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Two-dimensional linear spaces of symmetric matrices are classified by Segre symbols. After reviewing known facts from linear algebra and pro-jective geometry, we address new questions motivated by algebraic statistics and optimization. We compute the reciprocal curve and the maximum likelihood degrees, and we study strata of pencils in the Grassmannian. [ABSTRACT FROM AUTHOR]

We examine quadratic surfaces in 3-space that are tangent to nine given figures. These figures can be points, lines, planes or quadrics. The numbers of tangent quadrics were determined by Hermann Schubert in 1879. We study the associated systems of polynomial equations, also in the space of complete quadrics, and we solve them using certified numerical methods. Our aim is to show that Schubert's problems are fully real. [ABSTRACT FROM AUTHOR]

While Cystic Fibrosis is characterized by a high phenotypic variability, a correlation is reported between the pancreatic status and the CFTR genotype. Here we report an unusual case of a child with Cystic Fibrosis (F508del-duplication of exons 1-3 genotype) diagnosed at 8 years old for pancreatic insufficiency and non-pathological sweat test, in absence of respiratory symptoms and acute episodes of pancreatitis. Nasal potential differences and intestinal current measurements were normal, while the short-circuit current measured on patient-derived colonoids grown on Transwell ® indicated the presence of a reduced CFTR-dependent current relative to non-CF colonoids with, a modest improvement of CFTR activity record following treatment with elexacaftor/tezacaftor/ivacaftor.This case opens the discussion on the importance of performing CFTR sequencing and the search for large gene rearrangements in cases of pancreatic insufficiency of unclear etiology, also in the presence of non-pathological sweat test. Children with CF and non-pathological sweat chloride are likely to develop higher concentrations if they truly have CF., Competing Interests: Declarations. Ethics approval and consent to participate: An approval was obtained from the pediatric ethical committee of the Cystic Fibrosis center in Florence and for the Cystic Fibrosis Center AOUI of Verona (protocol#CFTR050). Consent for publication: Parents provided written informed consent for anonymous data processing and to participate in this case investigation. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers., Study Design: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period., Results: Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026)., Conclusions: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Predictions based on patient-derived materials of CFTR modulators efficacy have been performed lately in patient-derived cells, extending FDA-approved drugs for CF patients harboring rare variants. Here we developed intestinal organoids from subjects carrying S737F- and T465N-CFTR in trans with null alleles to evaluate their functional impact on CFTR protein function and their restoration upon CFTR modulator treatment. The characterization of S737F-CFTR was performed in two subjects recently assessed in nasal epithelial cells but not in colonoids., Results: Our functional analysis (Ussing chamber) confirmed that S737F-CFTR is a mild variant with residual function as investigated in colonoids of patients with S737F/Dele22-24 and S737F/W1282X genotypes. An increase of current upon Elexacaftor/Tezacaftor/Ivacaftor (ETI) treatment was recorded for the former genotype. T465N is a poorly characterized missense variant that strongly impacts CFTR function, as almost no CFTR-mediated anion secretion was registered for T465N/Q39X colonoids. ETI treatment substantially improved CFTR-mediated anion secretion and increased the rescue of mature CFTR expression compared to either untreated colonoids or to dual CFTR modulator therapies., Conclusions: Our study confirms the presence of a residual function of the S737F variant and its limited response to CFTR modulators while predicting for the first time the potential clinical benefit of Trikafta® for patients carrying the rare T465N variant., (© 2024. The Author(s).)

Modulators of cystic fibrosis transmembrane conductance regulator (CFTR) improved cystic fibrosis (CF) patients' outcome. The elexacaftor/tezacaftor/ivacaftor (ETI) combination was safe and effective improving lung function in patients with different CFTR genotypes, including at least one F508del mutation. However, cases with liver damage were reported. We describe 105 CF patients heterozygous for F508del in trans with another CFTR mutation, treated for 1 year with ETI. We analyzed liver biochemical parameters and cholesterol metabolism, including lathosterol and phytosterols, surrogate markers of cholesterol de-novo synthesis and absorption, respectively. The treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s, whereas it caused a significant increase of total and conjugated bilirubin, ALT and GGT, even if no patients developed CF liver disease. Such alterations were less relevant than those previously observed in ETI-treated F508del homozygous patients. Furthermore, ETI treatment significantly increased serum cholesterol by enhancing its absorption (correlation between serum cholesterol and phytosterols). Whereas, we observed a normalization of de-novo biosynthesis (lathosterol reduction) that was not observed in homozygous patients. These data suggest that the second mutation in trans with the F508del contributes to reduce the liver cholesterol accumulation and thus, the triggering of liver inflammation. However, no differences in the alteration of biochemical indexes were observed between CF patients with and without liver steatosis, and between patients with different mutations in trans with the F508del. Such data suggest to further investigate the effects of ETI therapy on liver function indexes and new predictive biomarkers., (© 2024. The Author(s).)

We reformulate the analysis of singularities of Feynman integrals in a way that can be practically applied to perturbative computations in the standard model in dimensional regularization. After highlighting issues in the textbook treatment of Landau singularities, we develop an algorithm for classifying and computing them using techniques from computational algebraic geometry. We introduce an algebraic variety called the principal Landau determinant, which captures the singularities even in the presence of massless particles or UV/IR divergences. We illustrate this for 114 example diagrams, including a cutting-edge 2-loop 5-point nonplanar QCD process with multiple mass scales.

Background: The upper airways of cystic fibrosis (CF) persons are an evolutionary niche where genetically adapted bacterial strains are selected for lung infection. The microbiological studies conducted up to now on the upper airways are not easily comparable., Methods: Using classical culture methods, we simultaneously studied the microbiological status of upper and lower airways in persons not chronically infected with P. aeruginosa . Each person had a single upper airways sampling and a concomitant lower airways sampling. Lower airways sampling was performed by oropharyngeal swab or sputum collection. Using a quasi-experimental design of study, we evaluated the performance of 2 different upper airways' sampling methods, nasal lavage according to method described by Mainz or nasal lavage with a rhino-set. Pain was measured with appropriate scales., Results: A total of 194 persons were enrolled in this study. Pathogenic flora was found in 128 (6.6%) of 194 upper airways samples and in 164 (84.6%) lower airways samples. A statistically significant difference between the upper airways and the lower airways was found in the isolation of S. aureus and non-fermenter gram negatives. Nasal lavage according to Mainz resulted in the isolation of more non-fermenter gramnegatives than the rhino-set (p < 0.05). No differences were found in the pain caused bythe two methods., Conclusions: In our study population, cultures of the upper airway and lower airway differ in CF persons. In people sampled with nasal lavage according to Mainz more non-fermenter gram negatives were detected than with rhino-set. The two sampling methods were comparable with regard to the caused pain, nasal lavage according to Mainz method being quicker to perform., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Giovanni Taccetti reports financial support was provided by 10.13039/501100009888Tuscany Region. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

There is limited information available on the clinical data, sweat test trends, and outcomes of individuals with cystic fibrosis (CF) who present with an isolated episode of hypoelectrolytemia with metabolic alkalosis (HMA). This study describes a cohort of Italian individuals with HMA as presenting symptom. The study is a retrospective multicenter analysis of individuals who presented with HMA as an initial symptom and was followed at 8 Italian CF Centers, from March 1988 to March 2022. Demographic, clinical, microbiological, biochemical, and genetic data were extracted from local health records. Ninety-three individuals were enrolled in the study. At first evaluation, 82 (88.2%) were diagnosed with CF, and 11 received a CFTR-Related Disorder (CFTR-RD) diagnostic label. Twenty-three (85.1%) out of the 27 subjects who underwent CF neonatal screening (NBS) resulted falsely negative. After a mean observational period of 11.5 years, most of subjects had a mild pulmonary phenotype, pancreatic sufficiency, and rarely CF-related complications. Four CFTR-RD changed to a CF diagnosis during the study period, resulting in 86 (92.4%) subjects classified as CF., Conclusions:  Most CF patients presenting with isolated HMA have a mild course of disease and rarely CF-related complications., What Is Known: • Isolated episode of hypoelectrolytemia with metabolic alkalosis is a well-known onset symptom of Cystic Fibrosis in infancy. • There is limited information available on the clinical data and outcomes of individuals with Cystic Fibrosis who present with electrolyte imbalance at diagnosis., What Is New: • Most patients with Cystic Fibrosis presenting with isolated hypoelectrolytemia and metabolic alkalosis have a mild course of disease and rarely CF-related complications. • Electrolyte imbalance at diagnosis of Cystic Fibrosis is a common symptom in children not screened for CF at birth, or in those who received a false negative result from newborn screening., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The sweat test (ST) is the current diagnostic gold standard for cystic fibrosis (CF). Many CF centres have switched from the Gibson-Cooke method to the Macroduct system-based method. We used these methods simultaneously to compare CF screening outcomes. STs using both methods were performed simultaneously between March and December 2022 at CF Centre in Florence. We included newborns who underwent newborn bloodspot screening (NBS), newborns undergoing transfusion immediately after birth, and children with CF screen-positive, inconclusive diagnosis (CFSPID). We assessed 72 subjects (median age 4.4 months; range 0-76.7): 30 (41.7%) NBS-positive, 18 (25.0%) newborns who underwent transfusion, and 24 (33.3%) children with CFSPID. No significant differences were found between valid sample numbers, by patient ages and groups ( p = 0.10) and between chloride concentrations ( p = 0.13), except for sweat chloride (SC) measured by the Gibson-Cooke and Macroduct methods in CFSPID group (29.0, IQR: 20.0-48.0 and 22.5, IQR: 15.5-30.8, respectively; p = 0.01). The Macroduct and Gibson-Cooke methods showed substantial agreement with the SC values, except for CFSPID, whose result may depend on the method of sweat collection. In case of invalid values with Macroduct, the test should be repeated with Gibson-Cooke method.

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: Improved therapy in CF has led to an overall improvement in nutritional status. The objectives of our study are: to cross-sectionally assess nutritional status and serum levels of fat-soluble vitamins; to retrospectively evaluate the efficacy of modulators on nutritional status and fat-soluble vitamin levels., Methods: In patients younger than 2 years of age, we evaluated growth, in patients aged 2-18 years, we assessed BMI z-scores, and in adults, we assessed absolute BMI values. Levels of 25(OH)D, vitamins A, and E were measured., Results: A cross-sectional analysis was conducted on 318 patients, 109 (34.3%) with pancreatic sufficiency. Only three patients were under 2 years old. In 135 patients aged 2-18 years, the median BMI z-score was 0.11, and 5 (3.7%) patients had malnutrition (z-score ≤ 2SD). In 180 adults, the median BMI was 21.8 kg/m 2 . Overall, 15 (13.7%) males (M) and 18 (25.3%) females (F) were underweight (18 < BMI > 20); 3 (2.7%) M and 5 (7.0%) F had a BMI < 18. Suboptimal 25(OH)D levels were found in patients with pancreatic insufficiency. The prevalence of deficiency of vitamins A and E is low. After one year of treatment with modulators, the increase in BMI was more consistent (M: 1.58 ± 1.25 kg/m 2 F: 1.77 ± 1.21 kg/m 2 ) in elexacaftor/tezacaftor/ivacaftor (ETI)-treated patients compared with other modulators, with a significant increase in levels of all fat-soluble vitamins., Conclusions: Malnutrition is present in a limited number of subjects. The prevalence of subjects with suboptimal 25(OH)D levels is high. ETI showed a beneficial effect on nutritional status and circulating levels of fat-soluble vitamins.

Pancreatitis-Associated Protein (PAP)-based Cystic Fibrosis (CF) newborn bloodspot screening (NBS) protocols detect less CFTR-Related Metabolic Syndrome (CRMS)/CF Screen Positive, Inconclusive Diagnosis (CFSPID). We prospectively evaluated the impact of PAP as the second step of the CF NBS protocol, before the CFTR genetic analysis, on NBS outcomes and CRMS/CFSPID detection in the Tuscany region, Italy. In parallel to the usual protocol (IRT/DNA, protocol 1), PAP was analyzed in IRT-positive infants (IRT/PAP/DNA, protocol 2) from 1 June 2020 until 31 May 2022. We defined an infant as NBS positive if PAP was >1.8 μg/L for IRT value 99th percentile-100 μg/L or >0.6 μg/L for IRT value >100 μg/L. To increase the positive predictive value (PPV) of protocol 2, we retrospectively lowered the upper IRT range value from 100 to 90 μg/L (modified protocol 2). We identified 8 CF and 13 CRMS/CFSPID with protocol 1, 5 CF and 5 CRMS/CFSPID with protocol 2 and 8 CF and 5 CRMS/CFSPID with modified protocol 2. With the PAP-based protocols, we observed a reduction of sweat tests, healthy carrier detection and a significant increase in PPV to 15.38%. Further data are needed in order to evaluate the outcomes of CRMS/CFSPID after a long follow-up.

The picornavirus named 'Ljungan virus' (LV, species Parechovirus B ) has been detected in a dozen small mammal species from across Europe, but detailed information on its genetic diversity and host specificity is lacking. Here, we analyze the evolutionary relationships of LV variants circulating in free-living mammal populations by comparing the phylogenetics of the VP1 region (encoding the capsid protein and associated with LV serotype) and the 3D pol region (encoding the RNA polymerase) from 24 LV RNA-positive animals and a fragment of the 5' untranslated region (UTR) sequence (used for defining strains) in sympatric small mammals. We define three new VP1 genotypes: two in bank voles ( Myodes glareolus ) (genotype 8 from Finland, Sweden, France, and Italy, and genotype 9 from France and Italy) and one in field voles ( Microtus arvalis ) (genotype 7 from Finland). There are several other indications that LV variants are host-specific, at least in parts of their range. Our results suggest that LV evolution is rapid, ongoing and affected by genetic drift, purifying selection, spillover and host evolutionary history. Although recent studies suggest that LV does not have zoonotic potential, its widespread geographical and host distribution in natural populations of well-characterized small mammals could make it useful as a model for studying RNA virus evolution and transmission.

The development of new diagnostic methods resulted in the discovery of novel hepaciviruses in wild populations of the bank vole ( Myodes glareolus , syn. Clethrionomys glareolus ). The naturally infected voles demonstrate signs of hepatitis similar to those induced by hepatitis C virus (HCV) in humans. The aim of the present research was to investigate the geographical distribution of bank vole-associated hepaciviruses (BvHVs) and their genetic diversity in Europe. Real-time reverse transcription polymerase chain reaction (RT-qPCR) screening revealed BvHV RNA in 442 out of 1838 (24.0%) bank voles from nine European countries and in one of seven northern red-backed voles ( Myodes rutilus , syn. Clethrionomys rutilus ). BvHV RNA was not found in any other small mammal species (n = 23) tested here. Phylogenetic and isolation-by-distance analyses confirmed the occurrence of both BvHV species ( Hepacivirus F and Hepacivirus J ) and their sympatric occurrence at several trapping sites in two countries. The broad geographical distribution of BvHVs across Europe was associated with their presence in bank voles of different evolutionary lineages. The extensive geographical distribution and high levels of genetic diversity of BvHVs, as well as the high population fluctuations of bank voles and occasional commensalism in some parts of Europe warrant future studies on the zoonotic potential of BvHVs.

Ljungan virus (LV), which belongs to the Parechovirus genus in the Picornaviridae family, was first isolated from bank voles ( Myodes glareolus ) in Sweden in 1998 and proposed as a zoonotic agent. To improve knowledge of the host association and geographical distribution of LV, tissues from 1685 animals belonging to multiple rodent and insectivore species from 12 European countries were screened for LV-RNA using reverse transcriptase (RT)-PCR. In addition, we investigated how the prevalence of LV-RNA in bank voles is associated with various intrinsic and extrinsic factors. We show that LV is widespread geographically, having been detected in at least one host species in nine European countries. Twelve out of 21 species screened were LV-RNA PCR positive, including, for the first time, the red vole ( Myodes rutilus ) and the root or tundra vole ( Alexandromys formerly Microtus oeconomus ), as well as in insectivores, including the bicolored white-toothed shrew ( Crocidura leucodon ) and the Valais shrew ( Sorex antinorii ). Results indicated that bank voles are the main rodent host for this virus (overall RT-PCR prevalence: 15.2%). Linear modeling of intrinsic and extrinsic factors that could impact LV prevalence showed a concave-down relationship between body mass and LV occurrence, so that subadults had the highest LV positivity, but LV in older animals was less prevalent. Also, LV prevalence was higher in autumn and lower in spring, and the amount of precipitation recorded during the 6 months preceding the trapping date was negatively correlated with the presence of the virus. Phylogenetic analysis on the 185 base pair species-specific sequence of the 5' untranslated region identified high genetic diversity (46.5%) between 80 haplotypes, although no geographical or host-specific patterns of diversity were detected.

The board game Kaledo was proven to be effective in improving nutrition knowledge and in modifying dietary behavior in students attending middle and high school. The present pilot study aims to reproduce these results in younger students (7-11 years old) attending primary school. A total of 1313 children from ten schools were recruited to participate in the present study. Participants were randomized into two groups: (1) the treatment group which consisted of playing Kaledo over 20 sessions and (2) the no intervention group. Anthropometric measures were carried out for both groups at baseline (prior to any treatment) and at two follow-up post-assessments (8 and 18 months). All the participants completed a questionnaire concerning physical activity and a 1-week food diary at each assessment. The primary outcomes were (i) BMI z-score, (ii) scores on physical activity, and (iii) scores on a dietary questionnaire. BMI z-score was significantly lower in the treated group compared to the control group at 8 months. Frequency and duration of self-reported physical activity were also significantly augmented in the treated group compared to the control group at both post-assessments. Moreover, a significant increase in the consumption of healthy food and a significant decrease in junk food intake were observed in the treated group., Conclusion: The present results confirm the efficacy of Kaledo in younger students in primary schools, and it can be used as a useful nutritional tool for obesity prevention programs in children. What is Known: • Kaledo is a new educational board game to improve nutrition knowledge and to promote a healthy lifestyle. • In two cluster randomized trials conducted in Campania region (Italy), we showed that Kaledo could improve nutrition knowledge and dietary behavior and have a positive effect on the BMI z-score in children with age ranging from 9 to 14 years old attending school. • Kaledo may be used as an effective tool for obesity prevention programs in middle and high school students. What is New: • Investigating the effects of Kaledo on younger primary school children (7-11 year olds), Kaledo could be an effective tool in obesity prevention programs for children as young as 7 years old.

Directly-transmitted rodent-borne zoonotic viruses, such as lymphocytic choriomeningitis virus (LCMV) can cause nervous system infections. Rodent-borne Ljungan virus (LV) is considered potentially zoonotic possibly causing neurological symptoms. Our objective was to understand the role of these two viruses compared to other pathogens in causing neurological infections in Finnish patients. Routine screening data were available for 400 patients aged 5-50 years, collected from December 2013 to December 2014 with suspected neurological infection. Depending on symptoms, patients were variously tested for herpesviruses, enteroviruses, varicella zoster virus, and Mycoplasma pneumoniae, while those suspected of tick bite were further tested for Borrelia spp. and tick-borne encephalitis virus using antibody and/or nucleic acid tests. For 380 patients, we also screened the RNA and antibody prevalence of LCMV and LV in order to test if either of these viruses were the causative agent. Data collected indicated that the causative microbial agent was confirmed in only 15.5% of all Finnish patients with neurological symptoms, with M. pneumoniae (26 cases) being the most common causative agent found in sera, whereas Borrelia spp. (15), herpes simplex viruses (7), and enteroviruses (5) were the most common agents confirmed in the CSF. The seroprevalences for LV and LCMV were 33.8% and 5.0%, respectively, but no samples were PCR-positive. In this study, M. pneumoniae and Borrelia spp. were the most common causative agents of neurological infections in Finland. No LCMV or LV infections were detected. We conclude there was no association of LV with neurological diseases in this patient cohort., (© 2017 Wiley Periodicals, Inc.)

Ljungan virus (LV) is a picornavirus originally isolated from Swedish bank voles ( Myodes glareolus ) in 1998. The association of LV with human disease has been debated ever since, but fundamental data on the ecology of the virus are still lacking. Here we present results of the first intensive study on the prevalence of LV in bank voles trapped in Fennoscandia (Sweden and Finland) from 2009-12 as determined by PCR. Using an LV-specific real-time reverse transcriptase PCR, LV was detected in the liver of 73 out of 452 (16.2%) individuals and in 13 out of 17 sampling sites across Sweden and Finland (mean per site prevalence 16%, SE 3%, range 0-50%). We found more infected animals in autumn compared to spring, and lighter and heavier individuals had a higher prevalence than those with intermediate body masses. The result that LV prevalence is also lower in heavier (i.e., older) animals suggests for the first time that LV infection is not persistent in rodents.