Search

Introduction: Respiratory pathogens are frequently isolated from airway samples in primary ciliary dyskinesia (PCD) patients. Few studies have investigated associations between these pathogens and lung function, with current management based on evidence from cystic fibrosis. We investigated the association between commonly isolated respiratory pathogens and lung function in PCD patients., Methods: Using a cross-sectional design, we prospectively collected clinical and concurrent microbiology data from 408 participants with probable or confirmed PCD, aged ≥5 years, from 12 countries. We used Global Lung Function Initiative 2012 references to calculate forced expiratory volume in 1 s (FEV 1 ) z-scores. For 351 patients (86%) with complete data, we assessed the association of the four most frequently isolated pathogens with lung function by fitting multilevel linear models with country as random intercept, adjusted for age at diagnosis, age at lung function, use of antibiotic prophylaxis and body mass index z-scores., Results: Individuals with Pseudomonas aeruginosa growth in culture had significantly lower FEV 1 z-scores (β= -0.87, 95% CI -1.40- -0.34), adjusted for presence of Haemophilus influenzae , methicillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae , and for covariates. When stratified by age, associations remained strong for adults but not for children. Results were similar when ciliary defects by transmission electron microscopy were included in the models and when restricting analysis to only confirmed PCD cases., Conclusions: We found that P. aeruginosa was associated with worse lung function in individuals with PCD, particularly adults. These findings suggest that it is prudent to aim for P. aeruginosa eradication in the first instance, and to treat exacerbations promptly in colonised patients., Competing Interests: Conflict of interest: M. Boon declares receiving grants or contracts from the Fund Alphonse and Jean Forton, managed by the King Baudouin Foundation, and by the Belgian Cystic Fibrosis Association (number 2020-J1810150-217926); and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex. Conflict of interest: S.B. Carr declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi Pharmaceuticals, and participation on a Data Safety Monitoring Board or Advisory Board for Vertex Pharmaceuticals. Conflict of interest: S. Dillenhöfer declares receiving support for attending meetings and/or travel from Vertex (Advance Program 2022). Conflict of interest: B. Karadag declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from VEM Ilac, Abdi Ibrahim and OMRON, and participating on a Data Safety Monitoring Board or Advisory Board for Abdi Ibrahim. Conflict of interest: C. Koerner-Rettberg declares receiving speaker honoraria from Berlin Chemie, and advisory board participation and being a member of the medical board of the German PCD patient organisation. Conflict of interest: V. Martinu declares having received grants or contracts from Ministry of Health of the Czech Republic (grant number NV19-07-00210) and participation on an advisory board for indication of tobramycin in noncystic fibrosis bronchiectasis for Chiesi, and receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi Pharmaceuticals. Conflict of interest: A. Moreno-Galdó declares receiving personal payment for lectures from AstraZeneca, Sanofi-Pasteur and Janssen, receiving support for attending meetings or travel from Sanofi-Pasteur and Vivisol, participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca and Sanofi-Pasteur, and is President of the Spanish Society of Pediatric Pulmonology. Conflict of interest: U. Ozcelik is Head of the Turkish Respiratory Disease and Cystic Fibrosis Society (unpaid). Conflict of interest: P. Pohunek declares receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GlaxoSmithKline, AstraZeneca and Chiesi, and consulting fees, support for attending meetings and/or travel, and participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca and GlaxoSmithKline. Conflict of interest: J. Raidt declares receiving the following funds: DFG CRU326 RA3522/1. Conflict of interest: P. Latzin declares receiving grants or contracts from Vertex and OM Pharma, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma, and participating on a Data Safety Monitoring Board or Advisory Board for the following: Polyphor, Santhera (DMC), Vertex, OM Pharma, Vifor, Allecra and Sanofi Aventis. Conflict of interest: J.S. Lucas declares receiving support for the present manuscript (funds the clinical investigations (spirometry, microbiology)) from NHS England, to the institution; and grants or contracts from COST ACTION to fund the BEATPCD COST Action BM1407, which funded the network that undertook this work, and the institution managed the funding. Conflict of interest: The other authors have nothing to disclose., (Copyright ©The authors 2024.)

Background: ARASENS was a randomized, double-blind, phase 3 trial comparing darolutamide + docetaxel + androgen deprivation therapy (ADT) with placebo + docetaxel + ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC)., Objective: To use clinical trial data from ARASENS to understand whether the addition of darolutamide to docetaxel + ADT leads to increased hospitalizations and to estimate the budget impact on the US health care system., Methods: We used mixed-effects negative binomial regression to estimate hospitalization and intensive care unit (ICU) admission rates and length of hospital stay (LoHS) counts. Hospitalization rates were estimated per treatment arm for the period during and after administration of docetaxel. Based on these estimates, a budget impact analysis evaluated the hospitalization costs (including ICU admissions) and standalone ICU hospitalization costs for the totality of the US population over a 5-year time horizon. The analysis compared a scenario without darolutamide vs one with darolutamide included in the US payer formulary. Hospitalization estimates were varied in a one-way sensitivity analysis., Results: The first 4 months of treatment (when patients were receiving docetaxel) were associated with increased hospitalizations across both arms. The addition of darolutamide was associated with a numerical reduction in the rate of hospitalization (per year) due to any reason both during docetaxel treatment (1.01 visits per year [95% CI = 0.82-1.20] vs 1.18 visits per year [95% CI = 0.96-1.41]) and after docetaxel treatment (0.28 visits per year [95% CI = 0.23-0.34] vs 0.33 visits per year [95% CI = 0.27-0.40]). Darolutamide was associated with a marginally longer LoHS per hospitalization compared with placebo (+1.90 days per year) both during and after docetaxel treatment. ICU admissions were low in the ARASENS data; admission rates were assumed to be the same during and after docetaxel treatment. ICU admission rate estimates were equivalent across arms (0.02 visits per year [95% CI = 0.01-0.03]). The budget impact per treated member per month represents a cost-neutral option after Year 5 with a cumulative budget impact of -$9.71., Conclusions: The addition of darolutamide to docetaxel + ADT was associated with a numerically lower rate of hospitalization but marginally longer LoHS compared with docetaxel + ADT alone. Darolutamide represents a cost-neutral alternative per treated member per month compared with docetaxel + ADT with regard to hospitalizations at the end of a 5-year time horizon.

Introduction: Platinum-based chemotherapy represents the standard of care (SoC) for the first-line treatment of advanced urothelial carcinoma (mUC). The benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy was recently investigated. We performed an individual patient data (IPD) meta-analysis of phase 3 clinical trials comparing ICI-based treatments., Methods: A systematic literature search was conducted on the MEDLINE and CENTRAL databases. The results were filtered by including only reports on clinical trials or randomized clinical trials from 2018 to 2023, including 3047 patients from four clinical trials (EV302, CHECKMATE-901, IMVIGOR130, KEYNOTE-361). An IPD meta-analysis was performed by reconstructing IPD from Kaplan-Meier curves. The primary endpoints were overall survival (OS) and progression-free survival (PFS) of Pembrolizumab + EV compared to experimental arms of the other trials of immunotherapy + chemotherapy., Results: The OS analysis showed an advantage of IPD from EV302 vs. all the other trials. For EV302 vs. KEYNOTE-361, the HR was 0.51; for EV302 vs. IMVIGOR130, the HR was 0.47; and for EV302 vs. CHECKMATE-901, the HR was 0.66 (CI 95% 0.51-0.85). In the PFS analysis, the EV302 arm showed a statistically significant advantage compared to CHECKMATE-901 (HR 0.66) and versus IMVIGOR130 (HR 0.51)., Limitations: By using reconstructed IPD curves, it was not possible to adjust patient-level covariates, and the heterogeneity of the included population may have affected the pooled results., Conclusions: The EV302 experimental arm showed better OS and PFS when compared to the other immunochemotherapy combinations. An immunochemotherapy combination strategy at the beginning of treatment in mUC seems to be superior in terms of OS and PFS compared to platinum-based chemotherapy alone. EV-Pembrolizumab resulted to have better outcomes compared to avelumab, rather than other immunochemotherapy combinations. However, given the heterogeneity of these studies, a longer follow up and prospective trials are needed to confirm these data.

In the last two-decades, innovative drugs have revolutionized cancer treatments, demonstrating a significant improvement in overall survival. These drugs may present several pharmacokinetics interactions with non-oncological drugs, and vice versa, and, non-oncological drugs can modify oncological treatment outcome both with pharmacokinetic interaction and with an "off-target impact" on the tumor microenvironment or on the peripheral immune response. It's supposed that the presence of a drug-drug interaction (DDI) is associated with an increased risk of reduced anti-tumor effects or severe toxicities. However, clinical evidence that correlate the DDI presence with outcome are few, and results are difficult to compare because of difference in data collection and heterogeneous population. This review reports all the clinical evidence about DDI to provide an easy-to-use guide for DDI management and dose adjustment in solid tumors treated with inhibitors of the cyclin-dependent kinases CDK4-6, Antibody-drug conjugates, Poly ADPribose polymerase inhibitors, androgen-receptor targeted agents, or immunecheckpoints inhibitors., Competing Interests: Declaration of Competing Interest All the authors declare no conflicts of interest for this manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Background: Although, in most children with asthma, good symptom control is achieved with a low to moderate dose of inhaled corticosteroids, a small group of patients still experiences frequent symptoms, and even severe exacerbations, impairment of lung function, and reduced quality of life. Some of these subjects with severe asthma require biologic drugs as add-on therapy. In the past decade, numerous monoclonal antibodies have been approved for children or adolescents with severe asthma, in addition to their increasing use in adult asthma. However, the available evidence on how to select the most appropriate biologic based on a single patient's clinical, functional, and laboratory characteristics is still scant, and is insufficient to guide clinicians in the decision-making process of a personalized treatment., Materials and Methods: We report a case series of four patients with severe eosinophilic asthma treated with mepolizumab, an anti-interleukin-5 monoclonal antibody, and review the existing literature on this treatment in children and adolescents., Results: Our patients, all with blood eosinophilia and elevated fractional exhaled nitric oxide levels, developed poor symptom control despite prolonged treatment with high-dose inhaled corticosteroids plus a second controller, addressing the addition of a biologic drug. In all of them, a 12-month treatment with subcutaneous mepolizumab showed a reduction in the blood eosinophil count and in asthma exacerbations, as well as an improvement on the Asthma Control Test. The results of the literature search focused on the strengths and limitations of the pediatric use of mepolizumab and highlighted the areas worthy of further research., Conclusions: Mepolizumab has proven effective in improving symptom control in pediatric patients with severe asthma. Additional well-powered clinical trials will be helpful in developing evidence-based guidelines regarding biologic drugs in the pediatric population.

Background: There are few molecular markers driving treatment selection in later lines of treatment for advanced colorectal cancer patients. The vast majority of patients who progress after first- and second-line therapy undergo chemotherapy regardless of molecular data., Objective: We aimed to assess the prognostic and predictive effects of specific RAS mutations on overall survival of patients receiving regorafenib (rego), trifluridine/tipiracil (TFD/TPI), or both., Patients and Methods: This was a retrospective observational study based on data from a previous study of our research network, involving nine Italian institutions over a 10-year timeframe (2012-2022). Extended RAS analysis, involving KRAS exon 2-4 and NRAS exon 2-4, and BRAF were the main criteria for inclusion in this retrospective evaluation. Patients with BRAF mutation were excluded. Patients were classified according to treatment (rego- or TFD/TPI-treated) and RAS mutational status (wild-type [WT], KRAS codon 12 mutations, KRAS codon 13 mutations, KRAS rare mutations and NRAS mutations, KRAS G12C mutation and KRAS G12D mutation)., Results: Overall, 582 patients were included in the present analysis. Overall survival did not significantly differ in rego-treated patients according to RAS extended analysis, although a trend toward a better median survival in patients carrying G12D mutation (12.0 months), Codon 13 mutation (8.0 months), and Codon 12 mutation (7.0 months) has been observed, when compared with WT patients (6.0 months). Overall survival did not significantly differ in TFD/TPI-treated patients according to RAS extended analysis, although a trend toward a better median survival in WT patients had been observed (9.0 months) in comparison with the entire population (7.0 months). Patients receiving both drugs displayed a longer survival when compared with the population of patients receiving rego alone (p = 0.005) as well as the population receiving TFD/TPI alone (p < 0.001), suggesting a group enriched for favorable prognostic factors. However, when each group was analyzed separately, the addition of TFD/TPI therapy to the rego-treated group improved survival only in all-RAS WT patients (p = 0.003). Differently, the addition of rego therapy to TFD/TPI-treated patients significantly improved OS in the Codon 12 group (p = 0.0004), G12D group (p = 0.003), and the rare mutations group (p = 0.02), in addition to all-RAS WT patients (p = 0.002). The rego-TFD/TPI sequence, compared with the reverse sequence, significantly improved OS only in the KRAS codon 12 group (p = 0.003)., Conclusions: Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded., (© 2024. The Author(s).)

There is an increasing need to implement neuromorphic systems that are both energetically and computationally efficient. There is also great interest in using electric elements with memory, memelements, that can implement complex neuronal functions intrinsically. A feature not widely incorporated in neuromorphic systems is history-dependent action potential time adaptation which is widely seen in real cells. Previous theoretical work shows that power-law history dependent spike time adaptation, seen in several brain areas and species, can be modeled with fractional order differential equations. Here, we show that fractional order spiking neurons can be implemented using super-capacitors. The super-capacitors have fractional order derivative and memcapacitive properties. We implemented two circuits, a leaky integrate and fire and a Hodgkin-Huxley. Both circuits show power-law spiking time adaptation and optimal coding properties. The spiking dynamics reproduced previously published computer simulations. However, the fractional order Hodgkin-Huxley circuit showed novel dynamics consistent with criticality. We compared the responses of this circuit to recordings from neurons in the weakly-electric fish that have previously been shown to perform fractional order differentiation of their sensory input. The criticality seen in the circuit was confirmed in spontaneous recordings in the live fish. Furthermore, the circuit also predicted long-lasting stimulation that was also corroborated experimentally. Our work shows that fractional order memcapacitors provide intrinsic memory dependence that could allow implementation of computationally efficient neuromorphic devices. Memcapacitors are static elements that consume less energy than the most widely studied memristors, thus allowing the realization of energetically efficient neuromorphic devices., (© 2024. The Author(s).)

Posterolateral corner (PLC) injuries are complex knee injuries that are becoming increasingly frequent. Often undiagnosed and underestimated, a systematic diagnostic workup is necessary to assess the severity of PLC injury in order to then be able to select the proper surgery approach. Anatomical and nonanatomical PLC-reconstruction techniques have been described. In this Technical Note, we describe our technique of biomechanical reconstruction of PLC in case of severe posterolateral rotational instability., Competing Interests: The authors report no conflicts of interest in the authorship and publication of this article. Full ICMJE author disclosure forms are available for this article online, as supplementary material., (© 2023 The Authors.)

Background: Dementia is the fourth leading cause of death in people >  65 years old in western countries., Objective: This cross-sectional assisted survey aimed to evaluate a multidisciplinary team approach of specialists of the Associazione Geriatri Extraospedalieri a favore di Anziani Svantaggiati and pharmacists to facilitate progress in the early identification and management of cognitive decline in patients >  60 years., Methods: A multidisciplinary team conducted this cross-sectional assisted survey. Patients (>60 years) with independent and/or assisted walking, subjective memory impairment, mild cognitive impairment or mild Alzheimer's disease (AD) who regularly attended pharmacies underwent the survey. An internal medical examination, a cardiovascular visit, and a short neuropsychological evaluation were conducted for each patient. Demographic, anamnestic, and clinical data were collected anonymously., Results: 279 eligible patients underwent the screening phase. 44% were overweight, 23% obese and 29% hypertensive. 62% of cases showed alterations of supra-aortic trunk with different percentages of stenosis. The neuropsychological evaluation highlighted that 67% of cases were normal according to age and education level, while 18% were in a state condition of cognitive frailty. Mild/moderate cognitive decline, or probably AD, was identified in 14% of cases., Conclusions: A multidisciplinary collaboration between pharmacists and specialist medical doctors is essential in early identification of prodromal symptoms of cognitive impairment and AD. The Prompt detection of the condition in this group of patients allowed the specialists to recommend in-depth diagnostic tests and follow-up procedures to slow the course of the disease. This would give time to carry out adequate caregiver training.

Introduction: The aim of this study was to evaluate (i) the knowledge about different dimensions of sexual identity in a group of family pediatricians and (ii) the efficacy of a training program to improve knowledge and reduce genderism and heteronormativity., Methods: A pre-post-follow-up study was conducted with 96 Italian pediatricians (48 men and 48 women) who participated in a 6-h training program and divided into 2 sections. The first section was theoretical and focused on the conceptual foundations of sexual identity, the depathologizing approach to gender diversity, and the role of pediatricians as the first contacts of children's or adolescents' family. The second part was experiential and included the presentation of a clinical case and the activation of a group reflection on the management of gender-diverse youth. Knowledge about sexual identity, genderism, and heteronormativity was measured., Results: Pre-training questionnaires revealed that the mean score of knowledge about sexual identity was 7.13 ± 3.21. One-way within-subject ANOVA revealed significant effects from pre- to post-training and from pre- to follow-up assessment but not from post-training to follow-up assessment, suggesting that significant changes in the knowledge about sexual identity (F = 39.75, p &lt; 0.001), in personal biases related to genderism (F = 7.46, p &lt; 0.01), and in heteronormative attitudes (F = 44.99, p &lt; 0.001) and behaviors (F = 79.29, p &lt; 0.001) were achieved through the training and maintained at follow-up., Conclusion: These findings indicate the importance of training pediatricians to work with gender-diverse youth and provide them with the best clinical interventions., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Competing Interests: FS is Core Member of the European Reference Network of Rare Lung Disease (specifically, the Primary Ciliary Dyskinesia Network). All other authors declare no competing interests.

Background : Patients with refractory metastatic colorectal cancer (mCRC) rarely receive third-line or further treatment. In this context, regorafenib (R) and trifluridine/tipiracil (T) are two important novel therapeutic choices with statistically significant increases in overall survival (OS), progression-free survival (PFS), and disease control, with different toxicity profiles. This study is a subgroup analysis of our larger retrospective study, already published, whose objective was to assess the outcomes of patients when R and T were given sequentially. Patients and Methods : The study involved thirteen Italian cancer centers on a 10-year retrospective observation (2012-2022). In this subgroup analysis, we focused our attention on the correlation between the first drug treatment duration (<3 months, 3 to <6 months and ≥6 months) and survival outcomes in patients who had received the sequence regorafenib-to-trifluridine/tipiracil, or vice versa. Results : The initial study included 866 patients with mCRC who received sequential T/R, or R/T, or T or R alone. This analysis is focused on evaluating the impact of the duration of the first treatment in the sequence on clinical outcomes (OS, PFS) and includes 146 and 116 patients of the T/R and R/T sequences, respectively. Based on the duration of the first drug treatment, subgroups for the T/R sequence included 27 patients (18.4%) who received T for <3 months, 86 (58.9%) treated for 3 to <6 months, and 33 (22.6%) treated for ≥6 months; in the reverse sequence (R as the first drug), subgroups included 18 patients (15.5%) who received their first treatment for <3 months, 62 (53.4%) treated for 3 to <6 months, and 35 (31.0%) treated for ≥6 months. In patients who received their first drug treatment for a period of 3 to <6 months, the R/T sequence had a significantly longer median OS (13.7 vs. 10.8 months, p = 0.0069) and a longer median PFS (10.8 vs. 8.5 months, p = 0.0003) than the T/R group. There were no statistically significant differences between groups with first drug treatment durations of <3 months and ≥6 months. Conclusions : Our analysis seems to suggest that the administration of R for a period of 3 to <6 months before that of T can prolong both OS and PFS, as compared to the opposite sequence.

At any age, respiratory manifestations are a major cause of increased morbidity and mortality of inherited metabolic diseases (IMDs). Type and severity are extremely variable, this depending on the type of the underlying disorder. Symptoms and signs originating from upper or lower airways and/or thoracic wall and/or respiratory muscles involvement can occur either at presentation or in the late clinical course. Acute respiratory symptoms can trigger metabolic decompensation which, in turn, makes airway symptoms worse, creating a vicious circle. We have identified 181 IMDs associated with various types of respiratory symptoms which were classified into seven groups according to the type of clinical manifestations affecting the respiratory system: (i) respiratory failure, (ii) restrictive lung disease, (iii) interstitial lung disease, (iv) lower airway disease, (v) upper airway obstruction, (vi) apnea, and (vii) other. We also provided a list of investigations to be performed based on the respiratory phenotypes and indicated the therapeutic strategies currently available for IMD-associated airway disease. This represents the thirteenth issue in a series of educational summaries providing a comprehensive and updated list of metabolic differential diagnoses according to system involvement., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

COVID-19 pandemics is rapidly changing. In this article, we review progresses published in the Italian Journal of Pediatrics in 2022. More data on clinical pictures, prevention strategies and active management in children have been provided. The continued evolution of knowledge has driven transformations in the clinical approach to the disease and allowed key advancements in the care of children with COVID-19., (© 2023. Società Italiana di Pediatria.)

The last year saw intensive efforts to advance knowledge in pediatric medicine. This review highlights important publications that have been issued in the Italian Journal of Pediatrics in 2022. We have chosen papers in the fields of allergy, anesthesiology, cardiology, dermatology, endocrinology, gastroenterology, genetics, global health, infectious diseases, metabolism, neonatology, neurology, oncology, pulmonology. Novel valuable developments in epidemiology, pathophysiology, prevention, diagnosis and treatment that can rapidly change the approach to diseases in childhood have been included and discussed., (© 2023. Società Italiana di Pediatria.)

Introduction: Cervical cancer is the fourth most common cancer in women, and its prevention is based on vaccination and screening. Screening consists of molecular human papillomavirus (HPV) testing and cytologic analysis of cervical smears, which require expensive equipment and the interaction of numerous professionals such as biologists, cytologists, laboratory technicians, and pathologists., Materials and Methods: We centralize the cervical samples from more than 51 clinics in 1 main laboratory, where automated HPV testing is performed. HPV-positive cases are collected and used to prepare a liquid-based cytology slide, which is stained and immediately scanned. The resulting whole-slide images (WSIs) are immediately available in a remote laboratory where they are examined by experienced cytologists using virtual microscopy. This setup was validated by making each of the 3 readers independently diagnose 506 specimens in random order, using both conventional light microscopy (CLM) and WSIs, with a minimum wash-out period of 3 weeks and with a final discussion for all cases., Results: Intraobserver agreement among CLM and WSI ranged from 0.71 to 0.79, and interobserver agreement for the 3 readers compared with the consensus diagnosis was similar for the 2 modes of assessment. Readers subjectively felt confident in their WSI diagnosis for inadequate and negative cases, but less so in other cases. The perceived difficulty was slightly higher in WSI readings., Conclusions: Interobserver agreement in cervicovaginal cytology is moderate and does not vary if the slides are examined conventionally or digitally. Despite higher reported subjective difficulty and lower confidence in the WSI diagnosis, we did not observe a deterioration in diagnostic performance using WSI compared with CLM., (Copyright © 2023 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Obstructive sleep-disordered breathing (SDB) has significant impacts on health, and therefore, a timely and accurate diagnosis is crucial for effective management and intervention. This narrative review provides an overview of the current approaches utilised in the diagnosis of SDB in children. Diagnostic methods for SDB in children involve a combination of clinical assessment, medical history evaluation, questionnaires, and objective measurements. Polysomnography (PSG) is the diagnostic gold standard. It records activity of brain and tibial and submental muscles, heart rhythm, eye movements, oximetry, oronasal airflow, abdominal and chest movements, body position. Despite its accuracy, it is a time-consuming and expensive tool. Respiratory polygraphy instead monitors cardiorespiratory function without simultaneously assessing sleep and wakefulness; it is more affordable than PSG, but few paediatric studies compare these techniques and there is optional recommendation in children. Nocturnal oximetry is a simple and accessible exam that has high predictive value only for children at high risk. The daytime nap PSG, despite the advantage of shorter duration and lower costs, is not accurate for predicting SDB. Few paediatric data support the use of home testing during sleep. Finally, laboratory biomarkers and radiological findings are potentially useful hallmarks of SDB, but further investigations are needed to standardise their use in clinical practice.

Background: Tracheal compression (TC) due to vascular anomalies is an uncommon, but potentially serious cause of chronic respiratory disease in childhood. Vascular slings are congenital malformations resulting from abnormal development of the great vessels; in this group of disorders the most prevalent entity is the aberrant innominate artery (AIA). Here we provide a report on diagnosis and treatment of AIA in nine children with unexplained chronic respiratory symptoms. We describe the cases, perform a literature review, and provide a discussion on the diagnostic workup and treatment that can help manage AIA., Methods: Clinical history, diagnostic procedures and treatment before and after the AIA diagnosis were retrospectively reviewed in nine children (5 boys and 4 girls), who were referred for recurrent-to-chronic respiratory manifestations over 10 years (2012-2022). We performed a comprehensive report on the ongoing clinical course and treatment as well as an electronic literature search on the topic., Results: Diagnoses at referral, before AIA was identified, were chronic dry barking cough associated with recurrent pneumonia (n = 8, 89%), lobar/segmental atelectasis (n = 3, 33%), atopic/non atopic asthma (n = 3, 33%); pneumomediastinum with subcutaneous emphysema complicated the clinical course in one case. When referred to our Unit, all patients had been previously treated with repeated antibiotic courses (n = 9, 100%), alone (n = 6, 67%) or combined with prolonged antiasthma medications (n = 3, 33%) and/or daily chest physiotherapy (n = 2, 22%), but reported only partial clinical benefit. Median ages at symptom onset and at AIA diagnosis were 1.5 [0.08-13] and 6 [4-14] years, respectively, with a relevant delay in the definitive diagnosis (4.5 years). Tracheal stenosis at computed tomography (CT) was ≥ 51% in 4/9 cases and ≤ 50% in the remaining 5 subjects. Airway endoscopy was performed in 4 cases with CT evidence of tracheal stenosis ≥ 51% and confirmed CT findings. In these 4 cases, the decision of surgery was made based on endoscopy and CT findings combined with persistence of clinical symptoms despite medical treatment. The remaining 5 children were managed conservatively., Conclusions: TC caused by AIA may be responsible for unexplained chronic respiratory disease in childhood. Early diagnosis of AIA can decrease the use of expensive investigations or unsuccessful treatments, reduce disease morbidity, and accelerate the path toward a proper treatment., (© 2023. The Author(s).)

Background: Patients with refractory mCRC rarely undergo third-line or subsequent treatment. This strategy could negatively impact their survival. In this setting, regorafenib (R) and trifluridine/tipiracil (T) are two key new treatment options with statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control with different tolerance profiles. This study aimed to retrospectively evaluate the efficacy and safety profiles of these agents in real-world practice., Materials and Methods: In 2012-2022, 866 patients diagnosed with mCRC who received sequential R and T (T/R, n = 146; R/T, n = 116]) or T (n = 325]) or R (n = 279) only were retrospectively recruited from 13 Italian cancer institutes., Results: The median OS is significantly longer in the R/T group (15.9 months) than in the T/R group (13.9 months) ( p = 0.0194). The R/T sequence had a statistically significant advantage in the mPFS, which was 8.8 months with T/R vs. 11.2 months with R/T ( p = 0.0005). We did not find significant differences in outcomes between groups receiving T or R only. A total of 582 grade 3/4 toxicities were recorded. The frequency of grade 3/4 hand-foot skin reactions was higher in the R/T sequence compared to the reverse sequence (37.3% vs. 7.4%) ( p = 0.01), while grade 3/4 neutropenia was slightly lower in the R/T group than in the T/R group (66.2% vs. 78.2%) ( p = 0.13). Toxicities in the non-sequential groups were similar and in line with previous studies., Conclusions: The R/T sequence resulted in a significantly longer OS and PFS and improved disease control compared with the reverse sequence. R and T given not sequentially have similar impacts on survival. More data are needed to define the best sequence and to explore the efficacy of sequential (T/R or R/T) treatment combined with molecular-targeted drugs.

Purpose: Primary ciliary dyskinesia (PCD) is a heterogeneous disorder that includes respiratory symptoms, laterality defects, and infertility caused by dysfunction of motile cilia. Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance., Methods: In addition to studies in mouse and planaria, clinical exome sequencing and functional analyses in human were performed., Results: In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms. Consistently, we found that Clxn is expressed in mice left-right organizer. Transmission electron microscopy depicted ODA defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1, and DNAI2 from the distal axonemes, and mislocalization or absence of DNAH9. In addition, CLXN was undetectable in ciliary axonemes of individuals with defects in the ODA-docking machinery: ODAD1, ODAD2, ODAD3, and ODAD4. Furthermore, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility., Conclusion: Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex-associated protein ODAD5., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Introduction: There are no recent data on primary ciliary dyskinesia (PCD) distribution, diagnosis and treatment in Italy., Methods: A descriptive study based on a survey questionnaire. It consisted of three sections (patients, diagnosis, and treatment), and sent to all the Italian PCD Centers., Results: Questionnaires obtained from 20/22 centers in 12/20 regions showed that the total number of PCD patients treated at the participating centers was of 416. Out of all centers, 55% follow <20 patients, two centers have >40 patients, and 75% follow both pediatric and adults. Age at diagnosis was between 4 and 8 years in 45% of the centers, <3 years in three centers. Nasal nitric oxide, transmission electron microscopy and ciliary high-speed video microscopy are performed in 75%, 90%, and 40% of centers, respectively. Immunofluorescence is available in five centers. Genetic analysis is offered in 55% of the centers, and in seven centers >50% of the patients have a known genetic profile. Patients treated at all centers receive inhaled saline solutions, corticosteroids and chest physiotherapy. Prophylactic antibiotics and mucolytics are prescribed in 95% and 50% of the centers, respectively. Pseudomonas infection is treated with oral or inhaled antibiotics., Conclusions: Many Italian centers care for a small number of pediatric and adult patients, and diagnosis is often delayed. We found a great variability in the available diagnostic procedures, as well in the prescribed therapies. Our study will help to uniform diagnostic algorithm and share treatments protocols for PCD in Italy and allowed to set specific national goals., (© 2023 Wiley Periodicals LLC.)

Neuromuscular disease (NMDs) encompass a heterogeneous group of genetic disorders, with respiratory problems of variable intensity and progression described at any pediatric age, from infancy to adolescence, and they are largely associated with significant lifelong morbidity and high mortality. Restriction of breathing, impaired gas exchange, decline of lung function and sleep disordered breathing progressively develop because of muscular weakness and culminate in respiratory failure. Depending on the disease progression, airways manifestations can take weeks to months or even years to evolve, thus depicting two major respiratory phenotypes, characterized by rapid or slow progression to respiratory failure. Assessing type and age at onset of airways problems and their evolution over time can support pediatricians in the diagnostic assessment of NMD. In addition, knowing the characteristics of patients' respiratory phenotype can increase the level of awareness among neonatologists, geneticists, neurologists, pulmonologists, nutritionists, and chest therapists, supporting them in the challenging task of the multidisciplinary medical care of patients. In this review we examine the issues related to the pediatric respiratory phenotypes of NMD and present a novel algorithm that can act as a guide for the diagnostic agenda and the key preventive or therapeutic interventions of airways manifestations. With prolonged survival of children with NMD, the advent of neuromuscular respiratory medicine, including accurate assessment of the respiratory phenotype, will help physicians to determine patients' prognoses and to design studies for the evaluation of new therapies., Competing Interests: Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment., (Copyright © 2023 the authors.)

The factor Q 10 is used in neuroscience to adjust reaction rates of voltage-activated membrane conductances to different temperatures and is widely assumed to be constant. By performing an analysis of published data of the reaction rates of sodium, potassium, and calcium membrane conductances, we demonstrate that 1) Q 10 is temperature dependent, 2) this relationship is similar across conductances, and 3) there is a strong effect at low temperatures (<15°C). We show that macromolecular rate theory (MMRT) explains this temperature dependency. MMRT predicts the existence of optimal temperatures at which reaction rates decrease as temperature increases, a phenomenon that we also found in the published data sets. We tested the consequences of using MMRT-adjusted reaction rates in the Hodgkin-Huxley model of the squid's giant axon. The MMRT-adjusted model reproduces the temperature dependence of the rising and falling times of the action potential. Furthermore, the model also reproduces these properties for different squid species that live in different climates. In a second example, we compare spiking patterns of biophysical models based on human pyramidal neurons from the Allen Cell Types database at room and physiological temperatures. The original models, calibrated at 34°C, failed to generate realistic spikes at room temperature in more than half of the tested models, while the MMRT produces realistic spiking in all conditions. In another example, we show that using the MMRT correction in hippocampal pyramidal cell models results in 100% differences in voltage responses. Finally, we show that the shape of the Q 10 function results in systematic errors in predicting reaction rates. We propose that the optimal temperature could be a thermodynamical barrier to avoid over excitation in neurons. While this study is centered on membrane conductances, our results have important consequences for all biochemical reactions involved in cell signaling., Competing Interests: Declaration of interests Authors declare no competing interests., (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Loss of habitat, urbanisation, climate change and its consequences are anthropogenic pressures that may cause stress in koalas. Non-invasive monitoring of faecal cortisol metabolites (FCMs) can be utilised to evaluate the impact of stressors. The aim was to determine if the tetrahydrocorticosterone (50c) and cortisol enzyme immunoassays (EIAs) could be effective in measuring FCM values in wild, stressed koalas. This research included 146 koalas from the Australia Zoo Wildlife Hospital (AZWH) and 88 from a study conducted by Endeavour Veterinary Ecology (EVE), Queensland, Australia. Faecal samples of diseased, injured and control koalas were analysed. The effect of hospitalisation on FCM values was also investigated. Diseased and injured koalas had significantly higher FCM values than clinically healthy control animals as measured by the 50c EIA. FCM values with the cortisol EIA differed significantly between control and diseased koalas, but not between control and injured ones. Moreover, only the 50c EIA detected higher absolute values in males compared to females, and also found that females showed a more elevated response to stress manifested by injury and disease compared to males. The 50c EIA detected stress during hospitalisation better than the cortisol EIA. The cortisol EIA was also found unreliable in detecting stress in rehabilitated koalas treated with synthetic glucocorticoids as it cross-reacts with these steroids providing artificially high values.

A comprehensive evaluation of obstructive sleep apnoea (OSA) may allow for the development of more efficient management of Down syndrome (DS). We aimed to evaluate the effect of a multidisciplinary approach to DS with OSA. A total of 48 DS children aged 4−12 years were prospectively investigated with nasal endoscopy, orthodontic examination, and overnight polygraphy (PG); the Italian Child Sleep Habits Questionnaire (CSHQ-IT) was filled out by the mothers. The total CSHQ-IT score was 63 (96% of children reporting sleep problems). The major ear, nose, and throat characteristics were enlarged palatine tonsils (62%), adenoid tonsils (85%), and chronic rhinosinusitis (85%). DS children showed orthognathic profile in 68% of cases, class I relationship in 63%, and cross-bite in 51%. PG revealed OSA in 67% of cases (37% mild, 63% moderate−severe). The oxygen desaturation index (ODI) was higher in the group with OSA (5.2) than with non-OSA (1.3; p < 0.001). The ODI was higher (p = 0.001) and SpO2 lower (p = 0.03) in children with moderate−severe OSA than with mild OSA. The apnoea−hypopnea index (AHI) and percentage time with SpO2 < 90% were higher in DS children with grade III than with grade I or II adenoids (5 vs. 1, p = 0.04, and 1.2 vs. 0.1, p = 0.01, respectively). No significant correlations were found between PG and the total CSHQ-IT score or orthodontic data. However, children showing associated cross-bite, grade III adenoids and size 3 or 4 palatine tonsils showed higher AHI and ODI than those without (p = 0.01 and p = 0.04, respectively). A coordinated multidisciplinary approach with overnight PG is a valuable tool when developing diagnostic protocols for OSA in DS.

In this review, we report the developments across pediatric subspecialties that have been published in the Italian Journal of Pediatrics in 2021. We highlight advances in allergy and immunology, critical care, endocrinology, gastroenterology, genetics, hematology, infectious diseases, neonatology, neurology, nutrition, palliative care, respiratory tract illnesses and telemedicine., (© 2022. The Author(s).)

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV 1 , FVC and FEV 1 /FVC z-scores declined over time (average crude annual FEV 1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV 1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis., Competing Interests: Conflict of interest: P. Latzin reports grants from Vertex and Vifor, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Vertex, Vifor and OM Pharma, and participation on a data safety monitoring board or advisory board for Polyphor, Santhera (DMC), Vertex, OM Pharma and Vifor. M.R. Loebinger reports consultancy fees from Insmed, AstraZeneca and Grifols, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Insmed and Grifols. The remaining authors disclose no potential conflicts of interest., (Copyright ©The authors 2022.)

In this article, the developments in the field of COVID-19 pandemic published in the Italian Journal of Pediatrics in 2021 are reflected. We describe progresses in SARS-CoV-2 transmission route, clinical presentation, diagnosis, treatment, and access to health care facilities in children. They led to substantial changes in the clinical approach., (© 2022. The Author(s).)

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients., Competing Interests: Conflict of interest: J. Raidt declares grants for Clinical Research Unit “Male Germ Cells: from Genes to Function” (CRU 326) – Subproject RA3522/1-1 from the Deutsche Forschungsgemeinschaft, in connection with the present manuscript; that they are a holder of patent WO 2020/165352 A1 (Treatment of ciliopathies); and an unpaid role as a Deputy Director of PCD-CTN. Conflict of interest: B. Maitre declares unpaid roles as a Deputy Director of PCD-CTN and as a member of the scientific committee of RADICO PCD. Conflict of interest: P. Pennekamp declares research grants to their institution from NEOCYST (BMBF, 01GM1903A); and that they are a holder of patent WO 2020/165352 A1 (Treatment of ciliopathies). Conflict of interest: M. Armengot declares research grant FIS PI19/00949 from Instituto de Salud Carlos III, in connection with the present manuscript. Conflict of interest: M. Boon declares Forton grant 2020-J1810150-217926 from the King Baudouin Foundation, in the 36 months prior to manuscript submission. Conflict of interest: S.B. Carr declares grants to their institution from the National Institute of Health Research (Programme Development Grant 202952; Health Technology Assessment Grant NIHR121889; HTA grant 14/22/23; NIHR RfPb QOL-PCD; NIHR RfPb VALU- CF); consulting fees paid to their institution by Vertex Pharmaceuticals; personal and institutional honoraria from Chiesi Pharmaceuticals; payment to their institution for participation on a Data Safety Monitoring Board or Advisory Board from Profile Pharma, Pharmaxis and Vertex Pharmaceuticals, all in the 36 months prior to manuscript submission; and that they are Chair of the UK CF Registry Steering Committee (payment to their institution) and of the European CF Society Patient Registry Scientific Committee (unpaid). Conflict of interest: M.A. Mall declares research grant 82DZL009B1 from the German Federal Ministry of Education and Research, in connection with the present manuscript. Conflict of interest: M. Narayanan declares that they have been a co-applicant on the National Institute for Health Research – Research for patient benefit (NIHR –RfPB) grant for ‘Parent reported quality of life measures for young children with primary ciliary dyskinesia (QOL-PCD study)’ in the 36 months prior to manuscript submission; and that they are a member of the British Paediatric Respiratory Society executive committee and the British Thoracic Society standards of care committee. Conflict of interest: P. Pohunek declares research grants from the Ministry of Health of the Czech Republic (NV19-07-00210) and Charles University Grant Agency (670119P) in connection with the present manuscript. Conflict of interest: S. Range declares an unpaid role as medical advisor to PCD Support. Conflict of interest: F.C. Ringshausen declares grants to their institution from the German Center for Lung Research (DZL), the German Center for Infection Research (DZIF), IMI (EU/EFPIA), iABC Consortium (including Alaxia, Basilea, Novartis and Polyphor), Mukoviszidose Institute, Novartis, Insmed Germany, Grifols, Bayer and InfectoPharm; consulting fees from Parion, Grifols, Zambon, Insmed and the Helmholtz-Zentrum für Infektionsforschung; payments or honoraria from I!DE Werbeagentur GmbH; Interkongress GmbH; AstraZeneca; Insmed; Grifols and Universitätsklinikum Frankfurt am Main; payment to their institution for expert testimony at the Social Court Cologne; support for attending meetings from German Kartagener Syndrome and PCD PAG and Mukoviszidose e.V; participation on a Data Safety Monitoring Board or Advisory Board for Insmed, Grifols and Shionogi; fees for clinical trial participation paid to their institution by Abbvie, AstraZeneca, Boehringer Ingelheim, Celtaxsys, Corbus, Insmed, Novartis, Parion, University of Dundee, Vertex and Zambon; and honorary roles as Coordinator of the ERN-LUNG Bronchiectasis Core Network, Chair of the German Bronchiectasis Registry PROGNOSIS, Member of the SteerCo of the European Bronchiectasis Registry EMBARC, Member of the SteerCo of the European NTM Registry EMBARC-NTM, Co-Speaker of the Medical Advisory Board of the German Kartagener Syndrome and PCD PAG, Speaker of the Respiratory Infections and TB group of the German Respiratory Society (DGP), Speaker of the Cystic Fibrosis group of German Respiratory Society (DGP), PI of the DZL, member of the protocol review committee of the PCD-CTN and Member of Physician Association of the German Cystic Fibrosis PAG. Conflict of interest: J. Roehmel declares payments or honoraria from Vertex Pharmaceuticals, in the 36 months prior to manuscript submission. Conflict of interest: G. Thouvenin declares unpaid membership of the RADICO PCD scientific committee. Conflict of interest: H. Omran declares grants for Clinical Research Unit “Male Germ Cells: from Genes to Function” (CRU 326) – Subproject RA3522/1-1 from the Deutsche Forschungsgemeinschaft, from Interdisziplinaeres Zentrum für Klinische Forschung Muenster (Om2/009/12; Om2/015/16; Om2/010/20), from BESTCILIA (EU FP7 GA 305404) and from Registry Warehouse (Horizon2020 GA 777295), all in connection with the present manuscript; in addition to grants to their institution from LYSOCIL (Horizon2020 GA n°811087) NEOCYST (BMBF, 01GM1903A) and Transkripttherapie für primäre ziliäre Dyskinesien (Zentrales Innovationsprojekt Mittelstand (ZIM), BMWi; ZF-4610102SK8), in the 36 months prior to manuscript submission; that they are a holder of patent WO 2020/165352 A1 (Treatment of ciliopathies); and unpaid roles as Head of the ERN-LUNG PCD Core and as a member of the PCD Family Support Group medical advisory board. Conflict of interest: K.G. Nielsen declares funding for the present manuscript from the Danish Children's Lung Foundation (Børnelungefonden); and an unpaid role as a Director of the PCD-CTN. Conflict of interest: All other authors declare no competing interests., (Copyright ©The authors 2022.)

Tiotropium bromide is the only long-acting muscarinic antagonist (LAMA) approved for treatment of patients aged ≥6 years old who have symptoms of uncontrolled asthma. Results from several clinical trials have found that once-daily inhaled tiotropium bromide is safe and efficacious in 6- to 17-year-olds with symptomatic asthma despite treatment with inhaled corticosteroids, with or without other medications. There are still few available studies investigating the impact of tiotropium bromide treatment in preschool children with suboptimal control. In this narrative review, we summarize the pharmacological effects of the LAMA tiotropium bromide, provide an overview about current asthma studies at different pediatric ages, and describe future research needs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Santamaria, Ziello, Lorello, Bouchè and Borrelli.)

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS: We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS: The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS: Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting side-effect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization. (Funded by the Telethon Foundation ETS, the European Commission Seventh Framework Programme, and the Isaac Foundation; ClinicalTrials.gov number, NCT03173521; EudraCT number, 2016-002328-10.)

Objective: Environmental enrichment is used to treat social, communication, and behavioral deficits and is known to modify the expression of synaptic receptors. We compared the effects of environmental enrichment in the expression of glutamate and endocannabinoid receptors, which are widely expressed in the cerebellar cortex. These two receptors interact to regulate neuronal function and their dysregulation is associated with behavioral changes. We used BTBR + Itpr3tf/J mice, a strain that models behavioral disorders, and C57BL/6 mice for comparison. We studied the effects of genetic background, sex, environmental conditions, and layer of the cerebellar cortex on the expression of each receptor., Results: The influence of genetic background and environmental enrichment had the same pattern on glutamate and endocannabinoid receptors in males. In contrast, in females, the effect of environmental enrichment and genetic background were different than the ones obtained for males and were also different between the glutamate and endocannabinoid receptors. Furthermore, an analysis of both receptors from tissue obtained from the same animals show that their expression is correlated in males, but not in females. Our results suggest that environmental enrichment has a receptor dependent and sexual dimorphic effect on the molecular expression of different receptors in the cerebellar cortex., (© 2022. The Author(s).)

We analyzed the number of cumulative positive cases of COVID-19 as a function of time in countries around the World. We tracked the increase in cases from the onset of the pandemic in each region for up to 150 days. We found that in 81 out of 146 regions the trajectory was described with a power-law function for up to 30 days. We also detected scale-free properties in the majority of sub-regions in Australia, Canada, China, and the United States (US). We developed an allometric model that was capable of fitting the initial phase of the pandemic and was the best predictor for the propagation of the illness for up to 100 days. We then determined that the power-law COVID-19 exponent correlated with measurements of human mobility. The COVID-19 exponent correlated with the magnitude of air passengers per country. This correlation persisted when we analyzed the number of air passengers per US states, and even per US metropolitan areas. Furthermore, the COVID-19 exponent correlated with the number of vehicle miles traveled in the US. Together, air and vehicular travel explained 70% of the variability of the COVID-19 exponent. Taken together, our results suggest that the scale-free propagation of the virus is present at multiple geographical scales and is correlated with human mobility. We conclude that models of disease transmission should integrate scale-free dynamics as part of the modeling strategy and not only as an emergent phenomenological property., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at higher risk of severe coronavirus disease 2019 (COVID-19), and therefore vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behaviour after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A COVID-19 vaccination questionnaire was emailed to participants in May 2021 and 423 participants from 31 countries replied (median age: 30 years, range 1-85 years; 261 (62%) female). Vaccination uptake and willingness were high, with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reason for hesitancy was fear of side effects, reported by 88%. Mild side effects were common, but no participant reported severe side effects. Half of the participants changed their social behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific information and involvement of representatives is important for high vaccine uptake.

In this article, we describe the advances in the field of pediatrics that have been published in the Italian Journal of Pediatrics in 2020. We report progresses in understanding allergy, autoinflammatory disorders, critical care, endocrinology, genetics, infectious diseases, microbiota, neonatology, neurology, nutrition, orthopedics, respiratory tract illnesses, rheumatology in childhood., (© 2021. The Author(s).)