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Abstract Background Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods In this study, 382 infants born at 24+0–27+6 weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. The secondary outcomes are BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0–27+6 weeks’ gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks’ postmenstrual age of life. Trial registration ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Drug delivery carriers are considered an encouraging approach for the localized treatment of disease with minimum effect on the surrounding tissue. Particularly, layer-by-layer releasing particles have gained increasing interest for their ability to develop multifunctional systems able to control the release of one or more therapeutical drugs and biomolecules. Although experimental methods can offer the opportunity to establish cause and effect relationships, the data collection can be excessively expensive or/and time-consuming. For a better understanding of the impact of different design conditions on the drug-kinetics and release profile, properly designed mathematical models can be greatly beneficial. In this work, we develop a continuum-scale mathematical model to evaluate the transport and release of a drug from a microparticle based on an inner core covered by a polymeric shell. The present mathematical model includes the dissolution and diffusion of the drug and accounts for a mechanism that takes into consideration the drug biomolecules entrapped into the polymeric shell. We test a sensitivity analysis to evaluate the influence of changing the model conditions on the total system behavior. To prove the effectiveness of this proposed model, we consider the specific application of antibacterial treatment and calibrate the model against the data of the release profile for an antibiotic drug, metronidazole. The results of the numerical simulation show that ∼85% of the drug is released in 230 h, and its release is characterized by two regimes where the drug dissolves, diffuses, and travels the external shell layer at a shorter time, while the drug is released from the shell to the surrounding medium at a longer time. Within the sensitivity analysis, the outer layer diffusivity is more significant than the value of diffusivity in the core, and the increase of the dissolution parameters causes an initial burst release of the drug. Finally, changing the shape of the particle to an ellipse produces an increased percentage of drugs released with an unchanged release time.

Abstract: Expert guidelines, meta-analyses, and multiple randomized controlled trials have demonstrated the effectiveness of long-acting inhaled antimuscarinic agents (LAMAs) as an additive medication for patients with poorly controlled moderate or severe persistent asthma. LAMAs play an essential role in blocking acetylcholine binding to muscarinic receptors and reducing bronchoconstriction and mucus production. By adding this medication to other combination inhalers, patients can use a triple inhaler to improve FEV1 values and reduce exacerbations., (Copyright © 2025 American Academy of Physician Associates.)

The coffee industry reaches over 80 billion US dollars in revenue partially due to the numerous chemicals that allow for coffee's highly attractive aroma and overall flavor. Many people integrate coffee into their everyday routine; therefore, understanding the attraction to coffee can facilitate, 1) the characterization of its attractive nature, and, 2) allow further understanding of how humans interpret taste and smell on a molecular and cellular level, from initial sensation to higher processing of these complex neural signals. We report that the model worm, C. elegans , can smell and perform strong attraction behavior using chemotaxis towards various types of coffee odors. In this study, we show that the nematode C. elegans is strongly attracted to various forms of coffee. We have also identified neuronal molecules that mediate this sensory-dependent behavior. Overall, we provide a platform to more thoroughly dissect the mechanisms and neuronal circuits that mediate odor-guided behavior to a complex human-sensed stimulus., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

Objective: This study evaluated physician associate/assistant (PA) training and confidence in leadership and leadership skills, as well as where best to incorporate leadership training for the profession., Methods: A quantitative survey was administered to assess PAs' perceptions of leadership and degree of leadership training during their primary PA education. The study also solicited where in the career trajectory leadership training is perceived to be most effective. Of the 284 participants who responded to the survey, 207 had complete responses that were used in the analysis., Results: Nearly 92% of PAs agreed that they aspire to be leaders, and 93.2% agreed or strongly agreed that leadership training would be beneficial during PA school. Additionally, more than 50% of PAs agreed that they had no training but desired more regarding personal mastery, teaching, administration, ideals of a healthy workforce, vision and goal setting, getting results, coalitions, and system transformation., Conclusions: This study demonstrated that PAs desired supplemental training in leadership to cultivate career goals and reported that formal leadership training would be useful to cope with and overcome adversity in clinical practice., (Copyright © 2024 American Academy of Physician Associates.)

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.

Objective: Drug delivery from a drug-loaded device into an adjacent tissue is a complicated process involving drug transport through diffusion and advection, coupled with drug binding kinetics responsible for drug uptake in the tissue. This work presents a theoretical model to predict drug delivery from a device into a multilayer tissue, assuming linear reversible drug binding in the tissue layers., Methods: The governing mass conservation equations based on diffusion, advection and drug binding in a multilayer cylindrical geometry are written, and solved using Laplace transformation. The model is used to understand the impact of various non-dimensional parameters on the amounts of bound and unbound drug concentrations as functions of time., Results: Good agreement for special cases considered in past work is demonstrated. The effect of forward and reverse binding reaction rates on the multilayer drug binding process is studied in detail. The effect of the nature of the external boundary condition on drug binding and drug loss is also studied. For typical parameter values, results indicate that only a small fraction of drug delivered binds in the tissue. Additionally, the amount of bound drug rises rapidly with time due to early dominance of the forward reaction, reaches a maxima and then decays due to the reverse reaction., Conclusions: The general model presented here can account for other possible effects such as drug absorption within the device. Besides generalizing past work on drug delivery modeling, this work also offers analytical tools to understand and optimize practical drug delivery devices., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Research Question: How do clinical rectovaginal examination and transvaginal ultrasound examination perform in the diagnosis of parametrial infiltration in patients with endometriosis?, Design: This was a multicentre prospective observational study. Patients with suspected deep endometriosis at clinical examination and/or at ultrasound evaluation and scheduled for surgery were included. Following multicentre multidisciplinary meetings, consensus was obtained on terms and methodology to define the parametrium at pelvic anatomy, ultrasound and surgery. Sensitivity, specificity, accuracy, and positive and negative likelihood ratios were calculated for clinical and ultrasound examinations with respect to surgery., Results: In total, 195 women were selected for the present study and 164 were included in the analysis. Ultrasound examination had good to high specificity (>80%) for all parameters, except the left lateral parametrium (78.8%). The sensitivity of ultrasound examination was good to high for fixity of the right and left ovaries, uterosacral ligaments, retrocervix and rectovaginal space; and low for the anterior and lateral parametria, vagina, bladder and bowel. Clinical examination had good to high specificity for fixity of the left ovary, anterior parametrium, right uterosacral ligament, retrocervix and vagina; and low specificity for fixity of the right ovary, lateral parametrium, left uterosacral ligament and rectovaginal space. The sensitivity of clinical examination was good for the uterosacral ligaments and rectovaginal space, and low for the remaining parameters., Conclusion: Ultrasound examination provided good specificity for all the parameters, but sensitivity was low for the anterior and lateral parametria. Clinical examination provided good specificity for the anterior and posterior parametria, but sensitivity was low for the anterior and lateral parametria. Further prospective studies are needed to validate this methodology and confirm the results., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Osteosarcoma (OS) is a rare form of primary bone cancer, impacting approximately 3.4 × 10 6 individuals worldwide each year, primarily afflicting children. Given the limitations of existing cancer therapies, the emergence of nanotheranostic platforms has generated considerable research interest in recent decades. These platforms seamlessly integrate therapeutic potential of drug compounds with the diagnostic capabilities of imaging probes within a single construct. This innovation has opened avenues for enhanced drug delivery to targeted sites while concurrently enabling real-time monitoring of the vehicle's trajectory. In this study, we developed a nanotheranostic system employing the layer-by-layer (LbL) technique on a core containing doxorubicin (DOXO) and in-house synthesized carbon quantum dots. By utilizing chitosan and chondroitin sulfate as polyelectrolytes, we constructed a multilayered coating to encapsulate DOXO and docetaxel, achieving a coordinated co-delivery of both drugs. The LbL-functionalized nanoparticles exhibited an approximate size of 150 nm, manifesting a predominantly uniform and spherical morphology, with an encapsulation efficiency of 48% for both drugs. The presence of seven layers in these systems facilitated controlled drug release over time, as evidenced by in vitro release tests. Finally, the impact of the LbL-functionalized nanoparticles was evaluated on U2OS and Saos-2 osteosarcoma cells. The synergistic effect of the two drugs was found to be crucial in inducing cell death, particularly in Saos-2 cells treated with nanoparticles at concentrations higher than 10  μ g/ml. Transmission electron microscopy analysis confirmed the internalization of the nanoparticles into both cell types through endocytic mechanisms, revealing an underlying mechanism of necrosis-induced cell death., Competing Interests: The authors have no conflicts to disclose., (© 2024 Author(s).)

Functionally graded materials (FGMs), possessing properties that vary smoothly from one region to another, have been receiving increasing attention in recent years, particularly in the aerospace, automotive and biomedical sectors. However, they have yet to reach their full potential. In this paper, we explore the potential of FGMs in the context of drug delivery, where the unique material characteristics offer the potential of fine-tuning drug-release for the desired application. Specifically, we develop a mathematical model of drug release from a thin film FGM, based upon a spatially-varying drug diffusivity. We demonstrate that, depending on the functional form of the diffusivity (related to the material properties) a wide range of drug release profiles may be obtained. Interestingly, the shape of these release profiles are not, in general, achievable from a homogeneous medium with a constant diffusivity., Competing Interests: Declaration of competing interest 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. Data accessibility All data supporting this study are provided within the main text., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The aim of this pilot study was to assess whether supplemental psychiatry training in the didactic year increases the scores on the Physician Assistant Education Association (PAEA) Psychiatry and Behavioral Health End of Rotation examination and psychiatry preceptor evaluation., Methods: Data were obtained from the physician assistant (PA) students on PAEA Psychiatry and Behavioral Health End of Rotation examination and psychiatry preceptor evaluation for a single institution. Then, a comparison was performed for PA students who did not participate in supplemental psychiatry/behavioral health training (Cohort 1/historical control group; n = 62) and PA students who participated in supplemental psychiatric and behavioral health training (Cohort 2/experimental group; n = 63) to determine the effects of the groups., Results: An independent t test demonstrated that the experimental group performed significantly better than the control group on both the Psychiatry and Behavioral Health PAEA End of Rotation examination and preceptor evaluation {control group (M = 83.4) and experimental group (M = 86.3; t [117] = 2.8; P < .05)} and the preceptor evaluation {control group (M = 90) and experimental group (M = 92.6; t [112] = 2.1; P < .05)}. In addition, both analyses demonstrated a moderate effect size (End of Rotation examination, d = 0.51; preceptor, d = 0.62). A multiple regression analysis was used to control for age, sex, grade point average (GPA), and training intervention. Age, sex, and GPA were found not to affect the results. However, treatment intervention was statistically significant for both the End of Rotation examination and preceptor evaluation scores., Discussion: Supplemental training in behavioral health and psychiatry, which included a standardized patient encounter and an interactive session dedicated to psychiatry interviewing techniques, resulted in students performing better on the Psychiatry and Behavioral Health PAEA End of Rotation examination and preceptor evaluation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Physician Assistant Education Association.)

Objectives: A high prevalence of eosinophilic esophagitis (EoE) has been reported in children with repaired esophageal atresia (EA). Topical steroids proved to be an effective and safe therapy in EoE, although not approved in pediatrics. We report the results of the first clinical trial of oral viscous budesonide (OVB) performed in children with EoE after repaired esophageal atresia (EoE-EA)., Methods: This open-label, single-arm, phase 2 clinical trial with randomized pharmacokinetic sampling, was conducted at the Bambino Gesù Children's Hospital between September 2019 and June 2021. EoE-EA patients received an age-banded dose of OVB twice daily for 12 weeks and were endoscopically evaluated. The primary endpoint was the rate of patients achieving histological remission. Secondary endpoints included clinical and endoscopic benefit after treatment, and safety assessments., Results: Eight consecutive EA-EoE patients were enrolled (median age 9.1 years, interquartile range 5.5). Of these, 5 received 0.8 mg and 3 received 1.0 mg twice daily of OVB. Histological remission was obtained in all but 1 patient (87.5%). The clinical score showed significant improvement at the end of treatment in all patients. No endoscopic features of EoE were found after treatment. No treatment-emergent adverse event occurred., Conclusion: OVB is an effective, safe, and well-tolerated formulation of budesonide for use in pediatric patients with EoE-EA., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Dissolution of drug from its solid form to a dissolved form is an important consideration in the design and optimization of drug delivery devices, particularly owing to the abundance of emerging compounds that are extremely poorly soluble. When the solid dosage form is encapsulated, for example by the porous walls of an implant, the impact of the encapsulant drug transport properties is a further confounding issue. In such a case, dissolution and diffusion work in tandem to control the release of drug. However, the interplay between these two competing processes in the context of drug delivery is not as well understood as it is for other mass transfer problems, particularly for practical controlled-release considerations such as an encapsulant layer around the drug delivery device. To address this gap, this work presents a mathematical model that describes controlled release from a drug-loaded device surrounded by a passive porous layer. A solution for the drug concentration distribution is derived using the method of eigenfunction expansion. The model is able to track the dissolution front propagation, and predict the drug release curve during the dissolution process. The utility of the model is demonstrated through comparison against experimental data representing drug release from a cylindrical drug-loaded orthopedic fixation pin, where the model is shown to capture the data very well. Analysis presented here reveals how the various geometrical and physicochemical parameters influence drug dissolution and, ultimately, the drug release profile. It is found that the non-dimensional initial concentration plays a key role in determining whether the problem is diffusion-limited or dissolution-limited, whereas the nature of the problem is largely independent of other parameters including diffusion coefficient and encapsulant thickness. We expect the model will prove to be a useful tool for those designing encapsulated drug delivery devices, in terms of optimizing the design of the device to achieve a desired drug release profile., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Myelodysplastic syndromes (MDS) can present as a cytopenia-often as unexplained anemia. Because MDS can progress to acute myelogenous leukemia, primary care providers should be aware of the signs and symptoms, which are associated with the corresponding cytopenia that patients experience and may include fatigue, infection, easy bruising, and bleeding. Treatment options center on managing related cytopenias. The only cure, stem cell transplant, is not readily available., (Copyright © 2023 American Academy of Physician Associates.)

Objective: Direct insertion of the trocar is an alternative method to Veress needle insertion for the creation of pneumoperitoneum. We conducted a systematic review and meta-analysis to compare these two entry closed techniques., Data Source: A systematic review of the literature was done on PubMed, MEDLINE, Embase, Scopus, and EBSCO., Methods: The literature search was constructed until May 01, 2022, around search terms for "Veress," "direct trocar," "needle," "insertion," and "laparoscopic ways of entry." This systematic review was reported according to the PRISMA Statement 2020., Results: Sixteen controlled trials (RCTs) and 5 observational studies were included in the systematic review. We found no significant differences in the risk of major complication during the access manoeuvres between DTI and VN: bowel injuries (OR = 0.76, 95% CI: 0.24-2.36, P = 0.63), major vascular injuries (OR = 1.74, 95% CI 0.56-5.38, P = 0.34), port site hernia (OR = 2.41, 95% CI: 0.28-20.71, P = 0.42). DTI has a lower risk of minor complications such as subcutaneous emphysema (OR = 5.19 95% CI: 2.27-11.87, P < 0.0001), extraperitoneal insufflation (OR = 5.93 95% CI: 1.69-20.87, P = 0.006), omental emphysema (OR = 18.41, 95% CI: 7. 01-48.34, P < 0.00001), omental bleeding (OR = 2.32, 95% CI: 1.18-4.55, P = 0.01), and lower number of unsuccessful entry or insufflation attempts (OR = 2.25, 95% CI: 1.05-4.81, P = 0.04). No significant differences were found between the two groups in terms of time required to achieve complete insufflation (MD =  - 15.53, 95% CI: - 91.32 to 60.27, P = 0.69), trocar site bleeding (OR = 0.66, 95% CI, 0.25-1.79, P = 0.42), and trocar site infection (OR = 1.19, 95% CI, 0.34-4.20, P = 0.78)., Conclusion: There were no statistically significant differences in the risk of major complications during the access manoeuvres between DTI and VN. A lower number of minor complications were observed in DTI compared with those in Veress access., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: infectious mononucleosis is very common during childhood and neurological manifestations are extremely rare. However, when they occur, an appropriate treatment must be undertaken to reduce morbidity and mortality as well as to ensure appropriate management., Methods: we describe the clinical and neurological records of a female patient with post-EBV acute cerebellar ataxia, whose symptoms rapidly resolved with intravenous immunoglobulin therapy. Afterwards, we compared our results with published data., Results: we reported the case of an adolescent female with a 5-day history of sudden asthenia, vomiting, dizziness, and dehydration, with a positive monospot test and hypertransaminasemia. In the following days, she developed acute ataxia, drowsiness, vertigo, and nystagmus with a positive EBV IgM titer, confirming acute infectious mononucleosis. The patient was clinically diagnosed with EBV-associated acute cerebellitis. A brain MRI showed no acute changes and a CT scan showed hepatosplenomegaly. She started therapy with acyclovir and dexamethasone. After a few days, because of her condition's deterioration, she received intravenous immunoglobulin and demonstrated a good clinical response., Conclusions: although there are no consensus guidelines for the treatment of post-infectious acute cerebellar ataxia, early intervention with intravenous immunoglobulin might prevent adverse outcomes, especially in cases that do not respond to high-dose steroid therapy.

Introduction : There is a strong need to conduct rigorous and robust trials for children and adolescents in mental health settings. One of the main barriers to meeting this requirement is the poor recruitment rate. Effective recruitment strategies are crucial for the success of a clinical trial, and therefore, we reviewed recruitment strategies in clinical trials on children and adolescents in mental health with a focus on prevention programs. Methods : We reviewed the literature by searching PubMed / Medline , the Cochrane Library database, and Web of Science through December 2022 as well as the reference lists of relevant articles. We included only studies describing recruitment strategies for pediatric clinical trials in mental health settings and extracted data on recruitment and completion rates. Results : The search yielded 13 studies that enrolled a total of 14,452 participants. Overall, studies mainly used social networks or clinical settings to recruit participants. Half of the studies used only one recruitment method. Using multiple recruitment methods (56.6%, 95%CI: 24.5-86.0) resulted in higher recruitment. The use of monetary incentives (47.0%, 95%CI: 24.6-70.0) enhanced the recruitment rate but not significantly (32.6%, 95%CI: 15.7-52.1). All types of recruitment methods showed high completion rates (82.9%, 95%CI: 61.7-97.5) even though prevention programs showed the smallest recruitment rate (76.1%, 95%CI: 50.9-94.4). Conclusions : Pediatric mental health clinical trials face many difficulties in recruitment. We found that these trials could benefit from faster and more efficient recruitment of participants when more than one method is implemented. Social networks can be helpful where ethically possible. We hope the description of these strategies will help foster innovation in recruitment for pediatric studies in mental health.

Objective: There is increasing interest in simultaneous endovascular delivery of more than one drug from a drug-loaded stent into a diseased artery. There may be an opportunity to obtain a therapeutically desirable uptake profile of the two drugs over time by appropriate design of the initial drug distribution in the stent. Due to the non-linear, coupled nature of diffusion and reversible specific/non-specific binding of both drugs as well as competition between the drugs for a fixed binding site density, a comprehensive numerical investigation of this problem is critically needed., Methods: This paper presents numerical computation of dual drug delivery in a stent-artery system, accounting for diffusion as well as specific and non-specific reversible binding. The governing differential equations are discretized in space, followed by integration over time using a stiff numerical solver. Three different cases of initial dual drug distribution are considered., Results: For the particular case of sirolimus and paclitaxel, results show that competition for a limited non-specific binding site density and the significant difference in the forward/backward reaction coefficients play a key role in determining the nature of drug uptake. The nature of initial distribution of the two drugs in the stent is also found to influence the binding process, which can potentially be used to engineer a desirable dual drug uptake profile., Conclusions: These results help improve the fundamental understanding of endovascular dual drug delivery. In addition, the numerical technique and results presented here may be helpful for designing and optimizing other drug delivery problems as well., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: An elevated heart rate is associated with an increased risk of death or cardiac transplant in children with dilated cardiomyopathy (DCM). Whether heart rate is a clinical marker to address therapy, is poorly investigated in children. Aim: To investigate the relationship between heart rate reduction (HRR) and left ventricular ejection fraction (LVEF) in DCM, treated with carvedilol. Methods: This is a multi center retrospective analysis conducted on all children with DCM (aged <18 years) between 2013 and 2020, with LVEF <40% and treated with carvedilol. Carvedilol was up titrated to the maximal tolerated dose or to 1 mg/kg/day. Echocardiographic data on left ventricular function and dimension were collected. The relationship between HRR and LVEF, left ventricular end-diastolic (LVEDd) and end-systolic diameter (LVESd) was assessed before and after HRR with carvedilol, using regression analysis. Results: 100 patients were enrolled (M: 51%; age 7 ± 8 years). The mean LVEF was 30.2 ± 10% before treatment and 43.7 ± 9.6% after treatment, at the maximum therapeutic dose ( p < 0.0001). There was a positive relationship between HRR and increase in LVEF ( R 2 = 0.06, p = 0.014). A HRR of >20% correlated with an improvement in LVEF >13%. At 3 years follow up, HRR demonstrated a significant reduction of LVESd (R2 = 0.1, p = 0.003) LVEDd (R2 = 0.07, p = 0.008) and LVEF recovery up to 15% ( p < 0.0001). No deaths or heart transplant occurred during follow-up. Conclusion: This study demonstrates that HRR is safe and improvement in LVEF is related to the degree of HRR. The magnitude of LVEF improvement was enhanced by a major reduction in HR. It provides evidence that HRR could be used as a clinical marker to treat HF in children., 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 Adorisio, Pontrelli, Cantarutti, Bellettini, Caiazza, Mencarelli, Limongelli, Poli, Drago, Kirk and Amodeo.)

Objective: Deep infiltrating endometriosis(DIE) of the bowel may require segmental bowel resection. The subsequent reconstruction can be performed through an end-to-end(E-E) or a side-to-end (S-E)anastomosis, the latter being used in low resection due to the reduced risk of anastomotic leakage. This study aims at comparing those two anastomosis techniques in women submitted to bowel resection for DIE, in terms of post-operative morbidity and functional outcomes., Methods: This was a single-center retrospective study on women undergoing laparoscopic rectal resection for deep infiltrating endometriosis with subsequent E-E or S-E anastomosis performed according to the level of rectal resection. The two groups were compared for postoperative complication rates and functional outcomes by means of validated questionnaires., Results: The study population included 30 patients undergoing a S-E anastomosis (group A), and 49 cases undergoing an E-E anastomosis (group B). No differences were found between the two groups in terms of length of hospital stay, anastomotic leakages, protective ileostomies and short-term complications. At follow up no differences were found between the two groups in terms of bowel function and pain symptoms., Conclusions: A S-E anastomosis in case of low rectal resections for DIE presents similar complication rates and functional outcomes compared with an E-E anastomosis., Competing Interests: Declaration of Competing Interest all Authors declare that there is no conflict of interests regarding the publication of this article, (Copyright © 2022. Published by Elsevier Masson SAS.)

Endothelial cell (EC) migration is crucial for a wide range of processes including vascular wound healing, tumor angiogenesis, and the development of viable endovascular implants. We have previously demonstrated that ECs cultured on 15-μm wide adhesive line patterns exhibit three distinct migration phenotypes: (a) "running" cells that are polarized and migrate continuously and persistently on the adhesive lines with possible spontaneous directional changes, (b) "undecided" cells that are highly elongated and exhibit periodic changes in the direction of their polarization while maintaining minimal net migration, and (c) "tumbling-like" cells that migrate persistently for a certain amount of time but then stop and round up for a few hours before spreading again and resuming migration. Importantly, the three migration patterns are associated with distinct profiles of cell length. Because of the impact of adenosine triphosphate (ATP) on cytoskeletal organization and cell polarization, we hypothesize that the observed differences in EC length among the three different migration phenotypes are driven by differences in intracellular ATP levels. In the present work, we develop a mathematical model that incorporates the interactions between cell length, cytoskeletal (F-actin) organization, and intracellular ATP concentration. An optimization procedure is used to obtain the model parameter values that best fit the experimental data on EC lengths. The results indicate that a minimalist model based on differences in intracellular ATP levels is capable of capturing the different cell length profiles observed experimentally., (© 2022. The Author(s).)

Objective: Customization of the rate of drug delivered based on individual patient requirements is of paramount importance in the design of drug delivery devices. Advances in manufacturing may enable multilayer drug delivery devices with different initial drug distributions in each layer. However, a robust mathematical understanding of how to optimize such capabilities is critically needed. The objective of this work is to determine the initial drug distribution needed in a spherical drug delivery device such as a capsule in order to obtain a desired drug release profile., Methods: This optimization problem is posed as an inverse mass transfer problem, and optimization is carried out using the solution of the forward problem. Both non-erodible and erodible multilayer spheres are analyzed. Cases with polynomial forms of initial drug distribution are also analyzed. Optimization is also carried out for a case where an initial burst in drug release rate is desired, followed by a constant drug release rate., Results: More than 60% reduction in root-mean-square deviation of the actual drug release rate from the ideal constant drug release rate is reported. Typically, the optimized initial drug distribution in these cases prevents or minimizes large drug release rate at early times, leading to a much more uniform drug release overall., Conclusions: Results demonstrate potential for obtaining a desired drug delivery profile over time by carefully engineering the drug distribution in the drug delivery device. These results may help engineer devices that offer customized drug delivery by combining advanced manufacturing with mathematical optimization., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We develop a lumped parameter model to describe and predict the mass release of (absorption from) an arbitrary shaped body of any dimension in a large environment. Through the one-to-one analogy between diffusion-dominated mass transfer systems and electrical circuits we provide exact solutions in terms of averaged concentrations and mass released. An estimate of the equivalent resistance and of the release time is also given, and shown to be inversely proportional to the diffusivity. The proposed electrical analogue approach allows a time constant to be defined and provides an easy extension to a multi-layer and multi-phase cases in planar and spherical geometries. The simulation results are compared with those obtained from the solution of the corresponding analytical, numerical and experimental solutions, showing a satisfactory accuracy and a good agreement., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The prediction of drug dissolution profiles is crucial for elucidating the pharmacokinetic behaviour of drugs and the bioavailability of dosage forms. In this work, we develop a mathematical model to describe the dissolution process of irregularly shaped particles. We use a complete dissolution model that accounts for both surface kinetics and convective diffusion. The mechanistic relationship between the mass transfer coefficient and the local curvature is derived from the fundamental physical laws governing these processes. Our model theoretically shows that the dissolution rate depends nonlinearly on the surface curvature. The subsequent recrystallization process in the bulk fluid is also considered. The main result of this work is its simplicity, since only two coupled nonlinear ordinary differential equations are needed to describe the dissolution process. Another remarkable advantage is the possibility to determine the model parameters using common independent techniques, so that the importance of the wettability of solids on the dissolution process can be evaluated. Finally, the proposed model demonstrated the importance of particle shape in describing the experimental dissolution data of theophylline monohydrate., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The objective of this study is to test how certain signs and symptoms related to COVID-19 in children predict the positivity or negativity of the SARS-CoV-2 nasopharyngeal swab in children., Methods: We review the data of children who were tested for SARS-CoV-2 for a suspected infection. We compared the clinical characteristics of the subjects who tested positive and negative, including the sensibility, positive and negative predictive value of different combination of signs and symptoms., Results: Of all the suspected infected, 2596 tested negative (96.2%) and 103 tested positive (3.8%). The median age was 7.0 and 5.3 years for the positive and negative ones, respectively. The female to male ratio was ~1:1.3. Fever and respiratory symptoms were mostly reported. Most positive children had a prior exposure to SARS-CoV-2-infected subjects (59.2%). A total of 99.3% of patients without fever nor exposure to the virus proved negative to the SARS-CoV-2 test., Conclusions: Our study suggests that a child without fever or contact with infected subjects is SARS-CoV-2 negative. If this were to be confirmed, many resources would be spared, with improved care of both COVID-19 and not COVID-19-affected children., Impact: Key message: lack of fever and exposure to SARS-CoV-2-infected people highly predicts a negative results of the SARS-CoV-2 nasopharyngeal swab in the paediatric population. Added value to the current literature: this is the first article to prove this point., Impact: reduction of emergency department accesses of children with suspected SARS-CoV-2 infection; increased outpatient management of children with cough or other common respiratory symptoms of infancy; sparing of many human and material health resources., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Controlled release of a drug contained in a spherical polymer capsule is of significant interest in many fields of medicine. There is growing interest in tailoring the erosion properties of the drug to help control and optimize the drug release process. Theoretical understanding of the nature of drug release from a bioerodible capsule is, therefore, important for designing effective drug delivery systems. While drug release from a fixed-radius capsule is relatively easier to model, the shrinking nature of a bioerodible capsule due to surface erosion presents several difficulties in theoretical modeling. This work presents a closed-form solution for the drug concentration distribution and drug delivery characteristics from a spherical capsule undergoing linear surface erosion. This problem is solved by a transformation that converts the moving boundary problem into a fixed boundary problem. For uniform initial drug distribution, the solution is shown to depend on a single non-dimensional parameter. The theoretical model is used to develop an understanding of the impact of varying the drug diffusion coefficient and rate of erosion on drug delivery characteristics. It is found that, in general, the nature of drug release in a bioerodible sphere is determined by a delicate balance between two simultaneously occurring processes - erosion and diffusion. This work improves the theoretical understanding of diffusion in drug delivery systems by accounting for the practical erosion phenomena, and may contribute towards the design and optimization of drug delivery systems., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Laparoscopic rectosigmoid resection for endometriosis is usually performed with the section of the inferior mesenteric artery (IMA) distal to the left colic artery (low-tie ligation). This study was to determine outcomes in IMA-sparing surgery in endometriosis cases. A single-center retrospective study based on the analysis of clinical notes of women who underwent laparoscopic rectosigmoid segmental resection and IMA-sparing surgery for deep infiltrating endometriosis with bowel involvement between March the 1st, 2018 and February the 29th, 2020 in a referral hospital. During the study period, 1497 patients had major gynecological surgery in our referral center, of whom 253 (17%) for endometriosis. Of the 100 patients (39%) who had bowel endometriosis, 56 underwent laparoscopic nerve-sparing rectosigmoid segmental resection and IMA-sparing surgery was performed in 53 cases (95%). Short-term complications occurred in 4 cases (7%) without any case of anastomotic leak. Preservation of the IMA in colorectal surgery for endometriosis is feasible, safe and enables a tension-free anastomosis without an increase of postoperative complication rates., (© 2022. The Author(s).)

The rate of drug delivery to cells and the subsequent rate of drug metabolism are dependent on the cell membrane permeability to the drug. In some cases, tissue may be composed of different types of cells that exhibit order of magnitude differences in their membrane permeabilities. This paper presents a brief review of the components of the tissue scale three-compartment pharmacokinetic model of drug delivery to single-cell-type populations. The existing model is extended to consider tissue composed of two different cell types. A case study is presented of infusion mediated delivery of doxorubicin to a tumor that is composed of a drug reactive cell type and of a drug resistive cell type. The membrane permeabilities of the two cell types differ by an order of magnitude. A parametric investigation of the population composition is conducted and it is shown that the drug metabolism of the low permeability cells are negatively influenced by the fraction of the tissue composed of the permeable drug reactive cells. This is because when the population is composed mostly of drug permeable cells, the extracellular space is rapidly depleted of the drug. This has two compounding effects: (i) locally there is simply less drug available to the neighboring drug resistant cells, and (ii) the depletion of the drug from the extracellular space near the vessel-tissue interface leaves less drug to be transported to both cell types farther away from the vessel., (Copyright © 2021 Elsevier Ltd. All rights reserved.)