Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least one F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026). CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

Optical computation of a spin glass dynamics with tunable complexity.

Spin glasses (SGs) are paradigmatic models for physical, computer science, biological, and social systems. The problem of studying the dynamics for SG models is nondetermistic polynomial-time (NP) hard; that is, no algorithm solves it in polynomial time. Here we implement the optical simulation of an SG, exploiting the N segments of a wavefront-shaping device to play the role of the spin variables, combining the interference downstream of a scattering material to implement the random couplings between the spins (the [Formula: see text] matrix) and measuring the light intensity on a number P of targets to retrieve the energy of the system. By implementing a plain Metropolis algorithm, we are able to simulate the spin model dynamics, while the degree of complexity of the potential energy landscape and the region of phase diagram explored are user defined, acting on the ratio [Formula: see text] We study experimentally, numerically, and analytically this Hopfield-like system displaying a paramagnetic, ferromagnetic, and SG phase, and we demonstrate that the transition temperature [Formula: see text] to the glassy phase from the paramagnetic phase grows with α. We demonstrate the computational advantage of the optical SG where interaction terms are realized simultaneously when the independent light rays interfere on the detector's surface. This inherently parallel measurement of the energy provides a speedup with respect to purely in silico simulations scaling with N.

Long-term effects of bronchopulmonary dysplasia on lung function: a pilot study in preschool children's cohort.

INTRODUCTION: Although the long term negative effects of bronchopulmonary dysplasia (BPD) are well known, follow-up studies of preterm infants with BPD into childhood are lacking. METHODS: Forty-two preschool children (age range 3-6 years) who were born before 32 weeks of gestational age and affected by BPD were enrolled. Pre-, peri-, and post-natal data were collected. During the follow up appointment complete physical examination and lung function (impulse oscillometry (IOS)) were recorded. The European Community Respiratory Health Survey (ECRHS) questionnaire was administered to all enrolled subjects. RESULTS: Thirty patients were included in the final analysis. The BPD group did not differ in comparison to the non-BPD group in terms of lung function (p > 0.05). By comparing all subjects enrolled, We detected extremely low-birth-weight (ELBW) infants with height-, weight-, and gender-related reference values and a significant trend of increasing resistance values (R5Hz, R5-20 Hz) and respiratory impedance (Z5Hz) (p < 0.05). No significant difference in bronchial reversibility test was observed among BPD non-BPD groups (p < 0.05). The frequency of gastroesophageal reflux disease was significantly higher in patients with BPD when compared to non-BPD group (p < 0.05). Significant differences in gestational age, oxygen supplementation (days), mechanical ventilation therapy (days), and sepsis between BPD and non-BPD groups were also observed (p < 0.05). There were no significant differences in the prevalence of family and personal history of atopy and/or allergic diseases, tobacco exposure, respiratory symptoms, respiratory syncytial virus bronchiolitis, exercise induced dyspnea, treatment with ß-2 bronchodilators and inhaled corticosteroids among the groups (p > 0.05). CONCLUSIONS: The respiratory function in preschool children born with ELBW is characterized by an increase in impedance and resistance of small airways. No statistically significant differences were found between ELBW children with BPD and without BPD. With regards to the smallest gestational age, the longer duration of O2 therapy during hospitalization, and sepsis significantly resulted in a worse respiratory function.

Scaling Law Describes the Spin-Glass Response in Theory, Experiments, and Simulations.

The correlation length ξ, a key quantity in glassy dynamics, can now be precisely measured for spin glasses both in experiments and in simulations. However, known analysis methods lead to discrepancies either for large external fields or close to the glass temperature. We solve this problem by introducing a scaling law that takes into account both the magnetic field and the time-dependent spin-glass correlation length. The scaling law is successfully tested against experimental measurements in a CuMn single crystal and against large-scale simulations on the Janus II dedicated computer.

Antihistamines in children and adolescents: A practical update.

Histamine is a chemical mediator, released predominantly by tissue mast cells, circulating basophils, and neurons, which are activated in response to various immunological and non-immunological stimuli. Histamine has to bind to specific receptors to exert its physiological and pathophysiological functions. Endogenous histamine is the main mediator of the immediate allergic response, which moreover, performs other multiple functions, including regulation of gastric secretion, neurotransmission in the central nervous system, and immunomodulatory activity. The involvement of histamine in various disorders and the importance of receptors in the clinical features have relevant implications in clinical practice. Anti-H1 antihistamines contrast the histamine-dependent effects, mainly concerning nasal symptoms and cutaneous itching and wheal. Antihistamines are among the most prescribed drugs in pediatric care. This review updates the practical use of antihistamines in children and adolescents.

Non-paraxial design and fabrication of a compact OAM sorter in the telecom infrared.

A novel optical device is designed and fabricated in order to overcome the limits of the traditional sorter based on log-pol optical transformation for the demultiplexing of optical beams carrying orbital angular momentum (OAM). The proposed configuration simplifies the alignment procedure and significantly improves the compactness and miniaturization level of the optical architecture. Since the device requires to operate beyond the paraxial approximation, a rigorous formulation of transformation optics in the non-paraxial regime has been developed and applied. The sample has been fabricated as 256-level phase-only diffractive optics with high-resolution electron-beam lithography, and tested for the demultiplexing of OAM beams at the telecom wavelength of 1310 nm. The designed sorter can find promising applications in next-generation optical platforms for mode-division multiplexing based on OAM modes both for free-space and multi-mode fiber transmission.

Pilot study shows right ventricular diastolic function impairment in young children with obstructive respiratory disease.

AIM: This study determined cardiovascular impairment in young children with obstructive respiratory disease who were assessed using the opening interrupter technique (RINT). METHODS: This pilot study enrolled 41 children who had been referred to pulmonology and allergology specialists at the University of Catania, Italy, from March to July 2017: 23 (mean age 4.13 ± 0.62 years) had chronic coughs and wheezing and 18 controls (mean age 4.27 ± 0.66 years) had obstructive chest disease, but were otherwise healthy. Airway resistance was evaluated using RINT and cardiac function by studying the ejection fraction, pulmonary artery systolic pressure (PASP), tricuspid annular plane systolic excursion and tricuspid flow propagation velocity (TFPV). RESULTS: The RINT and PASP values were significantly higher in the patient group when compared to the controls, but the TFPV values were lower. A direct and significant Spearman's correlation coefficient (r) between RINT and PASP values was observed (r = 0.81). We found a significant inverse correlation between RINT and TFPV (r = -0.83), as well as TFPV and PASP (r = -0.78). CONCLUSION: This study showed that children with obstructive respiratory diseases had a major risk of cardiovascular impairment. Impaired diastolic function of the right ventricle occurred very early when airway resistance was abnormally increased.

Aging Rate of Spin Glasses from Simulations Matches Experiments.

Experiments on spin glasses can now make precise measurements of the exponent z(T) governing the growth of glassy domains, while our computational capabilities allow us to make quantitative predictions for experimental scales. However, experimental and numerical values for z(T) have differed. We use new simulations on the Janus II computer to resolve this discrepancy, finding a time-dependent z(T,t_{w}), which leads to the experimental value through mild extrapolations. Furthermore, theoretical insight is gained by studying a crossover between the T=T_{c} and T=0 fixed points.

Numerical Construction of the Aizenman-Wehr Metastate.

Chaotic size dependence makes it extremely difficult to take the thermodynamic limit in disordered systems. Instead, the metastate, which is a distribution over thermodynamic states, might have a smooth limit. So far, studies of the metastate have been mostly mathematical. We present a numerical construction of the metastate for the d=3 Ising spin glass. We work in equilibrium, below the critical temperature. Leveraging recent rigorous results, our numerical analysis gives evidence for a dispersed metastate, supported on many thermodynamic states.

Matching Microscopic and Macroscopic Responses in Glasses.

We first reproduce on the Janus and Janus II computers a milestone experiment that measures the spin-glass coherence length through the lowering of free-energy barriers induced by the Zeeman effect. Secondly, we determine the scaling behavior that allows a quantitative analysis of a new experiment reported in the companion Letter [S. Guchhait and R. Orbach, Phys. Rev. Lett. 118, 157203 (2017)].PRLTAO0031-900710.1103/PhysRevLett.118.157203 The value of the coherence length estimated through the analysis of microscopic correlation functions turns out to be quantitatively consistent with its measurement through macroscopic response functions. Further, nonlinear susceptibilities, recently measured in glass-forming liquids, scale as powers of the same microscopic length.

In vivo development of daptomycin resistance in vancomycin-susceptible methicillin-resistant Staphylococcus aureus severe infections previously treated with glycopeptides.

Our aim was to describe the clinical and microbiological features of four cases of severe vancomycin-susceptible methicillin-resistant Staphylococcus aureus (MRSA) infections in which the vancomycin non-susceptibility development and daptomycin resistance occurred under therapy with teicoplanin (three cases) and daptomycin switched to vancomycin (one case). Clinical data were retrospectively reviewed. On nine clinical epidemiologically unrelated daptomycin-susceptible (DAP-S) and daptomycin-resistant (DAP-R) MRSA, we performed: (i) DAP-VAN-TEC-CFX-RIF minimum inhibitory concentrations (MICs); (ii) glycopeptide resistance detection (GRD) by δ-hemolysis; (iii) glycopeptide population analysis; (iv) molecular characterization by PFGE-MLST-SCCmec-agr-typing; (v) rpoB and mprF single nucleotide polymorphisms (SNPs); (vi) dltA-mprF-atl-sceD expression by real-time quantitative polymerase chain reaction (qPCR). Three out of the four patients did not survive despite salvage treatment; two died with active MRSA infection and one died because of Stenotrophomonas maltophilia sepsis. The fourth patient, in which a reversion to a DAP-S phenotype occurred, survived with daptomycin plus trimethoprim/sulfamethoxazole and oxacillin treatment, and endovascular device removal. Daptomycin resistance development was preceded by a stable heterogeneous vancomycin-intermediate S. aureus (hVISA) or VISA phenotype acquisition, while in one case, daptomycin resistance was preceded by an unstable daptomycin heteroresistance (hDAP) behavior reverting to DAP-S during vancomycin plus rifampin therapy followed by high doses of daptomycin. All DAP-R strains showed hVISA or DAP-R traits, including mutations and/or up-regulation of genes involved in cell wall turnover and cell membrane perturbation. In our study, daptomycin resistance arose during glycopeptide therapy. The emergence of DAP-R isolates was preceded by a stable VISA or hVISA phenotype or by instability reverting to a DAP-S heteroresistant phenotype. Daptomycin, as first-line therapy for the treatment of severe MRSA infections, should be used at optimal dosage combined with other agents such as beta-lactams, to prevent daptomycin resistance occurrence.

Soft Modes, Localization, and Two-Level Systems in Spin Glasses.

In the three-dimensional Heisenberg spin glass in a random field, we study the properties of the inherent structures that are obtained by an instantaneous cooling from infinite temperature. For a not too large field the density of states g(ω) develops localized soft plastic modes and reaches zero as ω(4) (for large fields a gap appears). When we perturb the system adding a force along the softest mode, one reaches very similar minima of the energy, separated by small barriers, that appear to be good candidates for classical two-level systems.

Mannitol bronchial challenge test in asthmatic children.

Bronchial asthma is a chronic inflammatory disease characterized by bronchial obstruction, usually reversible spontaneously or after therapy, bronchial hyperreactivity and accelerated decrease of lung function that may possibly evolve into irreversible obstruction of the respiratory tract. Bronchial provocation tests can be used in order to assess the presence and degree of bronchial hyper reactivity. The recently introduced mannitol powder inhalation indirect test seems to have an interesting and promising role, especially in childhood, because of its high diagnostic specificity, easiness of execution and best standardization. In this study the authors focused on the significance and clinical use of mannitol bronchial challenge test in asthmatic children.

EXHALED BREATH TEMPERATURE IN ASTHMATIC CHILDREN.

Asthma is characterized by chronic inflammation of airways. Currently, no traditional method allows an easy daily evaluation of the degree of airway inflammation. Measuring inflammatory biomarkers in the breath is a very attractive approach to monitor asthma inflammation. In recent years, the measurement of exhaled breath temperature (EBT) has been proposed as a method capable of detecting the inflammatory status of the airways. The objective of this study is to strengthen the role of EBT in the diagnosis and monitoring of asthma. The study sample was represented by a group of 40 patients, of both sexes, aged 6-15 years. The elective criteria for submitting patients to EBT determination were abstaining from drugs in the preceding 24 h, fasting for at least 2 h, physical resting for at least 30 minutes, a body temperature between 35-37°C. The temperature in the room of the surveys ranged from 18 to 25°C. The EBT values of asthmatic patients were higher [(median (IQR): 29.77°C (30.67°C to 29.38°C) range 28.46°C min-max 34.78°C] than those of non-asthmatic ones (median (IQR): 28.22°C (29.09°C-27.7°C), range 27.09°C min-max 30.07°C] and this difference was highly significant (p less than 0.001). Furthermore, no significant difference was found between the EBT values of the following groups of patients: those exposed and not exposed to passive smoking, those receiving and not receiving leukotriene drugs, those receiving and not receiving specific immunotherapy, monoallergic patients and poliallergic ones, those sensitized and not sensitized to house dust, perennial allergic patients and seasonal allergic ones. In addition, the evaluation of the correlation of EBT values with body temperature (r=0.119, p=0.464) and ambient temperature (r=-304, p = 0.057) did not show any significant correlation. Finally, no statistically significant correlation was demonstrated between EBT values and FEV1 (r=-0055, p=0.81, Fig. 4). In conclusion, the data of the present study further support the hypothesis that EBT can be considered a good method for monitoring asthma.

SERUM YKL-40 IN CHILDREN WITH ASTHMA.

Asthma is one of the most common chronic diseases in children. To date the diagnosis of asthma is mainly clinical, based on the clinical history, a careful physical examination and lung function tests. However, symptoms are often not specific and lung function tests are not very sensitive. In order to find a solution to this problem new biomarkers of airway inflammation are being developed. YKL-40 is a chitinase-like protein that has a role in the inflammation and tissue remodeling in several human diseases. The aim of this study is to evaluate serum levels of YKL40 in children with intermittent or persistent asthma. We performed a cross-sectional analysis of serum samples from a cohort of patients with asthma and healthy controls. Patients with asthma were stratified according to four levels of asthma severity (mild intermittent, mild persistent, moderate persistent, and severe persistent). The analysis of serum samples was performed with the use of a commercially available enzyme-linked immune-adsorbent assay (ELISA) kit (Quidel). The minimum detection limit of the assay for YKL-40 is 15.6 ng per milliliter (ng/ml). Our data showed that circulating YKL-40 levels are significantly higher in patients with asthma than healthy subjects (36±18.6 vs 14:41±2.88, p= 0.001). Furthermore, we found significantly higher values of YKL-40 in both groups of children with intermittent asthma (p less than 0.001) and persistent asthma (p less than 0.001) than healthy controls. However, no correlation was found with duration and severity of asthmatic disease (r = 0:18, p= 0:33, r = 0.28 P = 0:13, respectively). Our data allow us to suggest that YKL-40 represents a useful biomarker of asthma in children with intermittent or persistent asthma.

SAFETY AND EFFICACY OF SUBLINGUAL SPECIFIC IMMUNOTHERAPY TO HOUSE DUST MITE USING A DIFFERENT DOSAGE: A PILOT STUDY.

The aim of this randomized open study was to evaluate the safety and efficacy of different dosages (2000 UI vs 4000 UI) of sublingual immunotherapy (SLIT) in patients with allergic diseases such as asthma associated to rhinitis and rhinoconjunctivitis sensitized to house dust mites. We enrolled 61 patients with a history of allergic asthma, and a positive skin prick test for Dermatophagoides (D.) pteronyssinus/farinae. Patients were randomly assigned to receiving SLIT at dosage of 2000 UI (Group A) or 4000 UI (Group B) maintenance dose. We evaluated: subjective symptoms using a Visual Analogic Scale (VAS), the amount of prescribed symptomatic drugs, bronchial reactivity to methacoline and side effects using a specific questionnaire. A significant improvement in symptoms, assessed by VAS, was observed with both SLIT doses with no significant differences between groups. The provocation dose of methacoline inducing a 20% fall of FEV1 significantly increased after 12 months only in the 4000 UI dose group. In conclusion, both monomeric allergoid dosages of SLIT (2000 UI and 4000 UI) are a safe and efficacy option to reduce symptoms in patients with allergic asthma caused by house dust mites. Moreover, both dosages are efficacious even to protect against airway reactivity but it seems that monomeric allergoid of SLIT at higher dosage (4000 UI) is better than at the lower dosage (2000 UI).

DC current pulses for OTSC clip fragmentation: technology and experimental study.

BACKGROUND: The OTSC clip is used in endoscopic management of gastrointestinal lesions. In rare cases, the removal of the OTSC clip might be desirable. The objective of the study is to investigate feasibility, efficacy, and safety of a novel endoscopic instrument system for removal of the OTSC clip. METHODS: The study series has been conducted in a porcine model. Clip removal is performed with a prototype instrumentation that is designed to locally melt the clip by applying an electrical current pulse onto the clip structure. This system has been evaluated in an animal study (n = 10) in a pig model. A cap prototype with an elongated sleeve has been used for extraction of the OTSC clip fragments. RESULTS: 23 of 24 implanted OTSC clips were successfully opened by applying in a total of 74 current pulses. Superficial mucosal coagulation marks were observed in 14 of the 24 application sites. No other findings such as hemorrhage, deep thermal wall lesions, or perforation were observed. CONCLUSIONS: The study confirms the effectiveness and safety of the proposed endoscopic removal technique. Safe extraction of the clip fragments was feasible with an elongated sleeve at the distal cap. Limitations of the methods are the animal model and the experimental nature of the prototype instrumentation.

Manipulating intensity and phase distribution of composite Laguerre-Gaussian beams.

We propose a method to manipulate the intensity and phase distributions of a beam with non-zero orbital angular momentum (OAM). We investigate the superposition of coherent consecutive OAM modes, with concordant topological charges values, showing that it is possible to predict and control the phase and the radial and angular dimension of the resulting beam by acting on the number of superposed modes (N) and on their minimum value of the OAM (m(min)). A general analysis from the Wigner function formalism is adopted for the geometric characterization of the beam.

Humanisation and health needs in children: present or future?

AIM: For a few years, teledentistry has been an emerging innovative strategy with potential in the field of paediatric dentistry. There are still few studies in this regard, so further research is needed to verify and ensure that teledentistry is not only an accessible mode of communication, but above all effective and evidence-based. This study aimed to use a preliminary telematic approach to promote the compliance of patients in the developmental age during the first dental visit. MATERIALS: Two hundred patients were selected according to the eligibility criteria, and distributed in two groups: a study group with the preliminary telematic approach (ATP) before the first visit and a control group with traditional first visit without ATP. Through an ordinal semi-proportional regression model, the degrees of collaboration between the study and control groups were compared, correcting the estimate for age groups, the presence of systemic pathologies, disorders of cognition, attention and learning, degree of anxiety and previous medical-dental experiences. CONCLUSION: The preliminary telematic approach could be useful as a support to the traditional paediatric dental visit, to promote better management and fidelity of the patient, reducing anxiety and increasing collaboration during the first visit.

Aesthetic perception of patient in developmental age in interceptive orthodontic treatment.

AIM: Patients at development age show considerable attention to the shape of the face from both an aesthetic and relational point of view, to arouse interest from researchers. There are few studies related to profile analysis in patients of developmental age. Therefore, the objective of the present study was to analyse the importance of the aesthetic perception of the patient in development age in relation to the profile, before and after interceptive orthodontic treatment. MATERIALS: A sample of 25 patients who came to our observation for dentoskeletal malocclusions was considered. A questionnaire was proposed to each patient, before and after the interceptive orthodontic treatment (T0 and T1), to evaluate the aesthetic perception before and after the orthodontic treatment and its psychosocial impact. Profile analysis was performed using photographic documentation (at T0 and T1). The variables considered were the Ricketts line, the facial convexity angle, the nasolabial angle, and the labiomental angle. CONCLUSION: Interceptive orthodontic treatment has proven to be of valid clinical and psychological help. This result is confirmed by the complete aesthetic satisfaction of the patient in the frontal and latero-lateral planes.