Raman Spectroscopy and Cystic Fibrosis Disease: An Alternative Potential Tool for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Response Differentiation-A Pilot Study Based on Serum Samples.

Cystic fibrosis (CF) is a genetic disorder that alters chloride transport in mucous membranes. Recent studies have demonstrated that treatment with modulators of the chloride channel reduces inflammatory markers, restoring, among others, the imbalance of lipids. In this study, we analyzed the serum samples of treated and non-treated patients with modulators with Raman spectroscopy. Nineteen (eight treated an eleven non-treated) patients were considered. The main difference between the two groups appeared in the 3020-2800 cm-1 range. A Voigt deconvolution fit was performed, and nine sub-bands were identified. To distinguish between treated and non-treated patients, the area ratio between the CH3 and CH2 vibration modes was calculated for each patient. The results were validated using statistical analyses. In particular, receiver operating characteristic (ROC) curves and Youden index (Y) were calculated (Area Under Curve (AUC): 0.977; Y: 3.30). An ROC curve represents the performance of the classification, illustrating the diagnostic ability of Raman spectroscopy. It was demonstrated that Raman spectroscopy is able to highlight peculiar differences between elexacaftor/tezacaftor/ivacaftor (ETI)-treated and non-treated patients, in relation with lipids biomarkers.

Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study.

BACKGROUND: In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. METHODS: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. RESULTS: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV1 % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. CONCLUSIONS: ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.

A systematic review on gender dysphoria in adolescents and young adults: focus on suicidal and self-harming ideation and behaviours.

INTRODUCTION: Gender dysphoria (GD) is characterized by the incongruence between one's experienced and expressed gender and assigned-sex-at-birth; it is associated with clinically significant distress. In recent years, the number of young patients diagnosed with GD has increased considerably. Recent studies reported that GD adolescents present behavioural and emotional problems and internalizing problems. Furthermore, this population shows a prevalence of psychiatric symptoms, like depression and anxiety. Several studies showed high rates of suicidal and non-suicidal self-injurious thoughts and behaviour in GD adolescents. To increase understanding of overall mental health status and potential risks of young people with GD, this systematic review focused on risk of suicide and self-harm gestures. METHODS: We followed the PRISMA 2020 statement, collecting empirical studies from four electronic databases, i.e., PubMed, Scopus, PsycINFO, and Web of Science. RESULTS: Twenty-one studies on GD and gender nonconforming identity, suicidality, and self-harm in adolescents and young adults met inclusion criteria. Results showed that GD adolescents have more suicidal ideation, life-threatening behaviour, self-injurious thoughts or self-harm than their cisgender peers. Assessment methods were heterogeneous. CONCLUSION: A standardised assessment is needed. Understanding the mental health status of transgender young people could help develop and provide effective clinical pathways and interventions.

The centripetal endoscopic sinus surgery in patients with cystic fibrosis: A preliminary study.

OBJECTIVES: The main aim of this study is to analyze the possible differences between clinical, demographic or genetic characteristics, in Cystic Fibrosis (CF) patients with chronic rhinosinusitis (CRS) with different phenotype. The secondary objective is to describe the possible benefit of surgery with Centripetal Endoscopic Sinus Surgery (CESS). METHODS: The study includes 56 who performed CT scan of the paranasal sinuses. They were divided in 3 group according to phenotype: CRS without Nasal Polyps (NP); CRS with NP; CRS complicated with Mucocele. The clinical symptoms, age, gender, genotype, microbial colonization and pulmonary disease stage were collected and analyzed to assess possible statistically significant differences. Regarding the 7 patients who performed CESS surgery, the number of hospitalizations, intravenous (iv) antibiotic courses, respiratory exacerbations, the FEV1, the Lund-Mackay Score (LMS) and the SNOT 22 were evaluated before and 1 year after surgery. RESULTS: No statistically significant differences regarding clinical symptoms between the 3 groups were identified (p > 0.05). Furthermore, there were no differences in age, gender, genotype, microbial colonization and pulmonary disease stage (p > 0.05). Regarding the patients who performed CESS, no significative difference in FEV1 progression was found. A reduction in hospitalization, pulmonary exacerbation and in the number of iv antibiotic courses resulted statistically significant different (p = 0.004; <0.001 and <0.001 respectively). A significant improvement in SNOT-22 and LMS (p < 0.001) was obtained. CONCLUSION: Radiological monitoring of the rhinosinus disease is necessary regardless of the clinical expression of the disease. The presence of CRS with NP complicated by mucocele is frequent and independent of the patient's age and clinical manifestations. An extensive surgical approach could represent the gold standard for patients with CF in consideration of the potential important advantages to perform a total toilet of all the sinuses and nasal cavities and at the same time eliminating a potential microbiological reservoir.

Rescue by elexacaftor-tezacaftor-ivacaftor of the G1244E cystic fibrosis mutation's stability and gating defects are dependent on cell background.

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.

Firms' solidity before an exogenous shock: Covid-19 pandemic in Italy.

In this paper we study the structural robustness of the Italian business system, using the Covid-19 pandemic as an exogenous event to test it. To this aim, we use the ROC (Receiver Operating Characteristics) methodology, quite new for economics, to classify Italian firms according to their economic solidity, obtaining a taxonomy based on a wide set of characteristics. Our results show that the number of "Solid" firms is less than one-fifth of all Italian enterprises but they represent the lion's share in terms of employment and value added. "Fragile" and "At Risk" firms, albeit much less relevant for the creation of value added, account for over one-third of total employment, so they may be a worrisome issue for policymakers. Solidity conditions have clearly both a size and sector-related dimension: At Risk and Fragile conditions prevail among firms of smaller economic size (a broad definition of firm size) and among those operating in Construction and Other services. Finally, we find that factors such as firms' performance, and internal and external organization, although significant, play a less relevant role than economic size and digitalization/innovation in determining Italian firms' resilience to exogenous shocks such as the Covid-19 one.

Gastroparesis in Adolescent Patient with Type 1 Diabetes: Severe Presentation of a Rare Pediatric Complication.

Gastroparesis is a long-term complication of diabetes related to autonomic neuropathy. It is clinically characterized by delayed gastric emptying and upper gastrointestinal symptoms including early satiety, postprandial fullness, nausea, vomiting, and abdominal pain. Gastric emptying scintigraphy is the gold standard for the diagnosis as it reveals delayed gastric emptying. Therapeutic strategies include dietary modifications, improvement of glycemic control, and prokinetic drugs. Case descriptions of diabetic gastroparesis in pediatric age are very scarce. We hereby report the case of a 16-year-old adolescent with severe presentation of diabetic gastroparesis. She presented with recurrent episodes of nausea, vomiting and abdominal pain which led progressively to reduced oral intake and weight loss. Her past glycemic control had been quite brittle as demonstrated by several hospitalizations due to diabetic ketoacidosis and recurrent episodes of severe hypoglycemia. After the exclusion of infectious, mechanical, metabolic, and neurological causes of vomiting, a gastric emptying scintigraphy was performed, leading to the diagnosis of gastroparesis. Treatment with metoclopramide was started with progressive relief of symptoms. To improve glycemic control, insulin therapy with advanced hybrid closed loop system was successfully practiced. Pediatricians should seriously consider diabetic gastroparesis in children and adolescents with long-standing, poorly controlled diabetes.

Malassezia Folliculitis following Triple Therapy for Cystic Fibrosis.

Triple-combination therapy with elexacaftor, tezacaftor and ivacaftor has been recently approved for cystic fibrosis patients with at least one F508del mutation in the transmembrane conductance regulator of the cystic fibrosis gene. Among the adverse events of elexacaftor, tezacaftor and ivacaftor, the cutaneous ones have been rarely reported, mainly dealing with urticarial-like rashes. On this topic, we report two cases of Malassezia folliculitis following triple therapy administration in two young females. In the first patient, a papulopustular rush appeared before the folliculitis while in the second patient it was not preceded by other skin manifestations. The diagnosis was confirmed both by dermoscopy and histology. The prompt response to systemic antimycotic drugs provided further evidence for the causative role of Malassezia, requiring no discontinuation of cystic fibrosis therapy. We could hypothesize that the triple regimen treatment may induce changes in the skin microbiome, potentially able to favor colonization and proliferation of Malassezia species. Physicians should be aware of such associations to allow prompt diagnosis and early interventions, avoiding useless drug removal.

Recognizing the Emergent and Submerged Iceberg of the Celiac Disease: ITAMA Project-Global Strategy Protocol.

Coeliac disease (CD) is frequently underdiagnosed with a consequent heavy burden in terms of morbidity and health care costs. Diagnosis of CD is based on the evaluation of symptoms and anti-transglutaminase antibodies IgA (TGA-IgA) levels, with values above a tenfold increase being the basis of the biopsy-free diagnostic approach suggested by present guidelines. This study showcased the largest screening project for CD carried out to date in school children (n=20,000) aimed at assessing the diagnostic accuracy of minimally invasive finger prick point-of-care tests (POCT) which, combined with conventional celiac serology and the aid of an artificial intelligence-based system, may eliminate the need for intestinal biopsy. Moreover, this study delves deeper into the "coeliac iceberg" in an attempt to identify people with disorders who may benefit from a gluten-free diet, even in the absence of gastrointestinal symptoms, abnormal serology and histology. This was achieved by looking for TGA-IgA mucosal deposits in duodenal biopsy. This large European multidisciplinary health project paves the way to an improved quality of life for patients by reducing the costs for diagnosis due to delayed findings of CD and to offer business opportunities in terms of diagnostic tools and support.

State-of-the-art review of lung imaging in cystic fibrosis with recommendations for pulmonologists and radiologists from the "iMAging managEment of cySTic fibROsis" (MAESTRO) consortium.

OBJECTIVE: Imaging represents an important noninvasive means to assess cystic fibrosis (CF) lung disease, which remains the main cause of morbidity and mortality in CF patients. While the development of new imaging techniques has revolutionised clinical practice, advances have posed diagnostic and monitoring challenges. The authors aim to summarise these challenges and make evidence-based recommendations regarding imaging assessment for both clinicians and radiologists. STUDY DESIGN: A committee of 21 experts in CF from the 10 largest specialist centres in Italy was convened, including a radiologist and a pulmonologist from each centre, with the overall aim of developing clear and actionable recommendations for lung imaging in CF. An a priori threshold of at least 80% of the votes was required for acceptance of each statement of recommendation. RESULTS: After a systematic review of the relevant literature, the committee convened to evaluate 167 articles. Following five RAND conferences, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 28 main statements. CONCLUSIONS: There is a need for international guidelines regarding the appropriate timing and selection of imaging modality for patients with CF lung disease; timing and selection depends upon the clinical scenario, the patient's age, lung function and type of treatment. Despite its ubiquity, the use of the chest radiograph remains controversial. Both computed tomography and magnetic resonance imaging should be routinely used to monitor CF lung disease. Future studies should focus on imaging protocol harmonisation both for computed tomography and for magnetic resonance imaging. The introduction of artificial intelligence imaging analysis may further revolutionise clinical practice by providing fast and reliable quantitative outcomes to assess disease status. To date, there is no evidence supporting the use of lung ultrasound to monitor CF lung disease.

Child Distress Expression and Regulation Behaviors: A Systematic Review and Meta-Analysis.

The goal of the current study was to review and meta-analyze the literature on relationships between child distress expression behaviors (e.g., cry) and three clusters of child distress regulation behaviors (disengagement of attention, parent-focused behaviors, and self-soothing) in the first three years of life. This review was registered with PROSPERO (CRD42020157505). Unique abstracts were identified through Medline, Embase, and PsycINFO (n = 13,239), and 295 studies were selected for full-text review. Studies were included if they provided data from infants or toddlers in a distress task, had distinct behavioral measures of distress expression and one of the three distress regulation clusters, and assessed the concurrent association between them. Thirty-one studies were included in the meta-analysis and rated on quality. Nine separate meta-analyses were conducted, stratified by child age (first, second, and third year) and regulation behavior clusters (disengagement of attention, parent-focused, and self-soothing). The weighted mean correlations for disengagement of attention behaviors were -0.28 (year 1), -0.44 (year 2), and -0.30 (year 3). For parent-focused behaviors, the weighted mean effects were 0.00 (year 1), 0.20 (year 2), and 0.11 (year 3). Finally, the weighted mean effects for self-soothing behaviors were -0.23 (year 1), 0.25 (year 2), and -0.10 (year 3). The second year of life showed the strongest relationships, although heterogeneity of effects was substantial across the analyses. Limitations include only analyzing concurrent relationships and lack of naturalistic distress paradigms in the literature.

Vedolizumab-associated pulmonary manifestations in children with ulcerative colitis.

WHAT IS KNOWN AND OBJECTIVE: The off-label use of vedolizumab (VDZ) for inflammatory bowel disease in children is increasing. We report on possibly the first case of VDZ-associated pulmonary manifestations in paediatrics. CASE SUMMARY: This report details the case of a 13-year-old child with ulcerative colitis who was initiated on VDZ due to persistent active disease. After the first three doses, he developed a persistent and productive cough. Microbiological work-up was normal. VDZ discontinuation led to the resolution of symptoms. WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first case report of VDZ-associated pulmonary manifestations in paediatrics. A direct, pro-inflammatory effect of VDZ has been hypothesized, but further studies are warranted.

Management of respiratory tract exacerbations in people with cystic fibrosis: Focus on imaging.

Respiratory tract exacerbations play a crucial role in progressive lung damage of people with cystic fibrosis, representing a major determinant in the loss of functional lung tissue, quality of life and patient survival. Detection and monitoring of respiratory tract exacerbations are challenging for clinicians, since under- and over-treatment convey several risks for the patient. Although various diagnostic and monitoring tools are available, their implementation is hampered by the current definition of respiratory tract exacerbation, which lacks objective "cut-offs" for clinical and lung function parameters. In particular, the latter shows a large variability, making the current 10% change in spirometry outcomes an unreliable threshold to detect exacerbation. Moreover, spirometry cannot be reliably performed in preschool children and new emerging tools, such as the forced oscillation technique, are still complementary and need more validation. Therefore, lung imaging is a key in providing respiratory tract exacerbation-related structural and functional information. However, imaging encompasses several diagnostic options, each with different advantages and limitations; for instance, conventional chest radiography, the most used radiological technique, may lack sensitivity and specificity in respiratory tract exacerbations diagnosis. Other methods, including computed tomography, positron emission tomography and magnetic resonance imaging, are limited by either radiation safety issues or the need for anesthesia in uncooperative patients. Finally, lung ultrasound has been proposed as a safe bedside option but it is highly operator-dependent and there is no strong evidence of its possible use during respiratory tract exacerbation. This review summarizes the clinical challenges of respiratory tract exacerbations in patients with cystic fibrosis with a special focus on imaging. Firstly, the definition of respiratory tract exacerbation is examined, while diagnostic and monitoring tools are briefly described to set the scene. This is followed by advantages and disadvantages of each imaging technique, concluding with a diagnostic imaging algorithm for disease monitoring during respiratory tract exacerbation in the cystic fibrosis patient.

COVID-19 vaccination mimicking lymph-node progression in a patient with melanoma: a case report.

COVID-19 vaccination has been rapidly implemented among patients with cancer. We present the case of a patient with high-risk resected cutaneous melanoma, who was a candidate for adjuvant treatment, with postsurgery 18-fluorodeoxyglucose (FDG) PET/computed tomography (CT) scan showing positive axillary lymph nodes after COVID-19 vaccination. This report presents a 50-year-old man with a history of stage IIA cutaneous melanoma. During follow-up, the patient experienced subcutaneous and lymph-node disease progression, documented with 18FDG PET/CT scan. The patient underwent laparoscopic left para-aortic lymphadenectomy and excision of subcutaneous lesion. Histologic examination showed presence of melanoma metastases in 2 lymph nodes out of total 17 excised and neoplastic emboli to the subcutaneous tissue. In view of starting adjuvant nivolumab, the patient underwent CT scan restaging, with evidence of suspect centimetric periaortic and paracaval lymph nodes, which were deemed worthy of 18FDG PET investigation. The 18FDG PET/CT was negative for abdominal hypercaptation, but showed left axillary pathologic lymph nodes. The medical history of the patient revealed that he had received intramuscular Moderna COVID-19 mRNA vaccine in the left deltoid, one week before 18FDG PET examination. Since the patient's clinical examination was negative and suspecting postvaccination false-positive adenopathy, bilateral axillary ultrasound was performed, excluding the presence of pathologic lymph nodes. The patient has started adjuvant treatment with nivolumab, which is currently ongoing. This case demonstrates unexpected findings in response to COVID-19 vaccination in a patient with melanoma. In this specific case, the detection of 18FDG PET hypercaptation could significantly change the patient's management. With growing evidence about the pattern and occurrence of adenopathies after mRNA COVID-19 vaccination, recommendations for scheduling and interpretation of 18FDG PET/CT scans among cancer patients will be implemented, in order to reduce equivocal findings and improve outcomes.

Raman Spectroscopy Technique: A Non-Invasive Tool in Celiac Disease Diagnosis.

Celiac disease (CD) is diagnosed by a combination of specific serology and typical duodenal lesions. The histological confirmation of CD, mandatory in the majority of patients with suspected CD, is based on invasive and poorly tolerated procedures, such as upper gastrointestinal endoscopy. In this study we propose an alternative and non-invasive methodology able to confirm the diagnosis of CD based on the analysis of serum samples using the Raman spectroscopy technique. Three different bands centered at 1650, 1450 and 1003 cm-1 have been considered and the A1450/A1003 and A1650/A1003 ratios have been computed to discriminate between CD and non-CD subjects. The reliability of the methodology was validated by statistical analysis using receiver operating characteristic (ROC) curves. The Youden index was also determined to obtain optimal cut-off points. The obtained results highlighted that the proposed methodology was able to distinguish between CD and non-CD subjects with 98% accuracy. The optimal cut-off points revealed, for both the A1450/A1003 and A1650/A1003 ratios, high values of sensitivity and specificity (>95.0% and >92.0% respectively), confirming that Raman spectroscopy may be considered a valid alternative to duodenal biopsy and demonstrates spectral changes in the secondary structures of the protein network.

The longitudinal and concurrent relationship between caregiver sensitivity and preschool attachment: A systematic review and meta-analysis.

The present study aimed to systematically review and meta-analyze the concurrent and longitudinal relationship between caregiver sensitivity and preschool attachment measured using the Main and Cassidy (1988) and Cassidy and Marvin (1992) attachment classification systems. This review was pre-registered with the International Prospective Register of Systematic Reviews (PROSPERO; Registration Number CRD42017073417) and completed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The present review identified 36 studies made up of 21 samples (N = 3, 847) examining the relationship between caregiver sensitivity and preschool attachment. Eight primary meta-analyses were conducted separately according to the proximity of the assessment of sensitivity to attachment (i.e., concurrent versus longitudinal), operationalization of caregiver sensitivity (i.e., unidimensional versus multidimensional) and attachment categorizations (i.e., secure-insecure versus organized-disorganized). Overall, the meta-analyses revealed higher levels of caregiver sensitivity among caregivers with secure and organized preschoolers, relative to insecure and disorganized preschoolers, respectively. Medium effect sizes (g = .46 to .59) were found for both longitudinal and concurrent associations between caregiver sensitivity and preschool attachment when a unidimensional measure of caregiver sensitivity was employed, compared to small to medium effect sizes (g = .34 to .49) when a multidimensional measure of caregiver sensitivity was employed. Child age at attachment measurement was a significant moderator of the longitudinal association between unidimensional caregiver sensitivity and preschool attachment. Future directions for the literature and clinical implications are discussed.

GCK-MODY in a child with cystic fibrosis: the doubt of the treatment plan.

Objectives The diagnosis of cystic fibrosis related diabetes (CFRD) is not often easy as glucose homeostasis may be influenced by various disease-related conditions such as enteral continuous drip feeding, frequent acute illness, use of systemic corticosteroids and other concomitant medications. Other forms of diabetes should be considered in the diagnostic work-up, particularly in the first decade of life. Case presentation We hereby present the case of a cystic fibrosis 6-year-old female child diagnosed with glucokinase-maturity onset of diabetes of the young (GCK-MODY). The choice of treatment plan was doubtful since GCK-MODY does not usually require insulin treatment, but hyperglycemia could pose a threat to the respiratory tract. After intensive glucose monitoring, we decided to defer pharmacological treatment based on acceptable daily glycemic control. To date, no worsening in her respiratory function has been revealed. Conclusions Recognition of non-CFRD forms of diabetes is fundamental to plan the most suitable treatment and follow-up.