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Background: Elexacaftor/tezacaftor/ivacaftor (ETI), which is approved for people with cystic fibrosis (pwCF) with a F508del variant, was further approved based on in vitro data in the USA for those carrying at least one of 177 rare CFTR (cystic fibrosis transmembrane conductance regulator) variants., Methods: PwCF, aged ≥6 years, carrying no F508del variant but with at least one of these 177 rare variants, were identified within the US Cystic Fibrosis Foundation Patient Registry (CFFPR) between 2020 and 2022. The evolution of forced expiratory volume in 1 s (FEV 1 ) percentage predicted and rates of pulmonary exacerbations were analysed over the first year following ETI initiation, using a linear regression with generalised estimating equations and a negative binomial model, respectively., Results: A total of 1791 individuals aged ≥6 years with rare CFTR variants were eligible for ETI, corresponding to 5.2% of CFFPR participants. 815 individuals (45.5%), of which 57.9% were already treated with another CFTR modulator, initiated ETI within the first 2 years following approval. Individuals with more severe respiratory disease were more likely to initiate ETI, whereas those previously treated with another CFTR modulator or those with no private insurance coverage had less ETI initiation. ETI initiation was associated with an increase in mean FEV 1 % pred by +3.39 (95% CI 2.14-4.64) and a decrease in the rates of pulmonary exacerbations (adjusted rate ratio 0.55, 95% CI 0.38-0.79). These effects were greater in individuals naïve of previous CFTR modulators., Conclusions: Extension of the ETI label to rare CFTR variants is associated with meaningful improvements in lung function and a marked reduction in pulmonary exacerbations., Competing Interests: Conflict of interest: E.A. Cromwell reports support for the present study from the Cystic Fibrosis Foundation. J.S. Ostrenga has nothing to disclose. D.B. Sanders reports support for the present study from the Cystic Fibrosis Foundation (CFF), grants from the CFF, consultancy fees from the CFF for roles on the Registry Committee, Data Safety Monitoring Board (DSMB) and Grant Review Committee, and participation on a DSMB or Advisory Board with the CFF. W. Morgan reports support for the present study from the Cystic Fibrosis Foundation (CFF) as a paid consultant for work on the CFF Registry Committee, covering a range of activities including papers, analyses and reviews of protocol/data requests; additionally, grants were received from the NIH/NHLBI for the ORBEX study (Site PI and Executive Committee) and the Tucson Children's Respiratory Study, from Boston Children's Hospital/Harvard for consultancy to the PARK study (NIH/NIAID), and from the CFF for Data Safety Monitoring Board (DSMB) infrastructure; consultancy fees were also received from the CFF for DSMB-related activities; payment for lectures was received from the American College of Chest Physicians for the 2022 Pediatric Pulmonology Board Prep Course; support for attending meetings was provided by the CFF for travel to the CFF DSMB meeting in April 2023; participation on a DSMB or Advisory Board includes serving as Chair of the CFF DSMB, chairing several DSMBs for CF clinical research trials and participation on the NIH/NHLBI PRIMERO Observational Study Monitoring Board. C. Castellani reports participation on a Data Safety Monitoring Board or Advisory Board with Vertex and Chiesi. R. Szczesniak reports payment or honoraria for lectures, presentations, manuscript writing or educational events from the Cystic Fibrosis Foundation (CFF) Patient Registry Committee; additionally, support for attending meetings and/or travel was provided by the CFF Patient Registry Committee. P-R. Burgel reports grants or contracts from GSK and Vertex, and consultancy fees from AstraZeneca, Chiesi, GSK, Insmed, MSD, Sanofi, Viatris, Vertex and Zambon., (Copyright ©The authors 2024.)

Introduction: The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial., Aim: The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population., Materials and Methods: A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T 3mo ), 6 months (T 6mo ) and 12 months (T 12mo ) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del)., Results: Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T 3mo and T 6mo , but not at T 12mo , whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly., Conclusion: We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

Isolated musculoskeletal infantile myofibroma is a rare tumor of pediatric age. The majority of cases are seen in children under two years old, but it can occur at any age as a painless enlarging mass that involves bone, skin, or soft tissue, typically accompanied by compression symptoms. Perineural involvement is extremely rare in myofibromas. Neurological impairment can occur during infancy but isolated nerve palsy, particularly in peripheral nerves within the upper extremity, is very uncommon. Neonatal radial nerve palsy is a rare entity caused by different conditions. Among these, we mention local tumors affecting peripheral nerves, such as myofibroma. There are few cases described in the literature, which mainly concern adult patients. The authors present a case of congenital isolated radial nerve palsy in a newborn with MF of the right elbow, which resulted in impairment of the wrist and finger extension. Following a six-month monitoring period, the patient underwent surgical treatment to restore function to his right wrist and hand. This involved excising the infiltrated radial nerve segment associated with palliative surgery. Despite the benignity of this lesion, severe nerve damage and perineural involvement may require surgical treatment with nerve resection and reconstruction.

Background: The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU)., Methods: By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023., Results: Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications., Conclusion: We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US., Competing Interests: Declaration of competing interest Enrico Costa - Member of the Committee for Orphan Medicinal Products (COMP) at the EMA. The views expressed in this article are personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA. Silvia Girotti - None. Clément Mathieu - None. Carlo Castellani – Dr. Castellani has received payment or honoraria for lectures, presentations, speakers or educational events from Vertex Pharmaaceuticals and Chiesi, and he has participated on a Data Safety Monitoring Board or Advisory Board of Vertex Pharmaaceuticals and Chiesi. Joseph S. Ross - Dr. Ross currently receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Food and Drug Administration for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), and from Arnold Ventures; formerly received research support from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST) and from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644); and in addition, Dr. Ross was an expert witness at the request of Relator's attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. that was settled September 2022. Jennifer L. Taylor-Cousar - In the last 36 months, unrelated to this work, she has received grants to her institution from the Cystic Fibrosis Foundation, the National Institutes of Health, Vertex Pharmaceuticals Incorporated, Eloxx, and 4DMT; has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design and participation on advisory boards; and has provided clinical trial design consultation for 4DMT. She served on a DMC for AbbVie. She serves as the adult patient care representative to the CFF Board of Trustees, and on the CF Foundation's Clinical Research Executive Committee, Clinical Research Advisory Board, and as immediate past chair of the CF TDN's Sexual Health, Reproduction and Gender Research Working Group, on the scientific advisory board for Emily's Entourage, and on the ATS Respiratory Health Awards Committee and is the ICC Chair-elect and served previously on the ATS Scientific Grant Review and Clinical Problems Assembly Programming Committees. She is also a member of the International Advisory Board for Lancet Respiratory Medicine and the Editorial Board for the Journal of Cystic Fibrosis. Hubert G. M. Leufkens - None., (Copyright © 2024. Published by Elsevier B.V.)

Cystic fibrosis is a rare genetic disease caused by mutations in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). The discovery of CFTR in 1989 has enabled the unravelling of disease mechanisms and, more recently, the development of CFTR-directed therapeutics that target the underlying molecular defect. The CFTR protein functions as an ion channel that is crucial for correct ion and fluid transport across epithelial cells lining the airways and other organs. Consequently, CFTR dysfunction causes a complex multi-organ disease but, to date, most of the morbidity and mortality in people with cystic fibrosis is due to muco-obstructive lung disease. Cystic fibrosis care has long been limited to treating symptoms using nutritional support, airway clearance techniques and antibiotics to suppress airway infection. The widespread implementation of newborn screening for cystic fibrosis and the introduction of a highly effective triple combination CFTR modulator therapy that has unprecedented clinical benefits in up to 90% of genetically eligible people with cystic fibrosis has fundamentally changed the therapeutic landscape and improved prognosis. However, people with cystic fibrosis who are not eligible based on their CFTR genotype or who live in countries where they do not have access to this breakthrough therapy remain with a high unmet medical need., (© 2024. Springer Nature Limited.)

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NJS reports consulting fees and/or honoraria from Vertex, Chiesi, Gilead and Menarini. KDB reports consulting fees and/or honoraria from Vertex, ELoxx, Splisense and Arcturus. JGM reports honoraria from Vertex, Chiesi, Abbvie and Viatris. PGM reports consulting fees and/or honoraria from Vertex, AstraZenica, Limbic and MedEd. CS reports consulting fees and/or honoraria from Vertex, Chiesi, TFF and Pfizer. JC reports consulting fees for Astrazeneca, Boehringer Ingelheim, Grifols, Gilead sciences, Insmed, Genentech, Glaxosmithkline, Antabio, Zambon and Trudell. OCY reports consulting fees and honoraria from Vertex. DGD reports consulting fees and/or honoraria from Chiesi, Insmed and Vertex. DP reports payments for educational talks. DVD reports consulting fees for Arcturus, Arrevus, BiomX, Clarametyx, CFF, Enbiotix, Microbion, Pyros, Respirion and Zambon. ISG reports honoraria from Vertex. KWS, FB, VV, EDW, MW, EB, DD, PE, EG, GH, AK, DN, JAN, CR, IS, MDW report no personal fees/honoraria, (Copyright © 2024. Published by Elsevier B.V.)

Objective: Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis., Methods: This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA. The Kaplan-Meier method was applied to evaluate the ABA retention rate., Results: This analysis was conducted on 161 patients [male/female 21/140, median age 65 years, interquartile range (IQR) 18.7, median disease duration 169 months, IQR 144.0]. 111 patients (68.9%) received ABA subcutaneously. ABA was associated with methotrexate in 61.9% of patients and was the first biological disease-modifying antirheumatic drug in 41%. We observed a median ABA survival of 66 months [95% confidence interval (CI) 57.3-74.7], with a retention rate of 88% at 6 months and 50.9% at 5 years. Drug survival was significantly higher in patients treated with ABA subcutaneously and in male patients (p=0.039 and p=0.018, respectively). Adjusted for main confounders, female gender was the main predictor of withdrawal (hazard ratio 5.1, 95% CI 1.2-21.3)., Conclusions: Our study shows that better survival is associated with subcutaneous administration and male gender, confirming ABA effectiveness.

Background and Aims: Cystic fibrosis related diabetes (CFRD) is correlated with worsening of nutritional status and greater deterioration of lung function. The role of new technologies for the treatment of CFRD is little explored. The aim of the study was to evaluate the efficacy of Advanced Hybrid Closed Loop (AHCL) systems on glycemic control in CF patients., Methods: A single-center retrospective study on CFRD patients using AHCL systems was performed. Glycated hemoglobin (HbA1c) values and Continuous Glucose Monitoring (CGM) metrics were collected at T0 (AHCL placement), T1 (1-month), T2 (6-months) and T3 (1-year) to evaluate glycemic control., Results: 10 patients were included in the study. Data showed a reduction of HbA1c value (7.31 ± 0.34 to 6.35 ± 1.00; p=0.03), glycemic variability (p=0.05) and insulin requirement (p=0.03). The study population reached American Diabetes Association (ADA) recommended glycemic targets at 1-year. An increase in the Time in Range (TIR) and a reduction in time in hyperglycemia were also observed, although not statistically significant., Conclusions: In patients with CFRD, the use of AHCL leads to an improvement in glycemic control in terms of HbA1c and glycemic variability. The increase in TIR and the reduction of time in hyperglycemia, although not statistically significant, are extremely encouraging from a clinical point of view. Further studies with a larger population and a longer follow-up are needed. The results of this study demonstrate the importance of proposing the use of AHCL even in CF patients, who could benefit from glycemic improvement also in terms of nutritional status and respiratory function., 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 © 2024 Bassi, Franzone, Dufour, Spacco, Cresta, d’Annunzio, Tantari, Calevo, Castellani, Minuto and Casciaro.)

Electromagnetic waves propagating in a layered superconductor with arbitrary momentum, with respect to the main crystallographic directions, exhibit an unavoidable mixing between longitudinal and transverse degrees of freedom. Here we show that this basic physical mechanism explains the emergence of a well-defined absorption peak in the in-plane optical conductivity when light propagates at small tilting angles relative to the stacking direction in layered cuprates. More specifically, we show that this peak, often interpreted as a spurious leakage of the c -axis Josephson plasmon, is instead a signature of the true longitudinal plasma mode occurring at larger momenta. By combining a classical approach based on Maxwell's equations with a full quantum derivation of the plasma modes based on modeling the superconducting phase degrees of freedom, we provide an analytical expression for the absorption peak as a function of the tilting angle and light polarization. We suggest that an all-optical measurement in tilted geometry can be used as an alternative way to access plasma-wave dispersion, usually measured by means of large-momenta scattering techniques like resonant inelastic X-ray scattering (RIXS) or electron energy loss spectroscopy (EELS).

This review aims to reveal the effectiveness of myofunctional speech therapy on facial rejuvenation and/or improvement of orofacial function. A systematic review of four medical electronic databases (Medline, Google Scholar, SciELO, and LILACS) was conducted between January and March 2023. The research question was defined using the PICO model: Population (P): adult subjects with signs of physiological aging of facial skin. Intervention (I): aesthetic speech therapy (facial exercises and/or myofunctional therapy). Control (C): absence of treatment. Outcome (O): facial rejuvenation. Through the search process, a total of 472 potentially relevant articles were identified. A total of 21 studies were included in the review. Most of the studies required the participants to perform exercises learned during the weekly session on a daily basis. The subjects underwent an integrated treatment with facial exercises and worked on the stomatognathic functions for different durations. Many differences were found in the evaluation tools used to investigate the starting situation and the effects obtained following the treatment. At the diagnostic level, there was no concordance in the choice of the most appropriate scales and assessment tools, but great heterogeneity was observed. Indeed, forty-eight percent of the studies collected objective data through the use of various instruments (oral devices, electromyographs, cutometers, muscle ultrasound scans, and laser scans of the face). The observed improvements included not only a reduction in wrinkles and frown lines but also decreased muscle tension and slackness, enhanced facial symmetry and lip competence, improved skin elasticity, and restored stomatognathic function. These changes led to myofunctional restoration and facial rejuvenation, resulting in increased satisfaction with self-image and proprioception.

Background: Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (N 2 MBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (S acin *VT)., Methods: For this randomized, sham-controlled crossover trial, two N 2 MBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH 2 0) or a sham (<5 cmH 2 0) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the N 2 MBW operators were blinded to treatment allocation. Study outcomes were assessed with mixed-effect models., Results: The study sample was 19 cwCF (ten girls), aged 11.4 (2.7) years. The adjusted S acin *VT mean difference between the standard and the sham procedure was -0.015 (90% confidence interval [CI]: -∞ to 0.025) L -1 . There was no statistically significant difference in S cond *VT and lung clearance index between the two procedures: -0.005 (95% CI: -0.019 to 0.01) L -1 and 0.49 (95% CI: -0.05 to 1.03) turnovers, respectively., Conclusion: Our findings do not support evidence for an immediate effect of PEP mask physiotherapy on S acin *VT with pressure range 10-15 cmH 2 0. Measurement with the N 2 MBW and the crossover design were found to be time-consuming and unsuitable for a short-term study of airway clearance techniques., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders., 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., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Actions to strengthen climate resilience are gaining more traction. In order to ensure effective adaptation, it is important to monitor the outcomes and impacts of these actions. However, there are numerous challenges and a multitude of approaches when it comes to monitoring adaptation to climate change. This paper addresses challenges in setting up mechanisms for monitoring climate resilience and adaptation projects. Drawing from three EU Horizon 2020 projects under the EU Mission on Adaptation to Climate Change, it synthesizes challenges and insights to support future initiatives in their monitoring endeavors for other projects to learn from. Findings, acquired through workshops with experts who shared learnings and challenges, highlight four key themes: the challenge of tailoring global frameworks to local needs, data availability and evaluation of data, interdisciplinary collaboration in monitoring, and stakeholder engagement for monitoring endeavors., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Bilgram S et al.)

Background: Thrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical thrombectomy, estimate the age and organization of thrombi, and evaluate associations with the use of thrombolysis, antiplatelets, and heparin., Methods: This retrospective observational study involved 72 samples (44 from cerebral and 28 coronary arteries), which were stained with hematoxylin and eosin, anti-NE (neutrophil elastase) antibody, and anti-histone H2B (histone H2B) antibody, representing different components in NET formation, all detectable during the later stages of NETosis, for histochemical and digital quantification of NET content. The histological and morphological evaluations of the specimens were correlated, through univariate and mediation analyses, with clinical information and therapy administered before intervention., Results: The results demonstrated that the composition of cerebral and coronary thrombi differs, and there were significantly more lytic cerebral thrombi than coronary thrombi (66% versus 14%; P =0.005). There was a considerably higher expression of NETs in the cerebral thrombi as testified by the higher expression of H2B ( P =0.031). Thrombolysis was remarkably associated with higher NE positivity (average marginal effect, 6.461 [95% CI, 0.7901-12.13]; P =0.02555), regardless of the origin of thrombi. There was no notable association between the administration of antiaggregant therapy/heparin and H2B/NE amount when adjusted for the thrombus location. Importantly, the age of the thrombus was the only independent predictor of NET content without any mediation of the thrombolytic treatment ( P =0.014)., Conclusions: The age of the thrombus is the driving force for NET content, which correlates with impaired clinical outcomes. The therapy that is currently administered does not modify NET content. This study supports the need to investigate new pharmacological approaches added to thrombolysis to prevent NET formation or enhance their disruption, such as recombinant human DNase I (deoxyribonuclease I)., Competing Interests: Disclosures None.

Background: Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. We collected clinical, genetic and laboratory data of seven cases of biopsy-proven renal involvement by WM managed at our academic center and focused on three cases we judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options., Case: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. In our series AL Amyloidosis (n = 3/7) and tubulo-interstitial infiltration by lymphoma cells (n = 3/7) were the two more represented entities. BTKi did not seem to improve renal function (Case 1), while bortezomib-based regimens demonstrated a beneficial activity on the hematological and organ response, even when used as second-line therapy after chemoimmunotherapy (Case 3) and also with coexistence of anti-MAG neuropathy (Case 2). In case of poor response to bortezomib, standard chemoimmunotherapy (CIT), such as rituximab-bendamustine, represents an effective option (Case 1, 6, and 7). In our series, CIT generates durable responses more frequently in cases with amyloidogenic renal damage (Case 1, 5, and 7)., Conclusion: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. Studies with higher numerosity are needed to better clarify the pathological and clinical features of renal involvement during WM and to determine the potential benefit of different therapeutic regimens according to the histopathological subtypes., (© 2024 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Although cystic fibrosis (CF) standards of care have been produced and regularly updated, they are not specifically targeting at the adult population. The ECFS Standards of Care Project established an international task force of experts to identify quality standards for adults with CF and assess their adherence., Methods: This study was composed of two phases. In the first one, a task force of international experts derived from published guidelines and graded ten quality standards for adult CF care using a modified Delphi methodology. In the second phase, an international audit was conducted among adult CF centers to retrospectively validate the quality statements and monitor adherence., Results: The task force identified 10 quality standards specific to the care of adults with CF, mainly based on the 2018 ECFS standards of care. 14 adult CF centers participated in the audit, which showed that most quality standards for the management of CF in adults are met across Europe. Heterogeneity in adherence to standards was found across centers according to geographical setting and centers' characteristics., Conclusions: The identification of quality standards is a valuable resource for the standardization and monitoring of care delivery across centers taking care of adults with CF., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to this work., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Aim: To assess whether patients born with an abdominal wall defect (AWD) have impaired cardiorespiratory performance capacity, motor skills, core stability or quality of life in a long-term follow up., Methods: Patients diagnosed with AWD between 2002 and 2013 were invited to participate in the study, which included clinical examination, spirometry, cardiopulmonary exercise performance testing, assessment of motor activity, ultrasound, electromyography of the abdominal wall and assessment of the Gastrointestinal Quality of Life Index (GIQLI). The results were compared to a healthy control group matched for age, sex, BMI, and physical activity levels., Results: In total, 18 AWD patients (mean age 12.6 ± 3.5 years) were included and there were no significant differences in anthopometric data compared to the control group (n = 18). AWD patients had a significantly lower GIQLI score (AWD mean 137.2 ± 6.8 vs. control mean 141.4 ± 4.9; p = 0.038) and were affected by decreased motor abilities with significantly higher Dordel-Koch-Test values (AWD median 3.54/IQR 1 vs. control median 2.8/IQR 1; p = 0.005)., Conclusion: Follow-up examinations of AWD patients revealed decreased motor abilities and GIQLI scores while cardiopulmonary function was not different compared to healthy controls. The clinical impact of these findings remains to be elucidated., Impact: Clinical examination, assessment of the gastrointestinal quality of life, sport medical testing, electromyography and abdominal wall ultrasound were performed in patients with congenital abdominal wall defect and compared to an age and sex matched healthy control group. Results of spirometry and spiroergometry, ultrasound or electromyography did not significantly differ between the groups. Significantly decreased locomotor function and gastrointestinal quality of life were found in patients with abdominal wall defect. However, the clinical impact of these findings remains to be elucidated., (© 2023. The Author(s).)

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Determining the cause of interstitial lung disease (ILD) remains challenging. While surgical lung biopsy remains the gold standard approach, risks associated with it may be prohibitive. Transbronchial lung cryobiopsy (TBLC) is a minimally invasive alternative with an improved safety profile and acceptable diagnostic accuracy. We retrospectively assessed whether the use of Cone Beam computed tomography guidance for TBLC (TBLC-CBCT) improves safety and diagnostic yield compared to performing TBLC with fluoroscopic guidance (TBLC-F)., Methods: A retrospective cohort review of 120 patients presenting for evaluation of newly diagnosed ILD was performed. Demographic data, pulmonary function test values, chest imaging pattern, procedural information, and final multidisciplinary discussion (MDD) diagnosis were recorded., Results: 62 patients underwent TBLC-F and 58 underwent TBLC-CBCT. Patients undergoing TBLC-CBCT were older (67.86 ± 10.97 vs 61.45 ± 12.77 years, p = 0.004) and had a higher forced vital capacity percent predicted (73.80 ± 17.32% vs 66.00 ± 17.45%, p = 0.03) compared to the TBLC-F group. The average probe-to-pleura distance was 5.1 ± 2.3 mm in the TBLC-CBCT group with 4.0 ± 0.3 CBCT spins performed. Pneumothorax occurred more often in the TBLC-F group (n = 6, 9.7%) compared to the TBLC-CBCT group (n = 1, 1.7%, p = 0.06). Grade 2 bleeding only occurred in the TBLC-F group (n = 4, 6.5%). A final MDD diagnosis was obtained in 89% (n = 57) of TBLC-F patients and 95% (n = 57) of TBLC-CBCT patients., Conclusions: TBLC-CBCT appears to be safer compared to TBLC-F with both approaches facilitating an MDD diagnosis. Further studies from multiple institutions randomizing patients to each modality are needed to confirm these findings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy., Competing Interests: Declaration of competing interest KWS has no competing interests. See supplementary materials for full CoI statements for all authors., (Copyright © 2023. Published by Elsevier B.V.)

This project of Health technology assessment was aimed at defining the impacts of offering a cystic fibrosis (CF) carrier screening to the general population, compared to the current situation, where the test is offered to individuals at high-risk to give birth to a child with CF. Results revealed: i) a lack of robust and updated data; ii) a return on investment up to six years from the screening's introduction, despite important economic and organizational efforts; iii) a general positive attitude of healthcare professionals, people with CF, families and general population; iv) possible issues related to the social impact.

Human papilloma virus (HPV) is known as the main cause of cervical cancer. Data also indicate its role in head-neck cancer, especially oropharyngeal cancer. The correlation between high-risk HPV and oral cancer is still controversial. HPV-related lesions of the oral cavity are frequent and, in most cases, benign. The primary aim of this study was to establish if there is a different follow-up necessity between HPV-positive compared to HPV-negative oral lesions. The secondary aim was to evaluate the recurrence of HPV-related lesions. All patients who underwent a surgical procedure of oral biopsy between 2018 and 2022, with ulterior histopathological examination and HPV typing, were examined. A total of 230 patients were included: 75 received traumatic fibroma as diagnosis, 131 HPV-related lesions, 9 proliferative verrucous leukoplakia, and 15 leukoplakia. The frequency and period of follow-up varied in relation to HPV positivity and diagnosis. This study confirms what has already been reported by other authors regarding the absence of recommendations of follow-up necessity in patients with oral mucosal lesions. However, the data demonstrate that there was a statistically significant difference in the sample analyzed regarding the follow-up of HPV-positive vs. HPV-negative patients. It also confirms the low recurrence frequency of HPV-related oral lesions., Competing Interests: The authors declare no conflicts of interest.

Repeated European surveys of newborn bloodspot screening (NBS) have shown varied strategies for collecting missed cases, and information on data collection differs among countries/regions, hampering data comparison. The ECFS Neonatal Screening Working Group defined missed cases by NBS as either false negatives, protocol-related, concerning analytical issues, or non-protocol-related, concerning pre- and post-analytical issues. A questionnaire has been designed and sent to all key workers identified in each NBS programme to assess the feasibility of collecting data on missed cases, the stage of the NBS programme when the system failed, and individual patient data on each missed case.

There is considerable activity with respect to diagnosis in the field of cystic fibrosis (CF). This relates primarily to developments in newborn bloodspot screening (NBS), more extensive gene analysis and improved characterisation of CFTR-related disorder (CFTR-RD). This is particularly pertinent with respect to accessibility to variant-specific therapy (VST), a transformational intervention for people with CF with eligible CFTR gene variants. This advance reinforces the need for a timely and accurate diagnosis. In the future, there is potential for trials to assess effectiveness of variant-specific therapy for CFTR-RD. The guidance in this paper reaffirms previous standards, clarifies a number of issues, and integrates emerging evidence. Timely and accurate diagnosis has never been more important for people with CF., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: The most recent modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta ® ), has been shown to improve clinical outcomes in most patients with cystic fibrosis (PwCF). Unfortunately, the clinical benefits are sometimes variable; thus, improving our knowledge of the possible causes of this variability can help reduce it., Methods: Circulating mononuclear cells (CMCs) and plasma were collected from 16 PwCF (including those on Trikafta ® therapy) and 4 non-CF subjects. Cystic fibrosis transmembrane conductance regulator (CFTR) activity and matrix metalloprotease 9 (MMP9) expression were monitored before and after therapy, together with some clinical parameters. The relationship between MMP9 expression and the modulation of the extracellular-regulated 1/2 (ERK1/2) and nuclear factor-kB (NF-kB) pathways was also analyzed., Results: MMP9, markedly expressed in the CMCs and plasma of all the patients included in the study, was downregulated in the clinically responsive PwCF. In the non-responder, the MMP9 levels remained high. The modulation of MMP9 following treatment with Trikafta ® may be controlled by the NF-kB pathway., Conclusions: These data strongly suggest that MMP9 downregulation is a potential biomarker of therapy efficacy and that it could be useful in understanding the molecular events underlying the variable clinical responses of patients to Trikafta ® . This knowledge could be helpful for future studies of personalized medicine and thereby ensure improvements in individual responses to therapies.

Cancer therapy is often associated with severe side effects such as drug induced weight loss, also known as chemotherapy-induced cachexia. The aim of this study was to investigate the effects of a multispecies probiotic (OMNi-BiOTiC ® 10 AAD) in a chemotherapy mouse model. A total of 24 male BALB/c mice were gavage-fed with the probiotic formulation or water, once a day for 3 weeks. In the third week, the mice received intraperitoneal cyclophosphamide. At euthanasia, the organs were dissected, and serum was sampled for cytokine analysis. Tight junction components, myosin light chain kinase, mucins, and apoptosis markers were detected in the ileum and colon using histological analyses and qRT-PCR. Lipolysis was analyzed by enzymatic activity assay, Western blotting analyses, and qRT-PCR in WAT. The fecal microbiome was measured with 16S-rRNA gene sequencing from stool samples, and fecal volatile organic compounds analysis was performed using gas chromatography/mass spectrometry. The probiotic-fed mice exhibited significantly less body weight loss and adipose tissue wasting associated with a reduced CGI58 mediated lipolysis. They showed significantly fewer pro-inflammatory cytokines and lower gut permeability compared to animals fed without the probiotic. The colons of the probiotic-fed animals showed lower inflammation scores and less goblet cell loss. qRT-PCR revealed no differences in regards to tight junction components, mucins, or apoptosis markers. No differences in microbiome alpha diversity, but differences in beta diversity, were observed between the treatment groups. Taxonomic analysis showed that the probiotic group had a lower relative abundance of Odoribacter and Ruminococcus-UCG014 and a higher abundance of Desulfovibrio . VOC analysis yielded no significant differences. The results of this study indicate that oral administration of the multispecies probiotic OMNi-BiOTiC ® 10 AAD could mitigate cyclophosphamide-induced chemotherapy side effects.

Introduction: Nonvalvular atrial fibrillation (NVAF) is a highly prevalent arrhythmia where loss of synchronized atrial contraction increases the risk of intracardiac thrombus particularly within the left atrial appendage (LAA). Anticoagulation is the mainstay of stroke prevention based on the CHA 2 DS 2 -VASc score; however, it does not account for LAA structural characteristics., Methods: The research comprises a retrospective matched case-control study of 196 subjects with NVAF who underwent transesophageal echo (TEE). The control group, without thrombus (n = 117), was selected from two different groups, both pools had: NVAF and CHA 2 DS 2 -VASc score ≥ 3. One group underwent screening TEE before Watchman closure device placement from January 2015 to December 2019 (n = 74) the second underwent TEE before cardioversion from February to October 2014 (n = 43). The study group, with thrombus (n = 79), included patients with NVAF, TEE study performed between February 2014 and December 2020, and LAA thrombus. The propensity score method was utilized to determine the matched controls while accounting for confounding from prognostic variables resulting in 61 matched pairs included in the analysis data set. LAA ostial area (OA) (calculated from orthogonal measurements 0°, 90° or 45°, 135°), LAA maximal depth, and peak LAA outflow velocity were measured., Results: Patient characteristics and TEE data were collected and compared using the t test or χ 2 analysis. We observed a lower LAA peak exit velocity in the thrombus group as compared to the control group. Additionally, we found that patients in the thrombus group had smaller LAA OA at 0° and 90°, at 45° and 135°, using largest diameter, as well as using aggregate OA, and smaller maximum LAA depth compared to patients in the control group. Candidate conditional logistic regression models for the outcome of the presence of thrombus were evaluated. Statistical results from the best-fitting conditional regression model were calculated showing a significant association between aggregate OA and LAA exit velocity with presence of thrombus., Conclusion: Utilizing LAA structural characteristics to predict thrombus formation may help refine current cardioembolic stroke (CES) risk estimation., (© 2023 Wiley Periodicals LLC.)

Psoriatic arthritis (PsA) is a chronic inflammatory condition characterized by psoriasis, synovitis, enthesitis, spondylitis, and the possible association with other extra-articular manifestations and comorbidities. It is a multifaceted and systemic disorder sustained by complex pathogenesis, combining aspects of autoinflammation and autoimmunity. Features of PsA autoinflammation include the role of biomechanical stress in the onset and/or exacerbation of the disease; the evidence of involvement of the innate immune response mediators in the skin, peripheral blood and synovial tissue; an equal gender distribution; the clinical course which may encounter periods of prolonged remission and overlapping features with autoinflammatory syndromes. Conversely, the role of autoimmunity is evoked by the association with class I major histocompatibility complex alleles, the polyarticular pattern of the disease which sometimes resembles rheumatoid arthritis and the presence of serum autoantibodies. Genetics also provide important insights into the pathogenesis of PsA, particularly related to class I HLA being associated with psoriasis and PsA. In this review, we provide a comprehensive review of the pathogenesis, genetics and clinical features of PsA that endorse the mixed nature of a disorder at the crossroads of autoinflammation and autoimmunity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: No data are available on the values and role of lung clearance index (LCI) in cystic fibrosis (CF) Screen Positive Inconclusive Diagnosis (CFSPID) progressed to CF diagnosis (CFSPID > CF). This study aimed to assess the value of the LCI in correctly predicting the progression of CFSPID to CF., Methods: This is a prospective study carried out at the CF Regional Center of Florence, Italy from September 1, 2019. We compared LCI values in children with CF diagnosed for positive newborn screening (NBS), CFSPID or CFSPID > CF for pathological sweat chloride (SC). The Exhalyzer-D (EcoMedics AG, Duernten, Switzerland, software version 3.3.1) was used to conduct the LCI tests, every 6 months on stable children., Results: Forty-two cooperating children were enrolled (mean age at LCI tests: 5.4 years, range: 2.7-8.7): 26 (62%) had CF, 8 (19%) were CFSPID > CF for positive SC, while 8 (19%) kept the CFSPID label at last LCI test. The mean LCI value for patients with CF (7.39; 5.98-10.24) was statistically higher compared to both the mean LCI in the CFSPID > CF (6.62; 5.69-7.58) and in CFSPID (6.56; 5.64-7.21)., Conclusions: Most of asymptomatic CFSPID or progressed to CF have normal LCI. Further data on the longitudinal course of LCI during follow up of CFSPID and on larger cohorts is needed., (© 2023 Wiley Periodicals LLC.)

Background: genetic testing for cystic fibrosis (CF) has been offered to people with higher risk of being carrier., Objectives: to assess the effectiveness of population-based CF carrier screening for adults of reproductive age and its optimal organizational features., Design: systematic review., Setting and Participants: MedLine, Embase, Cochrane Library, CINAHL and LILACS (1990-2022) were searched to retrieve primary and secondary studies on adults (16 years and older), with no clinical indication or genetic risk, eligible for genetic testing for CF carrier status., Main Outcomes Measures: attitude to screening, uptake of screening offered, informed reproductive choices., Results: a total of 3,326 records were screened and 292 potentially eligible full-text publications assessed. The review included 71 publications, corresponding to 3 reviews, 40 cohort studies (11 comparative, 29 single-arm), and 6 model studies, published between 1992 and 2021 (median 1998). Only one study compared screening or no screening. This study suggested an association between carrier screening and a lower incidence of CF. Comparative studies examined different approaches for invitation and testing, i.e., settings, target population (individuals/couples, prenatal/preconceptional), how invitations are organized (primary care/maternal hospitals), and format and content of the pre-test information. However, no firm conclusions can be drawn on the impact of these features on informed reproductive choices, uptake, and attitude, because of the limitations of the evidence collected., Conclusions: the broad heterogeneity of the studies, methodological weaknesses, and the limited transferability of the results mean there is still uncertainty about the effectiveness of preconceptional and prenatal CF carrier screening in the general population.

Dilated Cardiomyopathy is a common myocardial disease characterized by dilation and loss of function of one or both ventricles. A variety of etiologies have been implicated including genetic variation. Advancement in genetic sequencing, and diagnostic imaging allows for detection of genetic mutations in sarcomere protein titin (TTN) and high resolution assessment of cardiac function. This review article discusses the role of cardiac MRI in diagnosing dilated cardiomyopathy in patients with TTN variant related cardiomyopathy., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Background: Diagnosing interstitial lung disease (ILD) remains challenging. Guidelines recommend utilizing a multidisciplinary discussion (MDD) to review clinical and radiographic data and if diagnostic uncertainty persists, then to obtain histopathology. Surgical lung biopsy and transbronchial lung cryobiopsy (TBLC) are acceptable methods, but risks of complications may be prohibitive. The Envisia genomic classifier (EGC) represents another option to determine a molecular usual interstitial pneumonia (UIP) signature to facilitate an ILD diagnosis at MDD with high sensitivity and specificity. We evaluated the concordance between TBLC and EGC at MDD and the safety of this procedure., Methods: Demographic data, pulmonary function values, chest imaging pattern, procedural information, and MDD diagnosis were recorded. Concordance was defined as agreement between the molecular EGC results and histopathology from TBLC in the context of the patient's High Resolution CT pattern., Results: 49 patients were enrolled. Imaging demonstrated a probable (n = 14) or indeterminate (n = 7) UIP pattern in 43% and an alternative pattern in 57% (n = 28). EGC results were positive for UIP in 37% (n = 18) and negative in 63% (n = 31). MDD diagnosis was obtained in 94% (n = 46) with fibrotic hypersensitivity pneumonitis (n = 17, 35%) and IPF (n = 13, 27%) most common. The concordance between EGC and TBLC at MDD was 76% (37/49) with discordant results seen in 24% (12/49) of patients., Conclusions: There appears to be reasonable concordance between EGC and TBLC results at MDD. Efforts clarifying the contributions of these tools to an ILD diagnosis may help identify specific patient populations that may benefit from a tailored diagnostic approach., Competing Interests: Declaration of Competing Interest Part of this study was presented as an abstract at the American Thoracic Society annual meeting, May 2021. JSK reports consulting and speaking fees from Veracyte. All other authors report no conflicts of interest., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)

Hand fractures represent commonly encountered injuries in pediatric patients. However, due to modern means of mobility and product safety, the occurrence and distribution of these fractures have changed during the last decades. Therefore, it was the aim of this study to present an update of the epidemiology, pattern, and treatment of hand fractures in a large pediatric cohort. All patients aged between 0 and 17 years treated in our Department in 2019 with fractures of the phalanges, metacarpus, or carpus were included. The medical records were reviewed for age, gender, injury mechanism, fracture localization, season, and treatment. Patients were divided into three different age groups (0-5, 6-12, and 13-17 years). A total of 731 patients with 761 hand fractures were treated during the 1-year study period. The mean age was 11.1 ± 3.5 years, and the majority was male (65%). Male patients were significantly older compared to female patients (p = 0.008). Also, 78.7% of the fractures affected the phalanges, 17.6% the metacarpals, and 3.7% the carpal bones. The proximal phalanges were the most commonly fractured bones (41.5%). Patients with fractures of the carpus were significantly older compared to children sustaining fractures of the metacarpus or phalangeal bones (p < 0.001). Sixteen percent of our patients were treated surgically; these patients were significantly older compared to conservatively treated patients (p = 0.011).  Conclusion: The epidemiology, mechanisms of injury, distribution, and treatment of hand fractures significantly varies among different age groups. This knowledge is of importance for educational purposes of younger colleagues entrusted with care of children and adolescents as well as development of effective prevention strategies. What is Known: • Pediatric hand fractures represent the second most common fractures in children. • The epidemiology of pediatric hand fractures has changed during the last decades and therefore there is a need for an update regarding distribution and epidemiology of pediatric hand fractures. What is New: • In this retrospective cohort study, 761 pediatric hand fractures of 731 patients were analyzed in detail. • The main mechanisms of younger patients were entrapment injuries, older children most commonly sustained their fractures due to ball sport injuries. There was an increasing rate of metacarpal and carpal fractures with increasing age, and these fractures had to be treated operatively more often than phalangeal fractures., (© 2023. The Author(s).)

In this paper, we investigate the XY model in the presence of an additional potential term that independently tunes the vortex fugacity favouring their nucleation. By increasing the strength of this term and thereby the vortex chemical potential µ , we observe significant changes in the phase diagram with the emergence of a normal vortex-antivortex lattice as well as a superconducting vortex-antivortex crystal (lattice supersolid) phase. We examine the transition lines between these two phases and the conventional non-crystalline one as a function of both the temperature and the chemical potential. Our findings suggest the possibility of a peculiar tricritical point where second-order, first-order, and infinite-order transition lines meet. We discuss the differences between the present phase diagram and previous results for two-dimensional Coulomb gas models. Our study provides important insights into the behaviour of the modified XY model and opens up new possibilities for investigating the underlying physics of unconventional phase transitions., (Creative Commons Attribution license.)

(1) Background: Displaced supracondylar humeral fractures in pediatric patients can be treated by either antegrade nailing (AN) or percutaneous crossed pinning (PCP). The aim of this study was to compare the intra- and perioperative management, complications and outcome of AN and PCP. (2) Methods: This retrospective study enrolled 271 individuals (median age 5 years, IQR 4-7 years) who underwent AN ( n = 173) or PCP ( n = 98). Patient history was analyzed for incidence of nerve injuries, postoperative treatment, postoperative malrotation, time of hospital stay, time to implant removal and revision rate. Operative procedures were investigated for duration and radiation exposure. (3) Results: PCP was associated with a significantly lower radiation exposure (dose area product: PCP mean 20.1 cGycm 2 vs. AN mean 34.7 cGycm 2 , p < 0.001; fluoroscopy time: PCP mean 1.1 min, range 0.1-8.1 min, vs. AN mean 1.5 min, range 0.1-7.1 min, p < 0.001), duration of surgery (PCP mean 32.2 min vs. AN mean 48.3 min, p < 0.001) and time to implant removal (PCP mean 37 days vs. AN mean 113 days, p < 0.001). Cast removal was performed earlier in the AN group (PCP mean 30.2 days vs. AN mean 20.4 days, p < 0.001) and there were fewer iatrogenic nerve lesions (PCP: 24% vs. AN: 8%, p < 0.001). (4) Conclusions: In the investigated study population, the analyzed parameters seem to favor the use of PCP. The advantages of AN should be weighed against its drawbacks. For special indications, AN remains a relevant technique in supracondylar fracture treatment, and surgeons should be familiar with this procedure.

Background: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance., Methods: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise., Results: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis., Conclusions: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator., Methods: By using molecular, biochemical and functional analyses we performed an in-depth characterization of the G1244E-CFTR mutant in heterologous and native cell models., Results: Our studies demonstrate that processing and function of the mutant protein, as well as its pharmacological sensitivity, are markedly dependent on cell background. In heterologous expression systems, elexacaftor mainly acted on G1244E-CFTR as a co-potentiator, thus ameliorating the gating defect. On the contrary, in the native nasal epithelial cell model, elexacaftor did not act as a co-potentiator, but it increased mature CFTR expression possibly by improving mutant's defective stability at the plasma membrane., Conclusions: Our study highlights the importance of the cell background in the evaluation of CFTR modulator effects. Further, our results draw attention to the need for the development of novel potentiators having different mechanisms with respect to ivacaftor to improve channel activity for mutants with severe gating defect., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

The aim of this study was to investigate the association between Cystic Fibrosis (CF) and affective temperaments, considering the relevance of ionic balances in neural excitability, as a possible neurobiological basis for temperamental expression. A cross-sectional study involving 55 adult CF patients was conducted. Sociodemographic, clinical and therapeutic characteristics, temperamental and personality dispositions and depressive and anxiety symptoms were evaluated through standardized semi-structured and structured interviews. The majority of the enrolled CF patients were receiving Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) therapy (72.7%), and most of them had hyperthymic temperament predominance (29.1%). Different TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire) dimensions were not associated with the type of CF phenotype-related mutation or with the use of CFTR-modulator therapy. However, a tendency towards irritability was noted in patients not undergoing CFTR modulator therapy (6.7 ± 4.72 vs. 4.7 ± 4.33; p = 0.13). In light of the limitations imposed by the cross-sectional nature of the study, a hyperthymic temperament was found to be protective against current or lifetime psychopathologic events, whereas the other temperaments were associated with positive psychopathological anamnesis. Based on the measurement of temperament profiles and the study of their associations with clinically relevant variables, we argue that subjecting CF patients to such a temperament assessment could prove beneficial in the transition towards integrated and personalized care.

S737F is a Cystic Fibrosis (CF) transmembrane conductance regulator (CFTR) missense variant. The aim of our study was to describe the clinical features of a cohort of individuals carrying this variant. In parallel, by exploiting ex vivo functional and molecular analyses on nasal epithelia derived from a subset of S737F carriers, we evaluated its functional impact on CFTR protein as well as its responsiveness to CFTR modulators. We retrospectively collected clinical data of all individuals bearing at least one S737F CFTR variant and followed at the CF Centre of Tuscany region (Italy). Nasal brushing was performed in cooperating individuals. At study end clinical data were available for 10 subjects (mean age: 14 years; range 1-44 years; 3 adult individuals). Five asymptomatic subjects had CF, 2 were CRMS/CFSPID and 3 had an inconclusive diagnosis. Ex vivo analysis on nasal epithelia demonstrated different levels of CF activity. In particular, epithelia derived from asymptomatic CF subjects and from one of the subjects with inconclusive diagnosis showed reduced CFTR activity that could be rescued by treatment with CFTR modulators. On the contrary, in the epithelia derived from the other two individuals with an inconclusive diagnosis, the CFTR-mediated current was similar to that observed in epithelia derived from healthy donors. In vitro functional and biochemical analysis on S737F-CFTR expressed in immortalized bronchial cells highlighted a modest impairment of the channel activity, that was improved by treatment with ivacaftor alone or in combination with tezacaftor/elexacaftor. Our study provide evidence towards the evaluation of CFTR function on ex vivo nasal epithelial cell models as a new assay to help clinicians to classify individuals, in presence of discordance between clinical picture, sweat test and genetic profile.

Lung disease in cystic fibrosis (CF) is characterized by reduced mucociliary clearance, airway plugging, recurrent infections, and chronic pulmonary inflammation. Patients who are affected undergo daily respiratory physiotherapy to improve airway clearance. Intrapulmonary percussive ventilation (IPV) is a technique used in clinical practice, but it is not commonly used in CF patients. Evidence for various respiratory pathologies, particularly in children, is still lacking. We present the case of an 11-year-old boy with cystic fibrosis who did not respond to traditional respiratory physiotherapy techniques. We proposed and tested the use of IPV during hospitalization. In this case, the use of IPV in physiotherapy treatment reduced the need for intravenous antibiotics, hospitalization, and improved radiologic features. IPV can be used successfully in CF patients who are resistant to traditional physiotherapy techniques.

This retrospective study aimed at analyzing the impact of metastasectomy on post-metastasis survival (PMS) in bone sarcoma patients with lung metastases. Altogether, 47 bone sarcoma patients (24 males, median age at diagnosis of lung metastases: 21.8 (IQR: 15.6-47.3) years) with primary (n = 8) or secondary (n = 39) lung metastases treated at a single university hospital were retrospectively included. Based on a propensity score, inverse probability of treatment weight (IPTW) was calculated to account for selection bias whether patients had undergone metastasectomy or not. The most common underlying histology was osteosarcoma (n = 37; 78.7%). Metastasectomy was performed in 39 patients (83.0%). Younger patients ( p = 0.025) with singular ( p = 0.043) and unilateral lesions ( p = 0.024), as well as those with an interval ≥ 9 months from primary diagnosis to development of lung metastases ( p = 0.024) were more likely to undergo metastasectomy. Weighted 1- and 3-year PMS after metastasectomy was 80.8% and 58.3%, compared to 88.5% and 9.1% for patients who did not undergo metastasectomy. Naive Cox-regression analysis demonstrated a significantly prolonged PMS for patients with metastasectomy (HR: 0.142; 95%CI: 0.045-0.450; p = 0.001), which was confirmed after IPTW-weighting (HR: 0.279; 95%CI: 0.118-0.662; p = 0.004), irrespective of age, time to metastasis, and the number of lesions. In conclusion, metastasectomy should be considered in bone sarcoma patients with lung metastases, after carefully considering the individual risks, to possibly improve PMS.

Objectives: The use of biosimilars is constantly growing, prompting healthcare payers to encourage the switch to these drugs which are less expensive than the reference bio-originator. While switching from a bio-originator to a biosimilar is supported by increasing evidence, data on the switch between different biosimilars of the same reference product are scant. Our study aimed to evaluate the effectiveness of the non-medical switch both between adalimumab (ADA) bio-originator and SB5 biosimilar and between two different ADA biosimilars in patients with inflammatory chronic arthritis., Methods: We observed adult patients with a diagnosis of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) treated with ADA bio-originator or ABP501 ADA biosimilar (Amgevita) who switched to SB5 ADA biosimilar (Imraldi) for administrative/economic reasons. Patients were followed up for 4 months., Results: One hundred and ten patients [33 RA, 40 PsA, 37 axSpA; F:M= 49:61; median age 56 years (25th-75th percentile 48-66)] switched from ADA bio-originator to SB5. After 4 months (T4), we observed a significant reduction of patients in remission/low disease activity (baseline 92.7% vs. T4 80.9%; p=0.009), with a risk of moderate-high disease activity significantly higher after the switch [RR 2.6 (95% IC 1.2 to 5.7), p=0.01]. However, no differences were found in DAS28-CRP, DAPSA, ASDAS-CRP, and BASDAI, while patients with RA and PsA experienced a worsening in the patient global assessment-VAS (p=0.04 and p=0.02, respectively), and in patients with PsA a worsening in HAQ was also observed (p=0.03). Forty patients switched from ABP501 biosimilar to SB5 [12 with RA, 25 with PsA, and 3 with axSpA; F:M=24:16; median age 56 years (25th-75th percentile 44-66)]. After 4 months, no differences in DAS28-CRP and DAPSA nor in the percentage of patients in remission/low disease activity were found compared to baseline. Likewise, no differences were found in patient-reported outcomes (PROs)., Conclusions: Our results provide a reassuring profile of effectiveness when switching from ADA originator to one of its biosimilars and between two different biosimilars. However, the worse outcome in PROs in patients initially treated with the bio-originator addresses the attention to a possible nocebo response, which should encourage comprehensive communication with patients.