Safety and effectiveness of direct-acting antiviral drugs in the treatment of hepatitis C in patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) management in Inflammatory Bowel Disease (IBD) is uncertain. The ECCO guidelines 2021 recommended HCV treatment but warn about the risk of IBD reactivation. We aimed to evaluate 1) the effectiveness and safety of direct-acting antivirals (DAAs) in IBD; 2) the interaction of DAAs with IBD drugs. METHODS: Multicentre study of IBD patients and HCV treated with DAAs. Variables related to liver diseases and IBD, as well as adverse events (AEs) and drug interactions, were recorded. McNemar's test was used to assess differences in the proportion of active IBD during the study period. RESULTS: We included 79 patients with IBD and HCV treated with DAAs from 25,998 IBD patients of the ENEIDA registry. Thirty-one (39.2 %) received immunomodulators/biologics. There were no significant differences in the percentage of active IBD at the beginning (n = 11, 13.9 %) or at the 12-week follow-up after DAAs (n = 15, 19 %) (p = 0.424). Sustained viral response occurred in 96.2 % (n = 76). A total of 8 (10.1 %) AEs occurred and these were unrelated to activity, type of IBD, liver fibrosis, immunosuppressants/biologics, and DAAs. CONCLUSIONS: We demonstrate a high efficacy and safety of DAAs in patients with IBD and HCV irrespective of activity and treatment of IBD.

Low ALT values amongst hospitalized patients are associated with increased risk of hypoglycemia and overall mortality: a retrospective, big-data analysis of 51 831 patients.

BACKGROUND: Sarcopenia and frailty influence clinical patients' outcomes. Low alanine aminotransferase (ALT) serum activity is a surrogate marker for sarcopenia and frailty. In-hospital hypoglycemia is associated, also with worse clinical outcomes. AIM: We evaluated the association between low ALT, risk of in-hospital hypoglycemia and subsequent mortality. DESIGN: This was a retrospective cohort analysis. METHODS: We included patients hospitalized in a tertiary hospital between 2007 and 2019. Patients' data were retrieved from their electronic medical records. RESULTS: The cohort included 51 831 patients (average age 70.88). The rate of hypoglycemia was 10.8% (amongst diabetics 19.4% whereas in non-diabetics 8.3%). The rate of hypoglycemia was higher amongst patients with ALT < 10 IU/l in the whole cohort (14.3% vs. 10.4%, P < 0.001) as well as amongst diabetics (24.6% vs. 18.8%, P < 0.001). Both the overall and in-hospital mortality were higher in the low ALT group (57.7% vs. 39.1% P < 0.001 and 4.3% vs. 3.2%, P < 0.001). A propensity score matching, after which a regression model was performed, showed that patients with ALT levels < 10 IU/l had higher risk of overall mortality (HR = 1.21, CI 1.13-1.29, P < 0.001). CONCLUSIONS: Low ALT values amongst hospitalized patients are associated with increased risk of in-hospital hypoglycemia and overall mortality.

Nanoscale refractory doped titanium nitride field emitters.

Refractory materials exhibit high damage tolerance, which is attractive for the creation of nanoscale field-emission electronics and optoelectronics applications that require operation at high peak current densities and optical intensities. Recent results have demonstrated that the optical properties of titanium nitride, a refractory and CMOS-compatible plasmonic material, can be tuned by adding silicon and oxygen dopants. However, to fully leverage the potential of titanium (silicon oxy)nitride, a reliable and scalable fabrication process with few-nm precision is needed. In this work, we developed a fabrication process for producing engineered nanostructures with gaps between 10 and 15 nm, aspect ratios larger than 5 with almost 90° steep sidewalls. Using this process, we fabricated large-scale arrays of electrically-connected bow-tie nanoantennas with few-nm free-space gaps. We measured a typical variation of 4 nm in the average gap size. Using applied DC voltages and optical illumination, we tested the electronic and optoelectronic response of the devices, demonstrating sub-10 V tunneling operation across the free-space gaps, and quantum efficiency of up to 1 × 10-3at 1.2µm, which is comparable to a bulk silicon photodiode at the same wavelength and three orders of magnitude higher than with nearly identical gold devices. Tests demonstrated that the titanium silicon oxynitride nanostructures did not significantly degrade, exhibiting less than 5 nm of shrinking of the average gap dimensions over few-µm2areas after 10 h of operation. Our results will be useful for developing the next generation of robust and CMOS-compatible nanoscale devices for high-speed and low-power field-emission electronics and optoelectronics applications.

Effects of the Antiparasitic Drug Moxidectin in Cattle Dung on Zooplankton and Benthic Invertebrates and its Accumulation in a Water-Sediment System.

Two anthelmintic macrocyclic lactones-ivermectin and moxidectin-have revolutionized parasite control in cattle. These drugs are only partly metabolized by livestock, and the main route of excretion is via feces. In seasonally inundated floodplains, cattle feces come into direct contact with surface water. Important differences in pharmacokinetics and pharmacodynamics between these drugs may bear on their ecotoxicology in aquatic ecosystems. Moxidectin strongly binds to organic matter and thereby may be consumed in aquatic food webs, but there is a scarcity of data on toxicity to freshwater invertebrates. The objectives of this work were to determine the effect of moxidectin spiked in cattle dung on survival and growth of three representative aquatic invertebrates: the zooplankton Ceriodaphnia dubia, the amphipod Hyalella curvispina, and the snail Pomacea canaliculata. Moxidectin-laced dung was added in microcosms and concentrations were measured in water, sediment + dung, roots of the aquatic plant Salvinia biloba, and the aforementioned invertebrates. The influence of moxidectin on nutrient concentrations was also evaluated. Dung was spiked with moxidectin to attain concentrations of 750, 375 and 250 µg kg-1 dung fresh weight, approximating those found in cattle dung at days 2, 3, and 5 following subcutaneous injection. Concentrations of moxidectin in dung during the first week of excretion were lethally toxic for the tested invertebrate taxa. The persistence of moxidectin in the sediment + dung and the uptake of the drug in roots of S. biloba increase its potential exposure to aquatic food webs. Moxidectin also reduced the rate of release of soluble reactive phosphorus to the water.

Aquatic toxicity of ivermectin in cattle dung assessed using microcosms.

Ivermectin (IVM) is a parasiticide widely used for livestock. It is a semisynthetic derivative of avermectin, a macrocyclic lactone produced by Streptomyces avermitilis. This drug is only partly metabolized by livestock; considerable amounts of parent drug are excreted mostly via feces. To simulate exposure of aquatic invertebrates and macrophytes to direct excretion of cattle dung into surface waters, a microcosm experiment with IVM spiked in cattle dung was conducted. The objectives of this study were to characterize accumulation of IVM in water, sediment+dung, roots of the floating fern Salvinia and the zooplankton Ceriodaphnia dubia, the amphipod Hyalella and the apple snail Pomacea; to determine the effect of this drug spiked in cattle dung on life-history traits of these invertebrates; and to evaluate the influence of IVM on aquatic nutrient cycling. Dung was spiked with IVM to attain concentrations of 1150, 458, 50 and 22µgkg-1dung fresh weight, approximating those found in cattle dung at days 3, 7, 16 and 29 following subcutaneous injection. Concentrations found in dung during the first week of excretion were lethally toxic to Ceriodaphnia dubia and Hyalella, whereas no mortality was observed in Pomacea. Concentrations of IVM in roots, sediment + dung and Pomacea increased significantly from the lowest to the highest treatment level. The effect of this drug on decomposition and release of nutrients from dung would have negative consequences for nutrient cycling in water. Increasing concentrations in sediment + dung with days of the experiment suggested that toxic concentrations would persist for an extended period in the water-sediment system. IVM represents an ecological risk for aquatic ecosystems, underscoring the need for livestock management strategies to limit its entry into water bodies.

Photonic-plasmonic-coupled nanoantennas for polarization-controlled multispectral nanofocusing.

We report on the design and experimental demonstration of array-enhanced nanoantennas for polarization-controlled multispectral nanofocusing in the near-IR spectral range. We design plasmonic double bow-tie nanoantennas-coupled to multiple-periodic nanoparticle arrays to harvest radiation of designed wavelengths from a large spatial area and to focus it into a targeted nanoscale region. Near-field calculations were performed on a gold nanoantenna array using three-dimensional finite difference time domain simulations. Cross-shaped optical nanoantennas were fabricated on glass substrates using electron beam lithography. The optical characterization of the fabricated nanoantennas was performed using second harmonic excitation spectroscopy that demonstrates multiwavelength photonic coupling in good agreement with the antenna modeling. The nanoantenna structures introduced in this Letter provide the ability to focus optical energy into deep subwavelength areas and to address multiple spectral regions with polarization control. Such attributes are highly desirable in optical biosensing, enhanced Raman scattering, and for nonlinear plasmonic applications.

New insights in mast cell modulation by palmitoylethanolamide.

Since its discovery palmitoylethanolamide was considered as an endogenous compound able to negatively modulate the inflammatory process. Its effects have been extensively investigated in in vitro, in vivo and in clinical studies. Notwithstanding some discrepancy, nowadays the efficacy of palmitoylethanolamide in controlling mast cell behaviour, which likely accounts for its many anti-inflammatory, anti-angiogenic and analgesic effects, is well recognized. In view of their strategic localization at sites directly interfacing with the external environment, mast cells act as surveillance antennae against different types of injury and can undergo activation, thereby regulating both innate and adaptive immune reactions through the release of several preformed and newly synthesized mediators. Mast cells are now viewed as key players in orchestrating several disorders including both acute and chronic inflammatory processes, and have a role in angiogenesis and hyperalgesia. Since mast cells exert also important physiological, homeostatic functions, the most recent goal for pharmacologists is to control, rather than block, mast cell degranulation in order to modulate the pathological scenario. The aim of the present review is to summarise the evidence regarding the role played by palmitoylethanolamide in the control of mast cell activation, starting from in vitro studies, going through in vivo evidence in animal models of disease sustained by mast cell activation, and finally reviewing recent clinical studies using this molecule.

The use of combination therapy in pulmonary arterial hypertension: new developments.

There is a strong clinical rationale for combination therapy in pulmonary arterial hypertension (PAH), as several pathological pathways have been implicated in its pathogenesis and no single agent has yet been shown to deliver completely satisfactory results. Registry data indicate that use of combination therapy is in fact common in existing clinical practice, even though support has been largely empirical or derived from small-scale observational studies. Data from large, adequately powered, randomised controlled trials of combination therapy in PAH are now emerging and suggest that combination therapy may be clinically beneficial. Studies of bosentan in combination with prostanoids and phosphodiesterase (PDE)-5 inhibitors show consistent evidence of improvements in exercise capacity compared with placebo. Similar improvements have been observed with PDE-5 inhibitors in combination with prostanoids. The appropriate timing of combination therapy requires further evaluation but goal-oriented therapy using combinations of oral and inhaled drugs has been shown to provide acceptable long-term results in patients with advanced PAH. Monitoring should be performed regularly and be based on repeatable, noninvasive, measurable parameters that have prognostic value.

Pulmonary arterial hypertension associated to connective tissue diseases.

Pulmonary arterial hypertension is a well-known complication of connective tissue diseases such as systemic sclerosis, systemic lupus erythematosus, mixed connective tissue diseases, and to a lesser extent, rheumatoid arthritis, dermatopolymyositis and primary Sjögren's syndrome. In these patients, pulmonary hypertension may occur in association with left heart disease, interstitial fibrosis or as a result of a isolated pulmonary arteriopathy. The incidence of pulmonary arterial hypertension in the limited form of systemic sclerosis is about 10%. The pathophysiologic mechanisms leading to pulmonary arterial hypertension remain unknown. Symptoms and clinical presentation are very similar to idiopathic pulmonary arterial hypertension but mortality was confirmed to be higher. Echocardiography is the reference investigation for the detection of pulmonary arterial hypertension but the results should be confirmed by right heart catheterization. Treatment appears more complex as compared to idiopathic pulmonary arterial hypertension. Intravenous epoprostenol therapy has been shown to be effective in a special trail. Also, the endothelin receptor antagonists bosentan and sitaxentan, the phosphodyesterase-type-5 sildenafil and subcutaneous treprostinil have shown favourable results.

Optical gain in silicon nanocrystals.

Adding optical functionality to a silicon microelectronic chip is one of the most challenging problems of materials research. Silicon is an indirect-bandgap semiconductor and so is an inefficient emitter of light. For this reason, integration of optically functional elements with silicon microelectronic circuitry has largely been achieved through the use of direct-bandgap compound semiconductors. For optoelectronic applications, the key device is the light source--a laser. Compound semiconductor lasers exploit low-dimensional electronic systems, such as quantum wells and quantum dots, as the active optical amplifying medium. Here we demonstrate that light amplification is possible using silicon itself, in the form of quantum dots dispersed in a silicon dioxide matrix. Net optical gain is seen in both waveguide and transmission configurations, with the material gain being of the same order as that of direct-bandgap quantum dots. We explain the observations using a model based on population inversion of radiative states associated with the Si/SiO2 interface. These findings open a route to the fabrication of a silicon laser.

Resistance to Pseudomonas toxin A: a sensitive marker to screen for mutagenic substances using V79 cells.

The goal of this study was the development of a mutagenicity assay in V79 cells using Pseudomonas toxin A (PTA) as a selective agent and to compare it with the V79/hypoxanthineguaninephosphoribosyl transferase (HGPT) assay. PTA inhibits protein synthesis by covalently modifying elongation factor 2 (EF-2). Mutations in the EF-2 gene, in genes responsible for the modification of EF-2, and also in genes for the transport of the toxin into the cells, lead to PTA resistance. This involvement of several genes might explain the relatively high spontaneous mean mutation frequency of (122.7 +/- 38.8) x 10(-6) in growing cells (2 micrograms PTA/ml) as compared with (3.97 +/- 4.68) x 10(-6) in the HGPRT test (10 micrograms thioguanine/ml), where only mutations in the HGPRT gene lead to resistance. Methyl methanesulphonate, methyl nitroso urea and UV light were directly mutagenic in the V79/PTA assay. Aflatoxin B1 was mutagenic in the presence of an S9 mix. Benzidine, procarbazine, 2-acetylaminofluorene (2-AAF) and 4-acetylaminofluorene (4-AAF) were positive in the V79/PTA test when rat hepatocytes were used for metabolic activation. Using cells treated together with those used for the PTA assay, benzidine, 2-AAF and 4-AAF were negative in the V79/HGPRT test, while procarbazine was found to be positive under these test conditions. Hexamethyl phosphoramide (HMPA) was tested in the presence of rat hepatocytes and was negative in both test systems. Phorbol-12-myristate-13-acetate was highly cytotoxic, but did not induce mutations at the PTA resistance loci. In conclusion, it was demonstrated that the V79/PTA assay is an easy and sensitive method to screen for gene mutations in mammalian cells.