexity (CMC) admitted to PICU. CMC are patients with chronic conditions with or without neurological impairment needing for tracheostomy and/or home mechanical or non-invasive ventilation and/or gastrostomy/jejunostomy. We evaluate CLABSI incidence in a PICU with high prevalence of CMC. METHODS: This was a retrospective study in the PICU of the Bambino Gesù Children Hospital from January 2017 to December 2020. The medical records were reviewed and demographic, clinical and microbiological data were extracted. CLABSI were defined according to the Center for Disease Control and Prevention's National Healthcare Safety Networks (NHSN) surveillance. RESULTS: A total of 101 children with 125 central lines (CLs) were included; 79/101 (78%) patients were CMC and 50/101 (50%) had a thracheostomy. CLABSI incidence was 2.75/1000 CL-days (9 cases/3269 CL-days); incidence was 0 in patients without underling conditions and 3.14/1000 in CMC (p < 0.001). CLABSI were due to gram negative bacteria in five patients, Candida spp in three and Staphylococcus hominis in one. CLs were removed in eight cases while in the later one, with CLABSI due to Pseudomonas aeruginosa, a conservative strategy was adopted cause of unavailable alternative venous access and removed at discharge with negative culture. All patients recovered. CONCLUSIONS: A target 0% CLABSI was possible in critically ill children without underling condition while a high incidence was reported in CMC and sustained by a peculiar CLABSI ecology. This ecology should be considered when a CLABSI was suspected in CMC for prompt antibiotics stewardship.

Parents' process of recognition and response to clinical deterioration of their children with medical complexity at home: A grounded theory.

AIM: To explore the process of recognition and response to clinical deterioration of children with medical complexity at home by their parents. BACKGROUND: Children with medical complexity are characterised by known chronic conditions associated with frailty and functional limitations, dependence on healthcare services and high use of technology and resources. Their medical complexity often leads to the onset of complications. Targeted care ensures timely recognition and response to clinical deterioration at home, thus avoiding serious sequelae, inappropriate hospitalisations and improving quality of life. Evidence on parents' process of the recognition and response to clinical deterioration at home is limited. DESIGN: Qualitative study using a Grounded Theory methodology. METHOD: Seven online focus groups were conducted with parents and healthcare providers experienced in their care. The interviews were transcribed verbatim and analysed through open, axial and selective coding, using a constant comparative iterative method. The COREQ guidelines guided the reporting of this work. RESULTS: Four categories and one core category were identified: (1) Awareness of the unique and shared characteristics of children with medical complexity; (2) Parents' care maintenance and management; (3) Parents' care monitoring; (4) Parents' response to clinical deterioration and (5) Seeking the Shift of Agency, the core category as the foundation of the Process of Recognition and rEsponse of PAREnts to Deterioration (PRE-PARE-D) theory. CONCLUSION: The role of parents of children with medical complexity is evolving into active care leaders, by developing care management and care monitoring competences and negotiating care with healthcare providers. RELEVANCE TO CLINICAL PRACTICE: The shift of agency from healthcare providers to parents requires education and counselling pathways to promote the development of parent's self-efficacy, competencies and empowerment in the care management of their children. Home care delivery for children with medical complexity should aim at sustaining this partnership between healthcare providers and parents.

The metaproteome of the gut microbiota in pediatric patients affected by COVID-19.

Introduction: The gut microbiota (GM) play a significant role in the infectivity and severity of COVID-19 infection. However, the available literature primarily focuses on adult patients and it is known that the microbiota undergoes changes throughout the lifespan, with significant alterations occurring during infancy and subsequently stabilizing during adulthood. Moreover, children have exhibited milder symptoms of COVID-19 disease, which has been associated with the abundance of certain protective bacteria. Here, we examine the metaproteome of pediatric patients to uncover the biological mechanisms that underlie this protective effect of the GM. Methods: We performed nanoliquid chromatography coupled with tandem mass spectrometry on a high resolution analytical platform, resulting in label free quantification of bacterial protein groups (PGs), along with functional annotations via COG and KEGG databases by MetaLab-MAG. Additionally, taxonomic assignment was possible through the use of the lowest common ancestor algorithm provided by Unipept software. Results: A COVID-19 GM functional dissimilarity respect to healthy subjects was identified by univariate analysis. The alteration in COVID-19 GM function is primarily based on bacterial pathways that predominantly involve metabolic processes, such as those related to tryptophan, butanoate, fatty acid, and bile acid biosynthesis, as well as antibiotic resistance and virulence. Discussion: These findings highlight the mechanisms by which the pediatric GM could contribute to protection against the more severe manifestations of the disease in children. Uncovering these mechanisms can, therefore, have important implications in the discovery of novel adjuvant therapies for severe COVID-19.

A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients.

Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naïve individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean±Standard error: 18.7 × 10-4 ± 2.1 × 10-4 vs. 3.3 × 10-4 ± 0.8 × 10-4 vs. 3.1 × 10-4 ± 0.8 × 10-4, P = 0.0003), peaking between Day 2 and 5. Molnupiravir drives the emergence of more G-A and C-T transitions than other mutations (P = 0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure does not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN > dS, P = 0.001); few amino acid mutations are enriched at specific sites. No RNA-dependent RNA polymerase (RdRp) or main proteases (Mpro) mutations conferring resistance to Molnupiravir or Paxlovid are found. This proof-of-concept study defines the SARS-CoV-2 within-host evolution during antiviral treatment, confirming higher in vivo variability induced by Molnupiravir compared to Paxlovid and drug-naive, albeit not resulting in apparent mutation selection.

COVID-19 in Infants Less than 3 Months: Severe or Not Severe Disease?

Compared to adults, severe or fatal COVID-19 disease is much less common in children. However, a higher risk for progression has been reported in infants. Different pediatric COVID-19 severity scores are reported in the literature. Methods: Subjects under 90 days of age admitted to 35 Italian institutions for COVID-19 were included. The severity of COVID-19 was scored as mild/moderate or severe/critical following the classification reported in the literature by Venturini, Dong, Kanburoglu, and Gale. To assess the diagnostic accuracy of each classification system, we stratified all enrolled patients developing a posteriori severity score based on clinical presentation and outcomes and then compared all different scores analyzed. Results: We included 216 infants below 90 days of age. The most common symptom was fever, followed by coryza, poor feeding, cough, and gastrointestinal manifestations. According to Venturini, Dong, Kanburoglu, and Gale's severity scores, 18%, 6%, 4.2%, and 29.6% of infants presented with severe/critical disease, respectively. A correlation analysis between these four scores and the a posteriori severity score assigned to all enrolled subjects was performed, and a crescent strength of correlation from Gale (R = 0.355, p < 0.001) to Venturini (R = 0.425, p < 0.001), Dong (R = 0.734, p < 0.001), and Kanburoglu (R = 0.859, p < 0.001) was observed. Conclusions: The percentage of infants with severe COVID-19 varies widely according to the score systems. A unique clinical score should be designed for neonates and infants with COVID-19.

Long-Term Cardiovascular Outcome in Children with MIS-C Linked to SARS-CoV-2 Infection-An Italian Multicenter Experience.

MIS-C is a multisystem inflammatory syndrome that is characterized by multi-organ failure and cardiac involvement. The aim of this study was to describe the long-term cardiovascular outcome in a cohort of MIS-C pediatric patients, who were admitted to two Italian Pediatric Referral Centers. Sixty-seven patients (mean age 8.7 ± 4.7 years, male 60%) were included; 65 (97%) of them showed cardiac involvement. All of the patients completed one month of the follow-up, and 47% completed 1 year of it. ECG abnormalities were present in 65% of them, arrhythmias were present in 9% of them during an acute phase and it disappeared at the point of discharge or later. Pericarditis were detected in 66% of them and disappeared after 6 months. Coronaritis was observed in 35% of the children during an acute phase, and there were no more instances at the 1-year point. An LV dysfunction was present in 65% of the patients at the beginning of the study, with them having a full recovery at the point of discharge and thereafter. Elevated values of the NTproBNP and hsTp were initially detected, which progressively decreased and normalized at the points of discharge and FU. The CMR at the point of FU, there was a presence of long-term myocardial scars in 50% of the patients that were tested. No deaths that were caused by MIS-C during the FU were recorded. Cardiac involvement in MIS-C patients is almost the rule, but the patients' clinical course was satisfactory, and no additional events or sequelae were observed apart from there being long-term myocardial scars in 50% of the patients that underwent CMR.

The Relationship Between Pediatric Gut Microbiota and SARS-CoV-2 Infection.

This is the first study on gut microbiota (GM) in children affected by coronavirus disease 2019 (COVID-19). Stool samples from 88 patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 95 healthy subjects were collected (admission: 3-7 days, discharge) to study GM profile by 16S rRNA gene sequencing and relationship to disease severity. The study group was divided in COVID-19 (68), Non-COVID-19 (16), and MIS-C (multisystem inflammatory syndrome in children) (4). Correlations among GM ecology, predicted functions, multiple machine learning (ML) models, and inflammatory response were provided for COVID-19 and Non-COVID-19 cohorts. The GM of COVID-19 cohort resulted as dysbiotic, with the lowest α-diversity compared with Non-COVID-19 and CTRLs and by a specific ß-diversity. Its profile appeared enriched in Faecalibacterium, Fusobacterium, and Neisseria and reduced in Bifidobacterium, Blautia, Ruminococcus, Collinsella, Coprococcus, Eggerthella, and Akkermansia, compared with CTRLs (p < 0.05). All GM paired-comparisons disclosed comparable results through all time points. The comparison between COVID-19 and Non-COVID-19 cohorts highlighted a reduction of Abiotrophia in the COVID-19 cohort (p < 0.05). The GM of MIS-C cohort was characterized by an increase of Veillonella, Clostridium, Dialister, Ruminococcus, and Streptococcus and a decrease of Bifidobacterium, Blautia, Granulicatella, and Prevotella, compared with CTRLs. Stratifying for disease severity, the GM associated to "moderate" COVID-19 was characterized by lower α-diversity compared with "mild" and "asymptomatic" and by a GM profile deprived in Neisseria, Lachnospira, Streptococcus, and Prevotella and enriched in Dialister, Acidaminococcus, Oscillospora, Ruminococcus, Clostridium, Alistipes, and Bacteroides. The ML models identified Staphylococcus, Anaerostipes, Faecalibacterium, Dorea, Dialister, Streptococcus, Roseburia, Haemophilus, Granulicatella, Gemmiger, Lachnospira, Corynebacterium, Prevotella, Bilophila, Phascolarctobacterium, Oscillospira, and Veillonella as microbial markers of COVID-19. The KEGG ortholog (KO)-based prediction of GM functional profile highlighted 28 and 39 KO-associated pathways to COVID-19 and CTRLs, respectively. Finally, Bacteroides and Sutterella correlated with proinflammatory cytokines regardless disease severity. Unlike adult GM profiles, Faecalibacterium was a specific marker of pediatric COVID-19 GM. The durable modification of patients' GM profile suggested a prompt GM quenching response to SARS-CoV-2 infection since the first symptoms. Faecalibacterium and reduced fatty acid and amino acid degradation were proposed as specific COVID-19 disease traits, possibly associated to restrained severity of SARS-CoV-2-infected children. Altogether, this evidence provides a characterization of the pediatric COVID-19-related GM.

Epidemiological characterization of SARS-CoV-2 variants in children over the four COVID-19 waves and correlation with clinical presentation.

Since the start of SARS-CoV-2 pandemic, children aged ≤ 12 years have always been defined as underrepresented in terms of SARS-CoV-2 infections' frequency and severity. By correlating SARS-CoV-2 transmission dynamics with clinical and virological features in 612 SARS-CoV-2 positive patients aged ≤ 12 years, we demonstrated a sizeable circulation of different SARS-CoV-2 lineages over the four pandemic waves in paediatric population, sustained by local transmission chains. Age < 5 years, highest viral load, gamma and delta clades positively influence this local transmission. No correlations between COVID-19 manifestations and lineages or transmission chains are seen, except for a negative correlation between B.1.1.7 and hospitalization.

One Year of Lung Ultrasound in Children with SARS-CoV-2 Admitted to a Tertiary Referral Children's Hospital: A Retrospective Study during 2020-2021.

During the COVID-19 pandemic, the lung ultrasound (LU) turned out to be a pivotal tool to study the lung involvement in the adult population, but the same was not well evaluated in children. We detected the LU patterns through an integrated approach with clinical−laboratory features in children hospitalized for COVID-19 in relation to the temporal trend of the Italian epidemic. We conducted a retrospective study which took place at a pediatric tertiary hospital from 15 March 2020 to 15 March 2021. We compared the characteristics of the initial phase of the first COVID-19 year­in the spring and summer (15 March−30 September 2020)­and those of the second phase­in the autumn and winter (1 October 2020−15 March 2021). Twenty-eight patients were studied both in the first and in the second phase of the first COVID-19 year. The disease severity score (DSS) was significantly greater in the second phase (p = 0.015). In the second phase of the first COVID-19 year, we detected a more significant occurrence of the following LU features than in the first phase: the irregular pleural line (85.71% vs. 60.71%; p = 0.035), the B-lines (89.29% vs. 60%; p = 0.003) and the several but non-coalescent B-lines (89.29% vs. 60%; p = 0.003). The LU score correlated significantly with the DSS, with a moderate relationship (r = 0.51, p < 0.001). The combined clinical, laboratory and ultrasound approaches might be essential in the evaluation of pulmonary involvement in children affected by COVID-19 during different periods of the pandemic.

Safety of Monoclonal Antibodies in Children Affected by SARS-CoV-2 Infection.

Monoclonal antibody therapies for COVID-19 have been frequently used in adults, whereas there are little data regarding the safety or efficacy of monoclonal antibody treatments in pediatric patients affected by COVID-19. We report our experience in the administration of mAb as a treatment for SARS-CoV-2 infection in children aged from 24 days to 18 years old.

SARS-CoV-2 infection as possible downstream disease precipitator in autoantibody-positive insulin-dependent diabetes mellitus: a case report.

BACKGROUND: SARS-CoV-2 causes lesions, in addition to lung, in endocrine organs such as the pancreas through ACE2 receptor. Recently the relationship between SARS-CoV-2 exposition and the incidence or evolution of clinical autoimmune diabetes has attracted the attention of diabetologists. CASE PRESENTATION: We report the analysis of the clinical history of a child diagnosed for insulin-dependent diabetes mellitus (Type 1 diabetes) at the time a paucisymptomatic COVID-19 infection occurred, followed by well-controlled metabolic status. As opposite to previous findings SARS-CoV2 did not cause ketosis and ketoacidosis. Polydipsia was reported a few months and weight loss 4 weeks before SARS- CoV-2 infection suggesting that SARS-CoV-2 could not be the trigger of Type 1 diabetes in this patient. CONCLUSIONS: SARS-CoV-2 in this patient was an unexpected event in the course of disease. We advance the hypothesis that the SARS-CoV-2 infection, even if paucisymptomatic could have acted in the present case report as a hypothetical downstream precipitating factor; whilst the inciting triggering event of the autoimmune disease, as confirmed by the presence of circulating autoantibodies, could have occurred even before, as generally assumed for this category of disorders. The precipitating mechanism could have been the acute interaction between virus and the ACE receptor on the beta cells, at the time that hyperglycemia and glycosuria were ascertained, and HbA1c levels confirmed a metabolic dysregulation over the previous 3 months in absence of ketoacidosis.

Glycopyrrolate for drooling in children with medical complexity under three years of age.

BACKGROUND: The aim of the study is to determine that Glycopirrolate is safe and effective in decreasing drooling in children with medical complexity under 3 years of age. Medical treatment is based on anticholinergic drugs as transdermal scopolamine, benzotropine and GLY. GLY (Glycopyrronium bromide) is a synthetic quaternary ammonium anticholinergic agent with poor blood-brain barrier penetration and consequently has limited central effects. Actually, the oral GLY formulation was approved by the United States Food and Drug Administration (FDA) to treat drooling in children aged 3-16 years. Five studies reported on GLY use for the treatment of drooling in children with cerebral palsy and other conditions with neurological impairment; four are prospective studies while one a retrospective review. METHODS: this is a case report of eighteen children (sex ratio 11/8, median age 17 months, range 2-36 months) under three years of age, followed by a multidisciplinary team at the Bambino Gesù Children Hospital. The median follow-up was of 31.5 months (range 1-69 months). Response to treatment was assessed according to the Drooling Impact Scale administered at time 0 and after 1 month. All patients have an important neurological impairment: nine patients have a cerebral palsy (Gross Motor Function Classification System class V) and nine a genetic/malformative syndrome. Twelve patients have a tracheostomy and two need mechanical ventilation. Gastrostomy is present in 16 out of 18 patients. All patients received Glycopirrolate. The median starting daily dose was 0.065 mg/kg/die (range 0.02-0.21 mg/kg/die) three times a day. The drooling impact scale was administered at time O and after 1 month. RESULTS: Four out 18 patients stopped treatment for adverse event, lack of efficacy or parental decision. The mean Drooling Impact Scale at time 0 was 89 (range 81-100) and after 1 month 61(range 43-78); the difference was statistically significant (P < 0.001). The overall response to treatment was 94%. CONCLUSIONS: This is the first study to determine the safety and effectiveness of Glycopyrrolate in decreasing drooling in a specific subset of patients. No major side effects were observed. Further comparative studies are needed to confirm our results.

Combining home monitoring temporal trends from implanted defibrillators and baseline patient risk profile to predict heart failure hospitalizations: results from the SELENE HF study.

AIMS: We developed and validated an algorithm for prediction of heart failure (HF) hospitalizations using remote monitoring (RM) data transmitted by implanted defibrillators. METHODS AND RESULTS: The SELENE HF study enrolled 918 patients (median age 69 years, 81% men, median ejection fraction 30%) with cardiac resynchronization therapy (44%), dual-chamber (38%), or single-chamber defibrillators with atrial diagnostics (18%). To develop a predictive algorithm, temporal trends of diurnal and nocturnal heart rates, ventricular extrasystoles, atrial tachyarrhythmia burden, heart rate variability, physical activity, and thoracic impedance obtained by daily automatic RM were combined with a baseline risk-stratifier (Seattle HF Model) into one index. The primary endpoint was the first post-implant adjudicated HF hospitalization. After a median follow-up of 22.5 months since enrolment, patients were randomly allocated to the algorithm derivation group (n = 457; 31 endpoints) or algorithm validation group (n = 461; 29 endpoints). In the derivation group, the index showed a C-statistics of 0.89 [95% confidence interval (CI): 0.83-0.95] with 2.73 odds ratio (CI 1.98-3.78) for first HF hospitalization per unitary increase of index value (P < 0.001). In the validation group, sensitivity of predicting primary endpoint was 65.5% (CI 45.7-82.1%), median alerting time 42 days (interquartile range 21-89), and false (or unexplained) alert rate 0.69 (CI 0.64-0.74) [or 0.63 (CI 0.58-0.68)] per patient-year. Without the baseline risk-stratifier, the sensitivity remained 65.5% and the false/unexplained alert rates increased by ≈10% to 0.76/0.71 per patient-year. CONCLUSION: With the developed algorithm, two-thirds of first post-implant HF hospitalizations could be predicted timely with only 0.7 false alerts per patient-year.