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Introduction: Type 2 diabetes mellitus (T2DM) is a common disease burdened with significant morbidity and mortality. Despite the substantial number of new available drug treatments, adherence to therapy and adverse drug reactions (ADRs) are the major constraint in the management of this disease. We evaluated the use, the adherence, and the safety of antidiabetic drugs in patients with T2DM. Methods: We performed an observational, retrospective, multicenter study on medical records of outpatients referred to general practitioners in Catanzaro (Calabria, Italy). Drug adherence was measured considering the packages of antidiabetic drugs prescribed at the time of admission, after three months, and 1 year later. ADRs were evaluated using the Naranjo probability scale. Collected data were analyzed using the Statistical Package for the Social Sciences. Results: During the study, we evaluated 12,170 medical records of seven general practitioners. The most prescribed drug was metformin alone (28.4%) or with other oral antidiabetics (19.6%) and then insulin (n: 354; men 190, women 164). Logistic regression showed an association between T2DM less than or equal to 5 years and low adherence (p = 0.023). During the study, we recorded 26 ADRs that were correlated with sex (women) and insulin treatment. Conclusions: this real-life study shows that patients with T2DM have a high adherence, probably related to their having a low number of ADRs.

The degu (Octodon degus) is a diurnal long-lived rodent that can spontaneously develop molecular and behavioral changes that mirror those seen in human aging. With age some degu, but not all individuals, develop cognitive decline and brain pathology like that observed in Alzheimer's disease including neuroinflammation, hyperphosphorylated tau and amyloid plaques, together with other co-morbidities associated with aging such as macular degeneration, cataracts, alterations in circadian rhythm, diabetes and atherosclerosis. Here we report the whole-genome sequencing and analysis of the degu genome, which revealed unique features and molecular adaptations consistent with aging and Alzheimer's disease. We identified single nucleotide polymorphisms in genes associated with Alzheimer's disease including a novel apolipoprotein E (Apoe) gene variant that correlated with an increase in amyloid plaques in brain and modified the in silico predicted degu APOE protein structure and functionality. The reported genome of an unconventional long-lived animal model of aging and Alzheimer's disease offers the opportunity for understanding molecular pathways involved in aging and should help advance biomedical research into treatments for Alzheimer's disease.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is commonly considered to be a potent driver of non-small cell lung cancer (NSCLC) development and related mortality. A growing body of evidence supports a role of the immune system, mainly played by alveolar macrophages (AMs), in key axes regulating the development of COPD or NSCLC phenotypes in response to harmful agents. MicroRNAs (miRNAs) are small non-coding RNAs that influence most biological processes and interfere with several regulatory pathways. The purpose of this study was to assess miRNA expression patterns in patients with COPD, NSCLC, and ever- or never-smoker controls to explore their involvement in smoking-related diseases. Bronchoalveolar lavage (BAL) specimens were collected from a prospective cohort of 43 sex-matched subjects to determine the expressions of hsa-miR-223-5p, 16-5p, 20a-5p, -17-5p, 34a-5p and 106a-5p by RT-PCR. In addition, a bioinformatic analysis of miRNA target genes linked to cancer was performed. Distinct and common miRNA expression levels were identified in each pathological group, suggesting their possible role as an index of NSCLC or COPD microenvironment. Moreover, we identified miRNA targets linked to carcinogenesis using in silico analysis. In conclusion, this study identified miRNA signatures in AMs, allowing us to understand the molecular mechanisms underlying smoking-related conditions and potentially providing new insights for diagnosis or pharmacological treatment.

Introduction: Hydrogen sulfide (H2S) is emerging as an important potential therapeutic option for respiratory inflammatory diseases. In this study, we investigated the effectiveness of a novel corticosteroid derivative, that is chemically linked to an H2S donor, in managing asthma features.Methods: The effects of prednisone (PS), H2S donor (4-hydroxybenzamide; TBZ), and their combination (PS-TBZ) have been evaluated in vitro and in vivo. The in vitro experiments were conducted using lipopolysaccharidestimulated J774 macrophages, while the in vivo experiments utilizing an experimental asthma model.Results: In the in vitro study we found that PS-TBZ exhibited an increased effect compared to the individual parent compounds in modulating the production of inflammatory mediators. TBZ also significantly reduced bronchial contractility and enhanced bronchial relaxation. In the in vivo experiments, where we administered PS, TBZ, or PS-TBZ to ovalbumin-sensitized BALB/c mice, we confirmed that PS-TBZ had a significantly better action in controlling airway hyperreactivity as compared to TBZ or PS alone. Moreover, PS-TBZ was more effective in restoring salbutamol-induced relaxation. The immunohistochemistry analysis demonstrated a significant reduction in the production of α-SMA and procollagen III, indicating the efficacy of PS-TBZ in controlling airway remodeling. Moreover, PS-TBZ also promoted epithelial repair, recovery of the bronchial and parenchyma structure and inhibited mucin production.Discussion: In conclusion, PS-TBZ offers an important opportunity to optimize the beneficial impact of corticosteroids on asthma features.

This paper presents the results from a campaign of unsaturated and saturated isotropic tests performed on two compacted silts of different coarseness, namely a clayey silt and a sandy silt, inside triaxial cells. Some tests involved an increase or a decrease of mean net stress at constant suction or an increase or a decrease of suction at constant mean net stress. Other tests involved an increase of mean net stress at constant water content with measurement of suction. During all tests, the void ratio and degree of saturation were measured to investigate the mechanical and retention behaviour of the soil. The experimental results were then simulated by the bounding surface hydromechanical model of A.W. Bruno and D. Gallipoli (2019. Computers and Geotechnics, 110: 287-295. doi:10.1016/j.compgeo.2019.02.025), which was originally formulated to describe the behaviour of clays and clayey silts. Model parameters were calibrated against unsaturated tests including isotropic loading stages at constant water content with measurement of varying suction. Loading at constant water content is relatively fast and allows the simultaneous exploration of large ranges of mean net stress and suction, thus reducing the need of multiple experiments at distinct suction levels. Predicted data match well the observed behaviour of both soils, including the occurrence of progressive yielding and hysteresis, which extends the validation of this hydromechanical model to coarser soils. Specific features of the unsaturated soil behaviour, such as wetting-induced collapse, are also well reproduced. Key words: unsaturated soils, hydromechanical behaviour, bounding surface plasticity, unsaturated triaxial testing, collapse-compression. Le but de la presente etude est de demontrer les resultats d'une campagne d'essais isotropes non satures et satures effectues sur deux limons compactes de granulometrie differente, a savoir un limon argileux et un limon sableux, a l'interieur de cellules triaxiales. Dans le premier cas, il s'agissait d'une augmentation ou diminution de la contrainte nette moyenne pour une aspiration constante ou d'une augmentation ou diminution de l'aspiration pour une contrainte nette moyenne constante. La contrainte nette moyenne a ete augmentee pour une teneur en eau constante avec une mesure de la succion. Au cours de tous les essais, le taux de vide et le degre de saturation ont ete mesures pour etudier le comportement mecanique et de retention du sol. Les resultats experimentaux ont ensuite ete simules par le modele hydromecanique de surface limite de A.W. Bruno et D. Gallipoli (2019. Computers and Geotechnics, 110: 287-295. doi:10.1016/j. compgeo.2019.02.025), initialement formule pour decrire le comportement des argiles et des limons argileux. La calibration des parametres du modele a ete realisee a partir d'essais non satures comprenant des etapes de chargement isotrope a teneur en eau constante avec mesure de la succion variable. Le chargement a teneur en eau constante est relativement rapide et permet l'exploration simultanee de larges gammes de contraintes nettes moyennes et de succion, reduisant ainsi le besoin d'experiences multiples a des niveaux de succion distincts. Les donnees predites correspondent bien au comportement observe des deux sols, y compris l'apparition d'une deformation progressive et d'une hysteresis, ce qui etend la validation de ce modele hydromecanique aux sols plus grossiers. Les caracteristiques specifiques du comportement des sols non satures, telles que l'effondrement induit par le mouillage, sont egalement bien reproduites. [Traduit par la Redaction] Mots-cles : sols non satures, comportement hydromecanique, plasticite de la surface limite, essais triaxiaux non satures, effondrement-compression., Introduction Geotechnical design often requires the prediction of the hydromechanical behaviour of unsaturated soils, as these make up a large proportion of earthworks including fills, embankments, and dams. Shallow natural [...]

Introduction: Drug–drug interactions (DDIs) represent an important clinical problem, particularly in older patients, due to polytherapy, comorbidity, and physiological changes in pharmacodynamic and pharmacokinetic pathways. In this study, we investigated the association between drugs prescribed after discharge from the hospital or clinic and the risk of DDIs with drugs used daily by each patient. Methods: We performed an observational, retrospective, multicenter study on the medical records of outpatients referred to general practitioners. DDIs were measured using the drug interaction probability scale. Potential drug interactions were evaluated by clinical pharmacologists (physicians) and neurologists. Collected data were analyzed using the Statistical Package for the Social Sciences. Results: During the study, we evaluated 1772 medical records. We recorded the development of DDIs in 10.3% of patients; 11.6% of these patients required hospitalization. Logistic regression showed an association among DDIs, sex, and the number of drugs used (p = 0.023). Conclusions: This observational real-life study shows that the risk of DDIs is common in older patients. Physicians must pay more attention after hospital discharge, evaluating the treatment to reduce the risk of DDIs.

Introduction: Drug treatment can be related to the development of adverse drug reactions (ADRs). Aim: In this paper, we evaluated ADRs in patients admitted to the Ambulatory of Pain Medicine of the University Hospital Renato Dulbecco in Catanzaro. Methods: We conducted a prospective analysis between 1 February 2021 and 20 July 2023 on patients with neuropathic pain referred to the Ambulatory of Pain Medicine of “Renato Dulbecco” University Hospital in Catanzaro (Calabria, Italy). Patients aged >18 years with clinical signs of neurologic pain and a score upon completing the Douleur Neuropathique en 4 Questions (DN4) questionnaire of ≥4 were included. The association between drugs and ADR or between drugs and drug–drug-interactions (DDIs) was evaluated using Naranjo’s probability scale and Drug Interaction Probability Scale (DIPS), respectively. Results: During the study period, we analyzed 2370 patients referred to the ambulatory of pain medicine. After the evaluation of inclusion and exclusion criteria, 33.5% of patients were enrolled. All patients presented at least one comorbidity and daily used a mean of five drugs (range 3–11). Using the Naranjo score, the development of ADRs was documented in 112 patients (score 6). Using parametric and non-parametric statistical analysis, we failed to report an association between ADR and dosage or ADR and patient characteristics. Conclusion: Our results show the development of ADRs in 18% of patients with neuropathic pain. This low percentage of drug interaction could be a limitation in real life because it is probably due to the site of the study and the appropriate prescription of drugs. Therefore, it shows that it is necessary to motivate healthcare to pay attention to the prescription of drugs in poly-treated patients to reduce the risk of ADRs.

Non-small cell lung cancer (NSCLC) is one of the deadliest diseases worldwide and represents an impending burden on the healthcare system. Despite increasing attention, the mechanisms underlying tumorigenesis in cancer-related diseases such as COPD remain unclear, making novel biomarkers necessary to improve lung cancer early diagnosis. MicroRNAs (miRNAs) are short non-coding RNA that interfere with several pathways and can act as oncogenes or tumor suppressors. This study aimed to compare miRNA lung expression between subjects with NSCLC and COPD and healthy controls to obtain the miRNA expression profile by analyzing shared pathways. Lung specimens were collected from a prospective cohort of 21 sex-matched subjects to determine the tissue miRNA expression of hsa-miR-34a-5p, 33a-5p, 149-3p, 197-3p, 199-5p, and 320a-3p by RT-PCR. In addition, an in silico prediction of miRNA target genes linked to cancer was performed. We found a specific trend for has-miR-149-3p, 197-3p, and 34a-5p in NSCLC, suggesting their possible role as an index of the tumor microenvironment. Moreover, we identified novel miRNA targets, such as the Cyclin-Dependent Kinase (CDK) family, linked to carcinogenesis by in silico analysis. In conclusion. this study identified lung miRNA signatures related to the tumorigenic microenvironment, suggesting their possible role in improving the evaluation of lung cancer onset.

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs to provide updates on therapy evolution regarding a proportion of CF non-responder patients to current treatment, and we summarize the role of MMPs in pathogenesis and as future therapeutic targets of CF.

The growing pressures of climate change, increased usage and unprecedented geo-hazards impose a modification in the way civil engineering structures are designed and constructed. This isparticularly true for geotechnical works, which are very sensitive to changes of environmental conditions. For instance, the response of a pile under lateral loading is strongly influenced by the stiffness and strength of the first few metres of soil below the surface, which are often partly saturated. To consider this effect, the present paper describes an analytical method, which extends the well-known Broms approach to predict thelateral capacity of piles in unsaturated soils. More specifically, the proposed method considers the combined effects of the position of the ground water table and the extra strength of the partially saturated soil above it. Compared to Broms approach, the solution introduces four additional non-dimensional parameters that relate the soil-water retention behaviour to the geometry of the pile. The method provides a direct evaluation of the lateral pile capacity in partly saturated soils, which can be used as a basis for more accurate design.

This paper extends the modified Cam-Clay model to describe the behaviour of unsaturated soils by replacing the effective stress with the scaled stress. The scaled stress accounts for the mechanical effect of capillarity by factoring Bishop’s stress with a power function of degree of saturation. The extendedmodified Cam-Clay model postulates the existence of a yield curve in the mean scaled stress 𝑝̅– deviatoric scaled stress 𝑞̅ plane. Coherently with the modified Cam-Clay model, the stress-strain behaviour is predicted by means of an elastic law inside the yield curve. As the scaled stress state evolves onto the yield curve, the behaviour becomes elasto-plastic and this is modelled by a plastic flow rule combined with a volumetric hardening law. The extended modified Cam-Clay model is then validated against experimental data published in the literature. Results show that the proposed approach is capable of well predicting the mechanical behaviour of unsaturated soils during triaxial loading. Future work will be directed at further validating the present formulation along different stress paths as well as accounting for the combined effect of partial saturation and cementation within a critical state framework based on bounding surface plasticity.

Raw earth is emerging as a viable building material with lower carbon emissions than conventional concrete and fired bricks. Raw earth is as an excellent passive hygro-thermal regulator, which improves occupants’ comfort while reducing the need for active heating/cooling installations. The coupled hygro-thermal response of earth materials is investigated by exploiting the principles of the thermodynamics of porous media and unsaturated soil mechanics. The degree of coupling between temperature and relative humidity (or water content) depends on the adopted simplifying assumptions. Some of these assumptions are valid for traditional building materials but may not be applicable to raw earth characterised by relatively high levels of liquid/gas permeability. The validity of current approaches is here assessed with reference to earth building via a simple one-dimensional transfer model, which simulates the behaviour of an unbounded earth wall subjected to time-dependent boundary conditions on the two faces. For typical values of water and vapour permeability, the complexity of the governing equations can be greatly reduced by neglecting variations of vapour mass and the dependency of suction on temperature without significantly reducing accuracy. Results are also strongly influenced by both initial state and water retention properties of the earth material.

High capacity tensiometers (HCT) allow the direct measurement of soil matric suction, and their major limitation is the occurrence of cavitation. In this paper HCT designs using different ceramic filters with varied air entry values (AEV), varied reservoir sizes, and different pressure transducers are assessed as to determine the impact that each component may have in the HCT performance. Moreover, the effectiveness of first saturation and resaturation processes is discussed in relation to the time required to prepare/recover HCTs. The results obtained with the different designs show that the measuring range is directly linked to the AEV of the ceramic filter and that the choice of materials used for the various components may affect the reliability of measurements in field installations if the thermal performance is not accounted for in the calibration procedure. The use of a 1hr high vacuum pre-stage followed by overnight water pressurisation at pressures equal or above the AEV of the ceramic filter was found to be the quickest process to fully saturate an HCT for the first time. While resaturation time for an HCT can be reduced to as little as a few minutes if the HCT is resaturated immediately after cavitation has occurred.

The vaccine weapon has resulted in being essential in fighting the COVID-19 outbreak, but it is not fully preventing infection due to an alarming spreading of several identified variants of concern. In fact, the recent emergence of variants has pointed out how the SARS-CoV-2 pandemic still represents a global health threat. Moreover, oral antivirals also develop resistance, supporting the need to find new targets as therapeutic tools. However, cocktail therapy is useful to reduce drug resistance and maximize vaccination efficacy. Natural products and metal-drug-based treatments have also shown interesting antiviral activity, representing a valid contribution to counter COVID-19 outbreak. This report summarizes the available evidence which supports the use of approved drugs and further focuses on significant clinical trials that have investigated the safety and efficacy of repurposing drugs and new molecules in different COVID-19 phenotypes. To date, there are many individuals vulnerable to COVID-19 exhibiting severe symptoms, thus characterizing valid therapeutic strategies for better management of the disease is still a challenge.

Asthma is characterized by chronic inflammation and a variable degree of airway hyperresponsiveness (AHR). Our previous papers documented a role for Nociceptin/Orphanin FQ (N/OFQ) and its receptor N/OFQ peptide (NOP) in AHR. Therefore, the aim of this study was to improve the bioavailability of N/OFQ by developing solid lipid nanoparticles (SLNs). N/OFQ-loaded SLNs were prepared by the Quasi Emulsion Solvent Diffusion (QESD) technique and then characterized. Brown Norway rats were sensitized to ovalbumin (OVA) and treated with an intratracheal administration of saline solution or N/OFQ-SLN. Then, 24 h after the last challenge, functional histological and molecular evaluations were performed. SLNs showed a mean diameter of 233 ± 0.03 nm, a polydispersity index (PDI) value around 0.28 ± 0.02 and a drug release percentage of 84.3. The in vitro release of N/OFQ from SLNs showed that the release of the peptide starts already after two hours of incubation. Animals receiving N/OFQ-SLN showed a significative decrease in allergen-induced AHR compared to the control group. These results showed the positive effects of N/OFQ-SLNs on the inflammatory process and on the mechanical properties of the airways, suggesting that the innovative nanotechnological approach may be therapeutically beneficial for asthmatic patients.

The multifunctional role of neuron-specific enolase (NSE) in lung diseases is well established. As the lungs are greatly affected in COVID-19, we evaluated serum NSE levels in COVID-19 patients with and without dyspnea. In this study, we evaluated both SARS-CoV-2-infected and uninfected patients aged >18 years who were referred to hospitals in Catanzaro, Italy from March 30 to July 30, 2020. Epidemiological, clinical, and radiological characteristics, treatment, and outcome data were recorded and reviewed by a trained team of physicians. In total, 323 patients (178 men, 55.1% and 145 women, 44.9%) were enrolled; of these, 128 were COVID-19 patients (39.6%) and 195 were control patients (60.4%). Westergren's method was used to determine erythroid sedimentation rate. A chemiluminescence assay was used for measurement of interleukin-6, procalcitonin, C-reactive protein, and NSE. We detected significantly higher NSE values (P

Cremation 168 from the second half of the 8th century BCE (Pithekoussai's necropolis, Ischia Island, Italy), better known as the Tomb of Nestor's Cup, is widely considered as one of the most intriguing discoveries in the Mediterranean Pre-Classic archaeology. A drinking cup, from which the Tomb's name derives, bears one of the earliest surviving examples of written Greek, representing the oldest Homeric poetry ever recovered. According to previous osteological analyses, the Cup is associated with the cremated remains of a juvenile, aged approximately 10-14 years at death. Since then, a vast body of literature has attempted to explain the unique association between the exceptionality of the grave good complex, the symposiac and erotic evocation of the Nestor's Cup inscription with the young age of the individual buried with it. This paper reconsiders previous assessments of the remains by combining gross morphology with qualitative histology and histomorphometric analyses of the burnt bone fragments. This work reveals the commingled nature of the bone assemblage, identifying for the first time, more than one human individual mixed with faunal remains. These outcomes dramatically change previous reconstructions of the cremation deposit, rewriting the answer to the question: who was buried with Nestor's Cup?.

Lung cancer is a common neoplasm, usually treated through chemotherapy, radiotherapy and/or surgery. Both clinical and experimental studies on cancer cells suggest that some drugs (e.g., statins) have the potential to improve the prognosis of cancer. In fact, statins blocking the enzyme “hydroxy-3-methylglutaryl-coenzyme A reductase” exert pleiotropic effects on different genes involved in the pathogenesis of lung cancer. In this narrative review, we presented the experimental and clinical studies that evaluated the effects of statins on lung cancer and described data on the effectiveness and safety of these compounds. We also evaluated gender differences in the treatment of lung cancer to understand the possibility of personalized therapy based on the modulation of the mevalonate pathway. In conclusion, according to the literature data, statins exert multiple effects on lung cancer cells, even if the evidence for their use in clinical practice is lacking.

Pulmonary arterial hypertension (PAH) is a rare but fatal disease characterized by persistent elevated blood pressure in the pulmonary circulation, due to increased resistance to blood flow, through the lungs. Advances in the understanding of the pathobiology of PAH clarify the role of leukotrienes (LTs) that appear to be an exciting new target for disease intervention. Over the years, our group has long investigated this field, detecting the 1,2-benzoquinone RF-22c as the most powerful and selective competitive inhibitor of the enzyme 5-lipoxygenase (5-LO). With the aim to improve the bioavailability of RF-22c and to confirm the role of 5-LO as therapeutic strategy for PAH treatment, we developed a solid lipid nanoparticle (SLN) loaded with drug. Therefore, in monocrotaline (MCT) rat model of PAH, the role of 5-LO has been investigated through the formulation of RF-22c-SLN. The rats were randomly grouped into control group, MCT group, and MCT + RF22-c group. After 21 days, all the animals were sacrificed to perform functional and histological evaluations. RF22-c-SLN treatment was able to significantly reduce the mean pulmonary arterial pressure (mPAP) and precapillary resistance (R-pre) compared to the MCT group. The MCT induced rise in medial wall thickness of pulmonary arterioles, and the cardiomyocytes width were significantly attenuated by RF22-c-SLN formulation upon treatment. The results showed that the selective inhibition of 5-LO improved hemodynamic parameters as well as vascular and cardiac remodeling by preventing induced pulmonary hypertension. The improved sustained release properties and targeting abilities achieved with the innovative nanotechnological approach may be therapeutically beneficial for PAH patients as a consequence of the increase of pharmacological effects and of the possible reduction and/or optimization of the drug frequency of administration.

Vitamin D is necessary for normal bone development and conservation. Moreover, it has extraskeletal effects, which play a pivotal role as a modulator of innate and adaptive immune responses. Many studies have highlighted the beneficial effect of vitamin D in protecting against acute respiratory viral infection, including COVID-19. Within this context, we described the effect of vitamin D supplementation in the immunological response to SARS-CoV-2 infection. Long-term IgG SARS-CoV-2 antibody responses were assessed in a cohort of twenty-two subjects diagnosed with COVID-19 by chemiluminescence assay (CLIA). Among them, a 61-year-old nurse undergoing vitamin D therapy showed a positive IgG response against SARS-CoV-2 nucleocapsid over nine months after infection, suggesting vitamin D played a role in modulating early antibody response against SARS-CoV-2. This result provides evidence of a positive effect of vitamin D on the decrease of functional humoral immunity.