Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least one F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: 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 one 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 0·026). 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.

Antimicrobial resistance in wildlife: detection of antimicrobial resistance genes in Apennine wolves (Canis lupus italicus Altobello, 1921) from Central Italy.

The aim of this study was to molecularly investigate the presence of antimicrobial resistance genes (ARGs) in organ samples from 11 Apennine wolves (Canis lupus italicus) collected in Central Italy. Samples from lung, liver, spleen, kidney, tongue and intestine were investigated by PCRs targeting the following genes: tet(A), tet(B), tet(C), tet(D), tet(E), tet(G), tet(K), tet(L), tet(M), tet(O), tetA(P), tet(Q), tet(S), tet(X), sul1, sul2, sul3, blaCTX-M, blaSHV, blaTEM and mcr-1. A PCR positivity was highlighted for 13 out of the 21 tested genes; no positive results were obtained for tet(C), tet(D), tet(E), tet(G), sul3, blaCTX, blaSHV and mcr-1 genes. All 11 animals sampled showed positivity for one or more resistance genes. The results confirm the potential role of the wolf as an indicator and/or vector of antimicrobial-resistant bacteria or ARGs.

Bridged bicyclic compounds: Comprehending a novel compound class as potential anti-seizure agents.

OBJECTIVE: In the present study, we describe a novel class of small-molecule synthetic compounds that ameliorate seizure-like behavior, using an electroshock assay to examine seizure duration in Caenorhabditis elegans. We also examine the hypothesis that these compounds, which we have called resveramorphs (RVMs), act by an irreversible binding mechanism. METHODS: Our electroshock assay examines seizure duration in C. elegans and can be used as a drug-screening platform for the identification of novel anti-seizure agents. The use of C. elegans allows for a rapid and efficient method of drug screening that may take years in other higher-order model organisms. A novel wash method, paired with our electroshock assay, allows us to discern differences in biological activity when the C. elegans are incubated in different drug solutions, to establish whether these compounds can be "washed" off. RESULTS: One of the RVMs (RVM-3), reported here for the first time, was found to be potent at picomolar concentrations. Insights also provided information on the potential mechanisms of action of this compound. Covalent binding is thought to provide a strong irreversible bond because of a change in structure between two of the novel RVMs described in this work. This was also discerned through the novel wash method paired with our electroshock assay. SIGNIFICANCE: RVM-3 was evaluated using our assay and found to possess anti-seizure activity at picomolar concentrations. These insights also provide information on the potential mechanisms of action of these compounds, which may include covalent binding. This was also discerned through a novel wash method paired with our electroshock assay.

Antimicrobial resistance genes in a golden jackal (Canis aureus L. 1758) from Central Italy.

In recent years an increasing interest has been focused on the contribution of wildlife in ecology and evolution of the antimicrobial resistance (AMR). The aim of this study was to molecularly investigate the presence of antimicrobial resistance genes (ARGs) in organ samples from a golden jackal (Canis aureus) found dead in the Marche region (Central Italy). Samples from lung, liver, spleen, kidney, and intestine were investigated by PCRs targeting the following genes: tet(A), tet(B), tet(C), tet(D), tet(E), tet(G), tet(K), tet(L), tet(M), tet(O), tet(S), tet(P), tet(Q), tet(X), sul1, sul2, sul3, blaCTX-M, blaSHV, blaTEM, and mcr-1 to mcr-10. One or more ARGs were detected in all organs tested, except the spleen. Specifically, the lung and liver were positive for tet(M) and tet(P), the kidney for mcr-1 and the intestine for tet(A), tet(L), tet(M), tet(O), tet(P), sul3 and blaTEM-1. These results, according to the opportunistic foraging strategy of the jackal, confirm its potential role as a good bioindicator of AMR environmental contamination.

Dynamical Axions in U(1) Quantum Spin Liquids.

Since their proposal nearly half a century ago, physicists have sought axions in both high energy and condensed matter settings. Despite intense and growing efforts, to date, experimental success has been limited, with the most prominent results arising in the context of topological insulators. Here, we propose a novel mechanism whereby axions can be realized in quantum spin liquids. We discuss the necessary symmetry requirements and identify possible experimental realizations in candidate pyrochlore materials. In this context, the axions couple to both the external and the emergent electromagnetic fields. We show that the interaction between the axion and the emergent photon leads to a characteristic dynamical response, which can be measured experimentally in inelastic neutron scattering. This Letter sets the stage for studying axion electrodynamics in the highly tunable setting of frustrated magnets.

Chiral Allenylcarbonyls - Underexploited Building Blocks for Complex Synthesis.

Chiral allenylcarbonyls such as allenoates remain underutilized in complex synthesis despite recent advances in synthesis methods to prepare them non-racemically. The field is now ripe for the employment of this class of allenes as building blocks to facilitate the construction of complex small-molecule compounds, such as bridged bicycles.

Could incremental haemodialysis be a new standard of care? A suggestion from a long-term observational study.

Introduction: The term incremental haemodialysis (HD) means that both dialysis dose and frequency can be low at dialysis inception but should be progressively increased, to compensate for any subsequent reduction in residual kidney function. Policy of the Matera Dialysis Center is to attempt an incremental start of HD without a strict low-protein diet in all patients choosing HD and with urine output (UO) >500 ml/day. The present study aimed at analyzing the results of this policy over the last 20 years. Subjects and methods: The dataset of all patients starting HD between January 1st, 2000 and December 31st, 2019 was retrieved from the local electronic database. Exclusion criteria were: urine output <500 ml/day or follow-up <3 months after the start of the dialysis treatment. Results: A total of 266 patients were retrieved; 64 of them were excluded from the study. The remaining 202 patients were enrolled into the study and subdivided into 3 groups (G1, G2 and G3) according to the frequency of treatment at the start of dialysis: 117 patients (57.9%) started with once-a-week (1HD/wk) (G1); 46 (22.8%) with twice-a-week (2HD/wk) (G2); 39 (19.3%) with thrice-a-week (3HD/wk) dialysis regimen (G3). Patients of G1 remained on 1HD/wk for 11.9 ±14.8 months and then transferred to 2HD/wk for further 13.0 ±20.3 months. Patients of G2 remained on 2HD/wk for 16.7 ±23.2 months. Altogether, 25943 sessions were administered during the less frequent treatment periods instead of 47988, that would have been delivered if the patients had been on 3HD/wk, thus saving 22045 sessions (45.9%). Gross mortality of the entire group was 12.6%, comparable to the mean mortality of the Italian dialysis population (16.2%). Survival at 1 and 5 years was not significantly different among the 3 groups: 94% and 61% (G1); 83% and 39% (G2); 84% and 46% (G3). Conclusions: Our long-term observational study suggests that incremental HD is a valuable option for incident patients. For most of them (80.7%) it is viable for about 1-2 years, with obvious socio-economic benefits and survival rates comparable to that of the Italian dialysis population. However, randomized controlled trials are lacking and therefore urgently needed. If they will confirm observational data, incremental HD will be a new standard of care.

Parsimonious hidden Markov models for matrix-variate longitudinal data.

Hidden Markov models (HMMs) have been extensively used in the univariate and multivariate literature. However, there has been an increased interest in the analysis of matrix-variate data over the recent years. In this manuscript we introduce HMMs for matrix-variate balanced longitudinal data, by assuming a matrix normal distribution in each hidden state. Such data are arranged in a four-way array. To address for possible overparameterization issues, we consider the eigen decomposition of the covariance matrices, leading to a total of 98 HMMs. An expectation-conditional maximization algorithm is discussed for parameter estimation. The proposed models are firstly investigated on simulated data, in terms of parameter recovery, computational times and model selection. Then, they are fitted to a four-way real data set concerning the unemployment rates of the Italian provinces, evaluated by gender and age classes, over the last 16 years.

Diastereoselective additions of H-phosphinates to alkenyl ketones under phase-transfer conditions.

Additions of bulky H-phosphinates to ß,ß-disubstituted alkenyl ketones under the action of a phase transfer-catalyst led to a new class of carbon quaternary center-containing phosphinates with unprecedented control of the relative configuration of the adjacent carbon and phosphorous chiral centers with high diastereoselectivity in most cases.

Emergent Fine Structure Constant of Quantum Spin Ice Is Large.

Condensed-matter systems provide alternative "vacua" exhibiting emergent low-energy properties drastically different from those of the standard model. A case in point is the emergent quantum electrodynamics (QED) in the fractionalized topological magnet known as quantum spin ice, whose magnetic monopoles set it apart from the familiar QED of the world we live in. Here, we show that the two greatly differ in their fine structure constant α, which parametrizes how strongly matter couples to light: α_{QSI} is more than an order of magnitude greater than α_{QED}≈1/137. Furthermore, α_{QSI}, the emergent speed of light, and all other parameters of the emergent QED, are tunable by engineering the microscopic Hamiltonian. We find that α_{QSI} can be tuned all the way from zero up to what is believed to be the strongest possible coupling beyond which QED confines. In view of the small size of its constrained Hilbert space, this marks out quantum spin ice as an ideal platform for studying exotic quantum field theories and a target for quantum simulation. The large α_{QSI} implies that experiments probing candidate condensed-matter realizations of quantum spin ice should expect to observe phenomena arising due to strong interactions.

Molecular and biochemical characterization of the bicarbonate-sensing soluble adenylyl cyclase from a bony fish, the rainbow trout Oncorhynchus mykiss.

Soluble adenylyl cyclase (sAC) is a HC O 3 - -stimulated enzyme that produces the ubiquitous signalling molecule cAMP, and deemed an evolutionarily conserved acid-base sensor. However, its presence is not yet confirmed in bony fishes, the most abundant and diverse of vertebrates. Here, we identified sAC genes in various cartilaginous, ray-finned and lobe-finned fish species. Next, we focused on rainbow trout sAC (rtsAC) and identified 20 potential alternative spliced mRNAs coding for protein isoforms ranging in size from 28 to 186 kDa. Biochemical and kinetic analyses on purified recombinant rtsAC protein determined stimulation by HC O 3 - at physiologically relevant levels for fish internal fluids (EC50 ∼ 7 mM). rtsAC activity was sensitive to KH7, LRE1, and DIDS (established inhibitors of sAC from other organisms), and insensitive to forskolin and 2,5-dideoxyadenosine (modulators of transmembrane adenylyl cyclases). Western blot and immunocytochemistry revealed high rtsAC expression in gill ion-transporting cells, hepatocytes, red blood cells, myocytes and cardiomyocytes. Analyses in the cell line RTgill-W1 suggested that some of the longer rtsAC isoforms may be preferentially localized in the nucleus, the Golgi apparatus and podosomes. These results indicate that sAC is poised to mediate multiple acid-base homeostatic responses in bony fishes, and provide cues about potential novel functions in mammals.

Higher baseline TSH levels predict early hypothyroidism during cancer immunotherapy.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance the immune response against cancer cells. ICIs are generally well tolerated, although endocrine immune-related adverse events (irAEs) are common. We investigated the risk factors for thyroid irAEs in patients treated with ICIs. Moreover, we evaluated the clinical outcome of subjects who became hypothyroid compared to euthyroid patients. PATIENTS AND METHODS: We retrospectively analyzed a series of 195 consecutively subjects treated with ICIs for metastatic tumors at the University of Naples "Federico II" between January 2014 and March 2020. Only subjects tested for thyroid function before and during the treatment with ICIs were included. RESULTS: In the 96 patients treated with ICIs who were included [66 males, median age: 62 years (27-87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was preceded by a transient thyrotoxicosis). Only baseline TSH levels above 1.67 mIU/L and positive anti-thyroid antibodies (Ab-T) were associated with a higher risk of hypothyroidism. Patients with hypothyroidism during ICI treatment showed an improved 2-year PFS (HR = 0.82 CI 0.47-1.43; p = 0.0132) and OS (HR = 0.38 CI 95% 0.17-0.80; p = 0.011) compared to euthyroid patients. CONCLUSIONS: Baseline TSH levels above 1.67 mIU/L and presence of Ab-T are risk factors for the development of thyroid irAEs. Patients affected by thyroid irAEs showed a longer survival than patients who remained euthyroid.

BROX haploinsufficiency in familial nonmedullary thyroid cancer.

BACKGROUND: The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3-8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim. METHODS: We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value. RESULTS: A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied. CONCLUSIONS: BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

Consequences of atmospheric contamination by radioiodine: the Chernobyl and Fukushima accidents.

PURPOSE: After the accidents of nuclear power plants at Chernobyl and at Fukushima, huge amounts of radioactive iodine were released into the atmosphere. METHODS: We reviewed data on the health consequences of these accidents with a focus on thyroid consequences. RESULTS: Among the 2 million children who were living in highly contaminated regions in Belarus, Ukraine and Russia, 7000 cases of thyroid cancer had occurred in 2005. This is the most significant radiation-induced consequence of the Chernobyl accident. The increased incidence of thyroid cancer observed in adult population who lived in these highly contaminated regions is at least in major part related to screening and it is not possible to individualize among these thyroid cancers those that are potentially caused by radiation exposure. For populations who lived outside these regions at the time of the accident, there is no detectable consequence of the radiation exposure on the thyroid gland. Among children who lived nearby the Fukushima power plant in 2011, there is currently no evidence of an increased incidence of thyroid cancer. Ultrasonography screening in these individuals detected a number of thyroid cancers that are probably not related to the accident. Because thyroid cancer is frequent, studies have been carried out to distinguish radiation-induced from their sporadic counterparts, and genomic signatures might be helpful. CONCLUSIONS: The consequences of the Chernobyl accident clearly demonstrate that populations living nearby a nuclear power plant should be protected in case of accident by sheltering, food restrictions and prophylaxis of thyroid irradiation by potassium iodine administration, if the predicted estimated dose to the thyroid gland of children might be >50 mGy. These countermeasures should be applied in priority to children, adolescents and pregnant women; they are safe and effective.

The Influence of Small Intestinal Bacterial Overgrowth in Digestive and Extra-Intestinal Disorders.

Small intestinal bacterial overgrowth (SIBO) is a condition hallmarked by an increase in the concentration of colonic-type bacteria in the small bowel. Watery diarrhea, bloating, abdominal pain and distension are the most common clinical manifestations. Additionally, malnutrition and vitamin (B12, D, A, and E) as well as minerals (iron and calcium) deficiency may be present. SIBO may mask or worsen the history of some diseases (celiac disease, irritable bowel disease), may be more common in some extra-intestinal disorders (scleroderma, obesity), or could even represent a pathogenetic link with some diseases, in which a perturbation of intestinal microbiota may be involved. On these bases, we performed a review to explore the multiple links between SIBO and digestive and extra-intestinal diseases.

A Machine Learning Based Intrusion Detection System for Mobile Internet of Things.

Intrusion detection systems plays a pivotal role in detecting malicious activities that denigrate the performance of the network. Mobile adhoc networks (MANETs) and wireless sensor networks (WSNs) are a form of wireless network that can transfer data without any need of infrastructure for their operation. A more novel paradigm of networking, namely Internet of Things (IoT) has emerged recently which can be considered as a superset to the afore mentioned paradigms. Their distributed nature and the limited resources available, present a considerable challenge for providing security to these networks. The need for an intrusion detection system (IDS) that can acclimate with such challenges is of extreme significance. Previously, we proposed a cross layer-based IDS with two layers of detection. It uses a heuristic approach which is based on the variability of the correctly classified instances (CCIs), which we refer to as the accumulated measure of fluctuation (AMoF). The current, proposed IDS is composed of two stages; stage one collects data through dedicated sniffers (DSs) and generates the CCI which is sent in a periodic fashion to the super node (SN), and in stage two the SN performs the linear regression process for the collected CCIs from different DSs in order to differentiate the benign from the malicious nodes. In this work, the detection characterization is presented for different extreme scenarios in the network, pertaining to the power level and node velocity for two different mobility models: Random way point (RWP), and Gauss Markov (GM). Malicious activity used in the work are the blackhole and the distributed denial of service (DDoS) attacks. Detection rates are in excess of 98% for high power/node velocity scenarios while they drop to around 90% for low power/node velocity scenarios.

Dichotomous unimodal compound models: application to the distribution of insurance losses.

A correct modelization of the insurance losses distribution is crucial in the insurance industry. This distribution is generally highly positively skewed, unimodal hump-shaped, and with a heavy right tail. Compound models are a profitable way to accommodate situations in which some of the probability masses are shifted to the tails of the distribution. Therefore, in this work, a general approach to compound unimodal hump-shaped distributions with a mixing dichotomous distribution is introduced. A 2-parameter unimodal hump-shaped distribution, defined on a positive support, is considered and reparametrized with respect to the mode and to another parameter related to the distribution variability. The compound is performed by scaling the latter parameter by means of a dichotomous mixing distribution that governs the tail behavior of the resulting model. The proposed model can also allow for automatic detection of typical and atypical losses via a simple procedure based on maximum a posteriori probabilities. Unimodal gamma and log-normal are considered as examples of unimodal hump-shaped distributions. The resulting models are firstly evaluated in a sensitivity study and then fitted to two real insurance loss datasets, along with several well-known competitors. Likelihood-based information criteria and risk measures are used to compare the models.

Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience.

BACKGROUND: As a consequence of the improvement in survival after solid organ transplantation, to visit transplant recipients with neoplastic and non-neoplastic skin disorders due to immunosuppressive treatment has become common for dermatologists. METHODS: Our endpoints were: 1) to investigate the most common skin diseases in a population of transplant recipients; 2) their associations with the type of immunosuppressant or transplant received; and 3) to compare our single center 40-year experience with the literature data. We retrospectively analyzed the clinical details of the adult patients transplanted in the years 1974-2014, visited for consultation at the Unit of Dermatology of our hospital. RESULTS: Pathologic conditions were observed in more than 3/4 of 812 adults during the follow-up (mean 12.1 years): nonmelanoma skin cancers or actinic keratoses were seen in 44.0% (N.=357) of patients, non-neoplastic events in 55.2% (N.=448). Heart transplant had the statistically significant highest rate of NMSC and AK (52.6%, P=0.0352). Patients receiving cyclosporine A developed at least one non-melanoma skin cancer or actinic keratosis in 57.7% of cases (P=0.0001), while tacrolimus showed a lower risk (33%, P=0.0001). CONCLUSIONS: As transplant recipients are susceptible to skin changes, especially after immunosuppressant treatments, a dermatological follow-up should be scheduled for each patient.