Search

Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

Anecdotally it has been suggested that exposure to some noise sources through leisure activities could have a significant effect on whole-of-life noise exposure. While exposure levels do vary, a typical night club or dance club attendee was found to experience an equivalent continuous A-weighted noise level of around 98 dB for up to 5 hours with an exposure of 12.2 Pa 2 h. This can extend up to 104 Pa 2 h in extreme cases. A study of "clubbers" reveals regular clubbing to be a source of high noise exposure, with a sustained period of regular club attendance contributing to a significant portion of whole-of-life noise exposure.

Our research goal was to use recent advances in global positioning system (GPS) and computer technology to apply just the right amount of fumigant where it is most needed (i.e., in a small target treatment zone in and around each tree replanting site) to control Prunus replant disease (PRD). We developed and confirmed the function of (1) GPS-based software that can be used on cleared orchard land to flexibly plan and map all of an orchard's future tree sites and associated spot fumigation treatment zones and 2) a tractor-based GPS-controlled spot fumigation system to quickly and safely treat the targeted tree site treatment zones. In trials in two almond orchards and one peach orchard, our evaluations of the composite mapping and application system, which examined spatial accuracy of the spot treatments, delivery rate accuracy of the spot treatments, and tree growth responses to the spot treatments, all indicated that GPS spot fumigation has excellent potential to greatly reduce fumigant usage while adequately managing the PRD complex.

As much as one-third of California's almond and stone fruit acreage is infested with potentially debilitating plant parasitic nematodes, and even more of the land is impacted by Prunus replant disease (PRD), a poorly understood soilborne disease complex that suppresses early growth and cumulative yield in replanted almond and peach orchards. Preplant soil fumigation has controlled these key replant problems, but the traditional fumigant of choice, methyl bromide, has been phased out, and other soil fumigants are increasingly regulated and expensive. We tested fumigant and nonfumigant alternatives to methyl bromide in multiple-year replant trials. Costs and benefits were evaluated for alternative fumigants applied by shanks in conventional strip and full-coverage treatments and applied by shanks or drip in novel spot treatments that targeted tree planting sites. Short-term sudangrass rotation and prudent rootstock selection were examined as nonfumigant approaches to managing PRD. Trial results indicated that integrations of the treatments may acceptably control PRD with relatively little soil fumigant.

Background : Temporomandibular disorders (TMDs) represent a prevalent multifactorial condition that impacts a significant portion of the global population. The objective of this study was to employ Fonseca's questionnaire for an initial assessment of TMDs. Methods: A cross-sectional study was conducted on a sample of 250 undergraduates from the Dental School of the University of Perugia, Italy. The chi-square test, with a significance level set at p < 0.05, was used to evaluate a statistically significant relationship between TMDs and several variables such as gender, age, employed/unemployed, and physically active or not. Results: The data obtained through the questionnaire indicated that a considerable percentage of students (78%) exhibited signs consistent with TMDs. The most frequently reported signs and symptoms included psychological stress (49.6%), dental clenching and grinding (34%), joint clicking (33.6%), frequent headaches (15.2%), and neck pain (23.2%). Notably, when considering moderate to severe symptoms of TMDs, females were more significantly affected than males. Furthermore, factors such as age, employment status, and physical activity did not appear to influence the prevalence of TMDs. Conclusions: The high prevalence of TMDs identified within this young population (university students), as measured by this questionnaire (albeit warranting validation through more rigorous methodologies) underscores the necessity for the implementation of new preventive strategies that specifically address this demographic.

Background: MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation., Materials and Methods: Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction., Results: At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response., Conclusions: Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice., Clinical Trial Registration: Eudract No. 2019-001146-17, NCT04028050., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Consolidative thoracic radiotherapy (TRT) has been commonly used in the management of extensive-stage small cell lung cancer (ES-SCLC). Nevertheless, phase III trials exploring first-line chemoimmunotherapy have excluded this treatment approach. However, there is a strong biological rationale to support the use of radiotherapy (RT) as a boost to sustain anti-tumor immune responses. Currently, the benefit of TRT after chemoimmunotherapy remains unclear. The present report describes the real-world experiences of 120 patients with ES-SCLC treated with different chemoimmunotherapy combinations. Preclinical data supporting the hypothesis of anti-tumor immune responses induced by RT are also presented., Methods: A total of 120 ES-SCLC patients treated with chemoimmunotherapy since 2019 in the South of Italy were retrospectively analyzed. None of the patients included in the analysis experienced disease progression after undergoing first-line chemoimmunotherapy. Of these, 59 patients underwent TRT after a multidisciplinary decision by the treatment team. Patient characteristics, chemoimmunotherapy schedule, and timing of TRT onset were assessed. Safety served as the primary endpoint, while efficacy measured in terms of overall survival (OS) and progression-free survival (PFS) was used as the secondary endpoint. Immune pathway activation induced by RT in SCLC cells was explored to investigate the biological rationale for combining RT and immunotherapy., Results: Preclinical data supported the activation of innate immune pathways, including the STimulator of INterferon pathway (STING), gamma-interferon-inducible protein (IFI-16), and mitochondrial antiviral-signaling protein (MAVS) related to DNA and RNA release. Clinical data showed that TRT was associated with a good safety profile. Of the 59 patients treated with TRT, only 10% experienced radiation toxicity, while no ≥ G3 radiation-induced adverse events occurred. The median time for TRT onset after cycles of chemoimmunotherapy was 62 days. Total radiation dose and fraction dose of TRT include from 30 Gy in 10 fractions, up to definitive dose in selected patients. Consolidative TRT was associated with a significantly longer PFS than systemic therapy alone (one-year PFS of 61% vs. 31%, p<0.001), with a trend toward improved OS (one-year OS of 80% vs. 61%, p=0.027)., Conclusion: Multi-center data from establishments in the South of Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy. Considering the limits of a restrospective analysis, these preliminary results support the feasibility of the approach and encourage a prospective evaluation., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Longo, Della Corte, Russo, Spinnato, Ambrosio, Ronga, Marchese, Del Giudice, Sergi, Casaluce, Gilli, Montrone, Gristina, Sforza, Reale, Di Liello, Servetto, Lipari, Longhitano, Vizzini, Manzo, Cristofano, Paolelli, Nardone, De Summa, Perrone, Bisceglia, Derosa, Nardone, Viscardi, Galetta and Vitiello.)

Congenital and pediatric nasal lesion resection and their reconstructive outcomes are not well studied. A surgeon must consider the site, depth, size, age, etiology and effect on future function (including growth). The path of total reconstruction or of portions of the cartilaginous / cutaneous nasal structure in the pediatric patient must undergo a series of totally different needs with respect to the management of the adult. First of all, it is essential to understand at what age to intervene, given that the child in the growth phase up to adolescence sees the nasal skeleton change significantly and in relation to the possible psychological repercussions that the tissue deficit can cause. This path will often require serious interventions in order to recreate a structure that is aesthetically ideal, functionally effective and finally suitable for the growth phase of the rest of the body and facial structures., Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03364-y., Competing Interests: Conflict of interestThe authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript., (© Association of Otolaryngologists of India 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Regulation 2017/625 allows and encourages the use of rating schemes as a means to increase transparency in the agri-food chain. Since its implementation, a need for greater fairness, consistency, transparency, and objectivity in official controls has been reported by member states. The present study compares the results of inspection activities concerning food hygiene principles in ethnic and traditional butcheries. The sample consists of 50 food business activities randomly selected from traditional and ethnic butcheries subject to official control in Turin from January to June 2019. Our objectives were to evaluate the degree of awareness and training of food business operators (FBOs) and to compare the written records drawn up by the competent authorities (CAs) during official inspections to evaluate their completeness and uniformity. The presence of old equipment is a common finding in both traditional and ethnic butchers. This could lead to ineffective cleaning operations and inappropriate functioning, which in turn could lead to a dangerous loss of control over products' temperatures. Ethnic butchers showed a higher number of non-compliances for documentary examination, the presence/correctness of self-control plans, and management aspects such as by-product disposal and personnel hygiene. Training is the key point for both CAs and FBOs; inspectors must maintain their professionalism but also adhere to harmonized and intellectually supported criteria, and FBOs must prevent improper behavior. Eventually, we propose strategies to increase the efficacy and homogeneity of records, together with suggestions on how to implement training both for consultants and operators., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest., (Copyright © 2023, the Author(s).)

This work describes a new methodology used in large scale retail trades in official food safety auditing processes developed during COVID19 emergency. The aim is to evaluate Food Business Operators' (FBOs) Food Safety Management System and its dynamic implementation and to understand the FBO's level of cultural maturity about food safety according to EU Regulation 2021/382. The innovation mainly consists of: a) a pre-audit phase when auditors analyse food business operator's (FBO) selfchecked plan and further documents to identify "markers" and useful evidences (that would be collected in on-site inspections) to evaluate the application of plan by FBO's workers; b) an audit phase consisted of both a check of the company procedures and documents performed by the auditors via web conference and of contextually onsite inspections in a sample of company's supermarkets performed by inspectors teams. The audit methodology here described may be useful, even though it is expensive in terms of time and energy used, for both Competent Authority (CA) and FBOs, regardless of the period of the COVID emergency. The so-structured official control allows the auditors to collect both documentary and on-site evidence at the same time, reaching a broader vision of auditees (not limited to single supermarkets) and a compliant with reality FBOs risk classification. The new approach may give advantages to both audit actors, CA as well as FBO, who may collect "markers" and evidence of the self-checked plan useful to improve FBO's food safety system on the basis of the critical aspects detected during auditing process., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s).)

Non-small cell lung cancer (NSCLC) accounts for 75-80% of all lung cancer cases. Stage III NSCLC represents a highly heterogenous stage characterized by different disease presentations and a wide range of treatment options. For patients with good performance status and unresectable-stage III NSCLC with programmed death-ligands 1 (PD-L1) tumor proportion score (TPS) ≥1%, durvalumab consolidation immunotherapy after a platinum-based chemo-radiotherapy is strongly recommended. However, age, poor performance status, underlying comorbidities may represent contraindications for chemotherapy to be used in a subgroup of patients. Herein, we report a case of an 80-year-old male affected by a stage IIIB lung adenocarcinoma with overexpression of PD-L1 (TPS 90%) treated with pembrolizumab, an immune checkpoint inhibitor targeting PD-1/PD-L1 pathways, which shows a complete resolution of lung lesion after four cycles of treatment. Although randomized controlled trials are required, this case report may suggest the potential role of pembrolizumab for chemotherapy unsuitable patients with overexpressing PD-L1 unresectable-stage III NSCLC.

Lung cancer is the leading cause of cancer-related death worldwide. Since prognosis of early-stage non-small cell lung cancer (NSCLC) remains dismal for common relapses after curative surgery, considerable efforts are currently focused on bringing immunotherapy into neoadjuvant and adjuvant settings. Previously, perioperative chemotherapy showed only a modest but significative improvement in overall survival. The presence of broad tumor neoantigens load at primary tumor prior to surgery as well as the known immunosuppressive status following resection represent the main rationale for immunotherapy in early disease. Several trials have been conducted in recent years, leading to atezolizumab and nivolumab approval in the adjuvant and neoadjuvant setting, respectively, and perioperative immunotherapy in NSCLC remains a field of active clinical and preclinical investigation. Unanswered questions in perioperative therapy in NSCLC include the optimal sequence and timing of chemotherapy and immunotherapy, the potential of combination strategies, the role of predictive biomarkers for patient selection and the choice of useful endpoints in clinical investigation.

Background: Tracheobronchial malignant stenosis is a life-threatening condition which may cause recurrent infections due to lung atelectasis. Despite immunotherapy is less toxic than standard chemotherapy, recurrent lung infections may represent a challenge for this treatment. We report a clinical case of a patient with metastatic squamous cell carcinoma suffering from pulmonary infections due to central airway obstruction who underwent endoscopic recanalization followed by immunotherapy., Case Presentation: A 64 year-old man was referred to our attention for the management of metastatic squamous cell carcinoma obstructing the right main bronchus with recurrent pulmonary infections. Patient exhibited strong positive PD-L1 expression (> 50%). Advanced disease stage contraindicated surgical treatment. Although therapy with immune check point inhibitors was indicated as first-line treatment, recurrent pulmonary infections made it unfeasible. Therefore, we planned a combined approach including endoscopic recanalization of central airway in order to resolve lung atelectasis, and lung infection followed by immunotherapy treatment with pembrolizumab in order to avoid local and systemic disease progression., Conclusions: At 16-week follow-up, the patient was alive in stable disease with improvement of clinical condition and no signs of lung infection.

Background: In the field of oncological assistance, nowadays we have to deal with a complex scenario where patients got used to obtain a huge amount of information through internet or social media and to apply them in performing their health-related decisions. This landscape requires that clinicians become able to handle therapeutical approaches and adequate skills in communication tools to satisfy the current needs. Our project aimed to build a communication model based on clinical oncologists' real experiences in order to find a simple way to share with patients all the innovative therapeutical opportunities today available in lung cancer. The final goal is to design a flexible and personalized model adaptable to clinician's personal characteristics and to the specific patient he is facing. We applied both traditional educational tools and innovative techniques in order to make the results effective and applicable to support peer learning., Methods: The first step consisted in a Board synthesized the definition of the diagnostic process, the identification of treatment strategies and any potential communication barrier clinicians may face dealing with patients. The second step consisted in teamwork including a theoretical part and a training part. In the third step we produce five training videos and video interviews regarding communication praxis and a "Small communication manual". The last step consisted in the publication of the produced material on website and its diffusion through the social media., Results: In medicine, the universal application of a single model of communication does not represent the optimal solution. By contrary, the availability of simple and practical suggestions to improve the communicative style could allow clinicians to abandon stereotyped formulas identically repurposed to all patients. The "from bottom to top" training, starting from real-life to take advantage of the clinician's experience, give the clinicians the possibility to meditate about their own communicative style and to train in the context of a protected environment. Applying these rules, we design an effective communication model, based on healthcare humanization, which could represent a fundamental support for the patient in order to be gently driven by the clinician to the most appropriate therapeutical choice, balancing efficacy and quality of life. The relational training may improve the quality of clinician-patient communication and could be widespread to other clinicians through the media., Conclusions: Considering the innovative therapeutical options available, particularly for lung cancer patients, and the increasing access of health-related information through internet or social media the clinician-patient communication has become crucial to support the achievement of the most appropriate therapeutical choice for the patient, facing the intricate illness experience. Building a shareable and easy-to-apply communication model represents a challenge aimed to help clinicians and including technology not as a threat, but as a positive tool., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.12.32). The series “Targeted Therapy and Non-Small Cell Lung Cancer: A New Era?” was commissioned by the editorial office without any funding or sponsorship. UM served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)

In this report we describe a case of pulmonary epithelioid hemangioendothelioma (PEH) in a young woman. The neoplasm manifested with dry cough, chest pain, finger clubbing, and multiple bilateral pulmonary nodules on chest x-ray and computed tomographic (CT) scan. She underwent thoracoscopy, and the histological features of the lung biopsies were initially interpreted as consistent with a not-well-defined interstitial lung disease. Our patient was clinically and radiologically stable over a period of four years, after which the disease progressed to involve not only the lung but also mediastinal lymph nodes, liver and bone. Fiberoptic bronchoscopy showed subtotal occlusion of the right middle and lower lobe bronchi. The histologic examination of bronchial biopsies revealed a poorly differentiated neoplasm immunohistochemically positive for vimentin and vascular markers CD31, CD34 and Factor VIII. A diagnosis of malignant hemangioendothelioma was made. Positron emission tomography (PET) is more sensitive than CT scan and bone scintigraphy in detecting PEH metastases. Furthermore, 18-fluorodeoxyglucose (FDG) uptake seems to be related to the grade of malignancy of PEH lesions. Therefore, we suggest that FDG-PET should be included in the staging system and follow-up of PEH.

How do student-athletes form opinions? This is a particularly important question given ongoing debates about whether student-athletes should be paid and/or allowed to unionize. These debates concern the rights and benefits accrued directly to student-athletes, and thus, understanding their attitudes is of obvious import. Yet, virtually no recent work has delved into how student-athletes form opinions on these issues. We fill this gap with a theoretical framework that predicts changes in social context alter opinions. This leads to the hypothesis that opinions will change once a student-athlete completes his/her career and finds him/herself in a distinct social network. We test the prediction with a survey, implemented in 2012, of one of the most notable athletic conferences in the National Collegiate Athletic Association (NCAA): the Big Ten. We find that post-career student-athletes demonstrate higher levels of support for pay for play and unionization. Our results suggest that student-athletes' opinions seem to depend on their extant social contexts. While our data, from 2012, neither speak to current opinions - given the quickly evolving landscape of college athletics - nor demonstrate what reforms may be "best," they do accentuate the power of social context in shaping student-athletes' attitudes.

The DNA barcoding proposes the use of a particular sequence from a single genomic region as the base for an identifying system capable to determine all animal species. This methodology comprises the analysis of a 655 base-pair region from the mithocondrial cytochrome C oxidase gene (COI). Its application in the species identification of fishery products has been very promising. However, in the last years some doubts about its usage have emerged. In this work, we make use of the DNA barcoding for the identification of some of the octopus species with higher commercial interest ( Octopus membranaceus , Octopus vulgaris , Octopus aegina , Octopus cyanea ) focusing the attention on the reliability and completeness of the available information on the databases. The study looked over 51 individuals apparently belonging to the Octopus genus. For the identification of O.aegina , O.cyanea, O.vulgaris species no particular problems were found. On the other hand, most of the samples of O.membranaceus , though they clearly presented the morphological characteristics of the species, were not identified with the biomolecular analyses., Competing Interests: the authors declare no potential conflict of interests.

Cellular neural/nonlinear networks (CNNs) are analog dynamic processor arrays, that present local interconnections. CNN models with polynomial interactions among the cells (Polynomial type CNNs) have been recently introduced. They are useful for solving some complex computational problems and for real-time implementation of PDE-based algorithms. This manuscript provides some simple and rigorous sufficient conditions for stability of polynomial type CNNs. A particular emphasis is given to conditions that can be expressed in terms of template elements, since they can be exploited for design purposes.

Fluctuations of mood and psychic activation were assessed in relation to "mobile" and "immobile" periods in 18 patients with Parkinson's disease presenting typical "end-of-dose deterioration". Twelve subjects with chronic but active rheumatoid arthritis presenting increased physical disability due to severe morning joint stiffness with a repetitive pattern of mobile and immobile periods acted as controls. The overall degree of disability and its fluctuations were close enough in the two groups for fair comparison of changes in affective behaviour. Temporary immobility was accompanied by adverse changes of mood and activation, which were significantly more marked in the Parkinson's disease group than in the controls, though to a lesser extent in those Parkinson's disease patients rated depressed even in their mobile periods. The possible correlation between mood changes and fluctuations of central dopaminergic function in the Parkinson's disease patients is discussed.