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.

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.

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.

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.

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.

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.

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.

Local ablative therapy of oligoprogressive TKI-treated thyroid cancer.

Metastatic cancer patients generally respond well to treatment with tyrosine kinase inhibitors (TKIs). However, TKI resistance occurs in almost all cases and often leads to a change in treatment. Recent guidelines, including thyroid cancer, raised the possibility of locally treating TKI-resistant oligoprogressive disease, i.e., one or a few progressing lesions in an otherwise treatment-responsive metastatic cancer, thereby obviating the need to change the ongoing TKI. To determine the benefits of this intervention, we reviewed studies on the use of LAT for TKI-treated oligoprogressive cancers. We found that in non-small cell lung cancer at least, LAT prolongs disease control and the duration of exposure to a TKI irrespective of the LAT used. Moreover, we reviewed the local ablative therapies (LATs) that are feasible for the local control of oligoprogressive thyroid cancer. Lastly, we report two illustrative cases of patients with oligoprogressive thyroid cancer treated with two different LATs while on therapy with TKIs. Both LATs extended the duration of disease control and the time of exposure to the ongoing TKI, thereby indicating that LAT is a favorable option for TKI-treated oligoprogressive thyroid cancer. Prospective randomized studies are needed to verify the benefit of LATs in terms of progression-free and overall survival in this increasingly frequent clinical setting.

Behavior and breakdown of higher-order Fermi-Pasta-Ulam-Tsingou recurrences.

We numerically investigate the existence and stability of higher-order recurrences (HoRs), including super-recurrences, super-super-recurrences, etc., in the α and ß Fermi-Pasta-Ulam-Tsingou (FPUT) lattices for initial conditions in the fundamental normal mode. Our results represent a considerable extension of the pioneering work of Tuck and Menzel on super-recurrences. For fixed lattice sizes, we observe and study apparent singularities in the periods of these HoRs, speculated to be caused by nonlinear resonances. Interestingly, these singularities depend very sensitively on the initial energy and the respective nonlinear parameters. Furthermore, we compare the mechanisms by which the super-recurrences in the two models breakdown as the initial energy and respective nonlinear parameters are increased. The breakdown of super-recurrences in the ß-FPUT lattice is associated with the destruction of the so-called metastable state and thus with relaxation towards equilibrium. For the α-FPUT lattice, we find this is not the case and show that the super-recurrences break down while the lattice is still metastable and far from equilibrium. We close with comments on the generality of our results for different lattice sizes.

The ß Fermi-Pasta-Ulam-Tsingou recurrence problem.

We perform a thorough investigation of the first Fermi-Pasta-Ulam-Tsingou (FPUT) recurrence in the ß-FPUT chain for both positive and negative ß. We show numerically that the rescaled FPUT recurrence time Tr=tr/(N+1)3 depends, for large N, only on the parameter S≡Eß(N+1). Our numerics also reveal that for small |S|, Tr is linear in S with positive slope for both positive and negative ß. For large |S|, Tr is proportional to |S|-1/2 for both positive and negative ß but with different multiplicative constants. We numerically study the continuum limit and find that the recurrence time closely follows the |S|-1/2 scaling and can be interpreted in terms of solitons, as in the case of the KdV equation for the α chain. The difference in the multiplicative factors between positive and negative ß arises from soliton-kink interactions that exist only in the negative ß case. We complement our numerical results with analytical considerations in the nearly linear regime (small |S|) and in the highly nonlinear regime (large |S|). For the former, we extend previous results using a shifted-frequency perturbation theory and find a closed form for Tr that depends only on S. In the latter regime, we show that Tr∝|S|-1/2 is predicted by the soliton theory in the continuum limit. We then investigate the existence of the FPUT recurrences and show that their disappearance surprisingly depends only on Eß for large N, not S. Finally, we end by discussing the striking differences in the amount of energy mixing between positive and negative ß and offer some remarks on the thermodynamic limit.

Deiodinases and stem cells: an intimate relationship.

Thyroid hormone is a major determinant of tissue functions in vivo. The deiodinase family controls the tissue-specific activation or inactivation of intracellular thyroid hormones. Precise control of the T3-dependent transcriptional program is required by multiple cell systems, including the stem cell. In this context, the identification of a close connection between thyroid hormones and different signal pathways involved in the control of stem cell functions suggested that the deiodinases may play a role in the definition of stem cell biology and physiology. Stem cells have an unlimited self-renewal capacity and the potential to differentiate into different types of mature cells. Deciphering how all these events are achieved, how the T3 signal is controlled and integrated in stem cells and their niches, and how it can impact on them is essentially unknown and represents a challenge for coming years. In this review, I will explore the role played by the deiodinases in the modulation of the TH signal in stem cells of adult tissues, namely muscle and intestine, and how their actions control the delicate balance among self-renewal, proliferation and differentiation. Elucidation of the molecular mechanisms presiding thyroid hormone action in stem cells may reveal therapeutic potential, for example in the fields of regenerative diseases and cancer.

A Cross-Layer, Anomaly-Based IDS for WSN and MANET.

Intrusion detection system (IDS) design for mobile adhoc networks (MANET) is a crucial component for maintaining the integrity of the network. The need for rapid deployment of IDS capability with minimal data availability for training and testing is an important requirement of such systems, especially for MANETs deployed in highly dynamic scenarios, such as battlefields. This work proposes a two-level detection scheme for detecting malicious nodes in MANETs. The first level deploys dedicated sniffers working in promiscuous mode. Each sniffer utilizes a decision-tree-based classifier that generates quantities which we refer to as correctly classified instances (CCIs) every reporting time. In the second level, the CCIs are sent to an algorithmically run supernode that calculates quantities, which we refer to as the accumulated measure of fluctuation (AMoF) of the received CCIs for each node under test (NUT). A key concept that is used in this work is that the variability of the smaller size population which represents the number of malicious nodes in the network is greater than the variance of the larger size population which represents the number of normal nodes in the network. A linear regression process is then performed in parallel with the calculation of the AMoF for fitting purposes and to set a proper threshold based on the slope of the fitted lines. As a result, the malicious nodes are efficiently and effectively separated from the normal nodes. The proposed scheme is tested for various node velocities and power levels and shows promising detection performance even at low-power levels. The results presented also apply to wireless sensor networks (WSN) and represent a novel IDS scheme for such networks.

Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination.

New bifunctional phase transfer agents were synthesized and investigated for their abilities to promote rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in molecular imaging with positron emission tomography (PET). The hydrolysis-resistant aryl silicon fragment is promising as a convenient synthon for labeling potential PET radiotracers.

Allenyl esters as quenching agents for ruthenium olefin metathesis catalysts.

In the attempt to synthesize substituted allenyl esters through a metathesis coupling of unsubstituted allenyl esters and alkenes using a variety of ruthenium catalysts, it was discovered that allenyl esters themselves cleanly arrested the activity of the catalysts. Further studies suggests possible utility of allene esters as general quenching agents for metathesis reactions. To explore this idea, several representative olefin metathesis reactions, including ring closing, were successfully terminated by the addition of simple allenyl esters for more convenient purification.

Appropriateness of percutaneous revascularization of coronary chronic total occlusions: an overview.

Coronary chronic total occlusions (CTOs) are commonly encountered in patients undergoing coronary angiography. Several observational studies have demonstrated that successful CTO revascularization is associated with better cardiovascular outcomes and enhanced quality of life (QOL). However, in the absence of randomized trials, its prognostic benefit for patients remains debated. Over the past decade, the interest of the interventional community in CTO percutaneous coronary intervention (PCI) has exponentially grown due to important developments in dedicated equipment and techniques, resulting in high success and low complication rates. Both European and American guidelines have assigned a class IIa (level of evidence B) recommendation for CTO PCI. In the current review, we focus on the impact of CTO revascularization on clinical outcomes and QOL and on appropriate patient selection, and we provide a critical assessment of the current guidelines and recommendations on CTO PCI.

A Teaching Experiment to Elucidate a Cation-π Effect in an Alkyne Cycloaddition Reaction and Illustrate Hypothesis Driven Design of Experiments.

An organic chemistry experiment is described that is based on recent research to elucidate a novel cation-π interaction between tetraalkammonium cations and propargyl hydrazines. This non-bonded interaction is a key component of the mechanism of ammonium-catalyzed intramolecular cycloaddition of nitrogen to the terminal carbon of a C-C triple bond of the propargyl substrate. In this teaching experiment, reactions and control experiments are employed to demonstrate the testing of two alternative mechanistic hypotheses. Specifically, cyclization reactions are performed with a soluble base (sodium phenoxide) with and without tetrabutylammonium bromide under homogeneous conditions. Students observe that the added ammonium salt accelerates the reaction. They are then encouraged to develop a testable hypothesis for the role of the ammonium salt in the cyclization mechanism: typical phase transfer or other. IR spectroscopy is then used to directly observe a dose dependent shift of the alkyne stretching mode due to a cation-π interaction. In this experiment, undergraduate "researchers" were able to practice the scientific method on a contemporary system and see how data are generated and interpreted to adjudicate between rival hypotheses in a way that emulates authentic and current research in a lab setting. This experimental design was tested on students enrolled in the introductory undergraduate Organic Chemistry Lab.

Characterization of developmental Na(+) uptake in rainbow trout larvae supports a significant role for Nhe3b.

Developing freshwater fish must compensate for the loss of ions, including sodium (Na(+)), to the environment. In this study, we used a radiotracer flux approach and pharmacological inhibitors to investigate the role of sodium/hydrogen exchange proteins (Nhe) in Na(+) uptake in rainbow trout (Oncorhynchus mykiss) reared from fertilization in soft water (0.1mM Na(+)). For comparison, a second group of embryos/larvae reared in hard water (2.2mM Na(+), higher pH and [Ca(2+)]) were also included in the experiment but were fluxed in soft water, only. Unidirectional rates of Na(+) uptake increased throughout development and were significantly higher in embryos/larvae reared in soft water. However, the mechanisms of Na(+) uptake in both groups of larvae were not significantly different, either in larvae immediately post-hatch or later in development: the broad spectrum Na(+) channel blocker amiloride inhibited 85-90% of uptake and the Nhe-inhibitor EIPA also caused near maximal inhibitions of Na(+) uptake. These data indicated Na(+) uptake was Nhe-mediated in soft water. A role of Nhe3b (but not Nhe2 or Nhe3a) in Na(+) uptake in soft water was also supported through gene expression analyses: expression of nhe3b increased throughout development in whole embryos/larvae in both groups and was significantly higher in those reared in soft water. This pattern of expression correlated well with measurements of Na(+) uptake. Together these data indicate that in part, rainbow trout embryos/larvae reared in low Na(+) soft water maintained Na(+) homeostasis by an EIPA sensitive component of Na(+) uptake, and support a primary role for Nhe3b.

Management strategies in patients affected by chronic total occlusions: results from the Italian Registry of Chronic Total Occlusions.

BACKGROUND: Through contemporary literature, the optimal strategy to manage coronary chronic total occlusions (CTOs) remains under debate. OBJECTIVES: The aim of the Italian Registry of Chronic Total Occlusions (IRCTO) was to provide data on prevalence, characteristics, and outcome of CTO patients according to the management strategy. METHODS: The IRCTO is a prospective real world multicentre registry enrolling patients showing at least one CTO. Clinical and angiographic data were collected independently from the therapeutic strategy [optimal medical therapy (MT), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)]; a comparative 1-year clinical follow-up was performed. RESULTS: A total of 1777 patients were enrolled for an overall CTO prevalence of 13.3%. The adopted therapeutic strategies were as follows: MT in 826 patients (46.5%), PCI in 776 patients (43.7%), and CABG in the remaining 175 patients (9.8%). At 1-year follow-up, patients undergoing PCI showed lower rate of major adverse cardiac and cerebrovascular events (MACCE) (2.6% vs. 8.2% and vs. 6.9%; P < 0.001 and P < 0.01) and cardiac death (1.4% vs. 4.7% and vs. 6.3%; P < 0.001 and P < 0.001) in comparison with those treated with MT and CABG, respectively. After propensity score-matching analysis, patients treated with PCI showed lower incidence of cardiac death (1.5 vs. 4.4%; P < 0.001), acute myocardial infarction (1.1 vs. 2.9%; P = 0.03), and re-hospitalization (2.3 vs. 4.4% P = 0.04) in comparison with those managed by MT. CONCLUSIONS: Our data showed how CTO PCI might significantly improve the survival and decrease MACCE occurrence at 1 year follow-up in comparison with MT and/or CABG.

Ammonia excretion in the Atlantic hagfish (Myxine glutinosa) and responses of an Rhc glycoprotein.

Hagfishes, the most ancient of the extant craniates, demonstrate a high tolerance for a number of unfavorable environmental conditions, including elevated ammonia. Proposed mechanisms of ammonia excretion in aquatic organisms include vesicular NH(4)(+) transport and release by exocytosis in marine crabs, and passive NH(3) diffusion, active NH(4)(+) transport, and paracellular leakage of NH3 or NH(4)(+) across the gills of fishes. Recently, an emerging paradigm suggests that Rhesus glycoproteins play a vital role in ammonia transport in both aquatic invertebrates and vertebrates. This study has identified an Rh glycoprotein ortholog from the gills of Atlantic hagfish. The hagfish Rhcg shares a 56-60% amino acid identity to other vertebrate Rhcg cDNAs. Sequence information was used to produce an anti-hagfish Rhcg (hRhcg) antibody. We have used hRhcg to localize protein expression to epithelial cells of the gill and the skin. In addition, we have quantified hRhcg expression following exposure to elevated plasma ammonia levels. Animals exposed to a 3 mmol/kg NH(4)Cl load resulted in significantly elevated plasma ammonia concentrations compared with controls for up to 4 h postinjection. This correlated with net ammonia excretion rates that were also significantly elevated for up to 4 h postinjection. Rhcg mRNA expression in both the gill and skin was significantly elevated by 15 min and 1 h, respectively, and hRhcg protein expression in gills was significantly elevated at 2, 4, and 8 h postinjection. These results demonstrate a potential role for Rhcg in the excretion of ammonia in the Atlantic hagfish.