The clinical and economic costs associated with regional disparities in varicella vaccine coverage in Italy over 50 years (2020-2070).

Italy implemented two-dose universal varicella vaccination (UVV) regionally from 2003 to 2013 and nationally from 2017 onwards. Our objective was to analyze regional disparities in varicella outcomes resulting from disparities in vaccine coverage rates (VCRs) projected over a 50-year time-horizon (2020-2070). A previously published dynamic transmission model was updated to quantify the potential public health impact of the UVV program in Italy at the national and regional levels. Four 2-dose vaccine strategies utilizing monovalent (V) and quadrivalent (MMRV) vaccines were evaluated for each region: (A) MMRV-MSD/MMRV-MSD, (B) MMRV-GSK/MMRV-GSK, (C) V-MSD/MMRV-MSD, and (D) V-GSK/MMRV-GSK. Costs were reported in 2022 Euros. Costs and quality-adjusted life-years (QALYs) were discounted 3% annually. Under strategy A, the three regions with the lowest first-dose VCR reported increased varicella cases (+ 34.3%), hospitalizations (+ 20.0%), QALYs lost (+ 5.9%), payer costs (+ 22.2%), and societal costs (+ 14.6%) over the 50-year time-horizon compared to the three regions with highest first-dose VCR. Regions with low first-dose VCR were more sensitive to changes in VCR than high first-dose VCR regions. Results with respect to second-dose VCR were qualitatively similar, although smaller in magnitude. Results were similar across all vaccine strategies.

Proteins in amorphous saccharide matrices: structural and dynamical insights on bioprotection.

Bioprotection by sugars, and in particular trehalose peculiarity, is a relevant topic due to the implications in several fields. The underlying mechanisms are not yet clearly elucidated, and remain the focus of current investigations. Here we revisit data obtained at our lab on binary sugar/water and ternary protein/sugar/water systems, in wide ranges of water content and temperature, in the light of the current literature. The data here discussed come from complementary techniques (Infrared Spectroscopy, Molecular Dynamics simulations, Small Angle X-ray Scattering and Calorimetry), which provided a consistent description of the bioprotection by sugars from the atomistic to the macroscopic level. We present a picture, which suggests that protein bioprotection can be explained in terms of a strong coupling of the biomolecule surface to the matrix via extended hydrogen-bond networks, whose properties are defined by all components of the systems, and are strongly dependent on water content. Furthermore, the data show how carbohydrates having similar hydrogen-bonding capabilities exhibit different efficiency in preserving biostructures.

Prevention of fecal-orally transmitted diseases in travelers through an oral anticholeric vaccine (WC/rBS).

INTRODUCTION: Estimate the efficacy of oral anticholeric vaccine Dukoral in subjects travelling to high-risk areas for traveler's diarrhoea and cholera. METHODS: The study involved subjects of both genders who planned to travel to high-risk areas for traveler's diarrhoea and cholera. Immunization with oral anticholeric vaccine Dukoral was offered to each one of them. Upon returning, all the participants in the study were asked to complete a self-administered questionnaire consisting of 40 close-ended questions mainly concerning: personal and health data, characteristics (length, destination, reason) of the travel, onset of gastrointestinal symptoms, data relating to the assumption of anticholeric vaccine and possible adverse reactions. RESULTS: 296 questionnaires have been collected. Mean age was 38.2 years (55.4% males and 44.6% females). Mean travel length was 22.2 days. Reasons for the travel: 66.8% tourism and 33.2% work-cooperation. Most frequent destination was Africa (48.1%), followed by Asia (32.1%) and central South-America (17.8%). 199 subjects (67.2%) properly executed vaccination with Dukoral. The diarrhoea affected 14.1% of vaccinated subjects and 20.6% of non vaccinated ones. The following cohorts showed statistically significant differences in incidence of diarrhoea: <35 years old age (13.7% vs. 27.1%), travel for work-cooperation (14.1% vs. 35%) and travel length >28 days (12.1% vs. 40%). No serious adverse events were reported following vaccination. DISCUSSION: Oral Anticholeric vaccine proved to be effective and safe in preventing fecal-oral diseases in travelers exposed to high risk conditions.

Corrigendum: Nano-Theranostics for the Sensing, Imaging and Therapy of Prostate Cancers.

[This corrects the article DOI: 10.3389/fchem.2022.830133.].

Nano-Theranostics for the Sensing, Imaging and Therapy of Prostate Cancers.

We highlight hereby recent developments in the emerging field of theranostics, which encompasses the combination of therapeutics and diagnostics in a single entity aimed for an early-stage diagnosis, image-guided therapy as well as evaluation of therapeutic outcomes of relevance to prostate cancer (PCa). Prostate cancer is one of the most common malignancies in men and a frequent cause of male cancer death. As such, this overview is concerned with recent developments in imaging and sensing of relevance to prostate cancer diagnosis and therapeutic monitoring. A major advantage for the effective treatment of PCa is an early diagnosis that would provide information for an appropriate treatment. Several imaging techniques are being developed to diagnose and monitor different stages of cancer in general, and patient stratification is particularly relevant for PCa. Hybrid imaging techniques applicable for diagnosis combine complementary structural and morphological information to enhance resolution and sensitivity of imaging. The focus of this review is to sum up some of the most recent advances in the nanotechnological approaches to the sensing and treatment of prostate cancer (PCa). Targeted imaging using nanoparticles, radiotracers and biomarkers could result to a more specialised and personalised diagnosis and treatment of PCa. A myriad of reports has been published literature proposing methods to detect and treat PCa using nanoparticles but the number of techniques approved for clinical use is relatively small. Another facet of this report is on reviewing aspects of the role of functional nanoparticles in multimodality imaging therapy considering recent developments in simultaneous PET-MRI (Positron Emission Tomography-Magnetic Resonance Imaging) coupled with optical imaging in vitro and in vivo, whilst highlighting feasible case studies that hold promise for the next generation of dual modality medical imaging of PCa. It is envisaged that progress in the field of imaging and sensing domains, taken together, could benefit from the biomedical implementation of new synthetic platforms such as metal complexes and functional materials supported on organic molecular species, which can be conjugated to targeting biomolecules and encompass adaptable and versatile molecular architectures. Furthermore, we include hereby an overview of aspects of biosensing methods aimed to tackle PCa: prostate biomarkers such as Prostate Specific Antigen (PSA) have been incorporated into synthetic platforms and explored in the context of sensing and imaging applications in preclinical investigations for the early detection of PCa. Finally, some of the societal concerns around nanotechnology being used for the detection of PCa are considered and addressed together with the concerns about the toxicity of nanoparticles-these were aspects of recent lively debates that currently hamper the clinical advancements of nano-theranostics. The publications survey conducted for this review includes, to the best of our knowledge, some of the most recent relevant literature examples from the state-of-the-art. Highlighting these advances would be of interest to the biomedical research community aiming to advance the application of theranostics particularly in PCa diagnosis and treatment, but also to those interested in the development of new probes and methodologies for the simultaneous imaging and therapy monitoring employed for PCa targeting.

SAXS study on myoglobin embedded in amorphous saccharide matrices.

We report on Small Angle X-ray Scattering (SAXS) measurements performed on samples of carboxy-myoglobin and met-myoglobin embedded in low hydrated matrices of four different saccharides (trehalose, sucrose, maltose and lactose). Results confirm the already reported occurrence of inhomogeneities, which are not peculiar of trehalose samples, but appear also in maltose and lactose, and in some cases also sucrose, being dependent on the sample hydration and on the presence of sodium dithionite. This behaviour confirms our previous interpretation about the nature of the inhomogeneities, and prompt it as a possible general behaviour for highly concentrated sugar matrices.

The Cost-Effectiveness of Universal Varicella Vaccination in Italy: A Model-Based Assessment of Vaccination Strategies.

BACKGROUND: In 2017, varicella vaccination became mandatory for all children in Italy, based on a two-dose schedule administered at 12-15 months of age and 5 to 6 years of age. Varicella vaccines are available in different formulations (as a single vaccine or as a combination vaccine together with measles, mumps, and rubella) and are made by multiple manufacturers with different effectiveness profiles. This study calculates the cost-effectiveness of a range of varicella vaccination strategies to identify the optimal strategy for Italy. METHODS: A dynamic transmission cost-effectiveness model was applied in Italy to simulate the long-term (50 years) costs and outcomes associated with different varicella vaccination strategies. Five vaccination strategies were evaluated using the model: two doses of two different combination Measles-Mumps-Rubella-Varicella vaccines (either Vaccine A (MSD) [denoted QQVa] or Vaccine B (GSK) [denoted QQVb]); a first dose of a single Varicella vaccine followed by a second dose of a combination vaccine (either Vaccine C (MSD) followed by Vaccine A [denoted MQVa] or Vaccine D (GSK) followed by Vaccine B [denoted MQVb]); or no vaccine at all (NV). The model was adapted for Italy using publicly available Italian data and expert opinion. RESULTS: Over the 50-year time-horizon, in the absence of universal varicella vaccination, there would be 34.8 million varicella cases, 142 varicella-infection-related deaths, and €23 billion in societal costs. The cost per capita from a societal perspective ranged from €164.55 to €392.18 with NV being the most expensive and QQVa the least expensive. The most effective strategy was QQVa, which resulted in a 66% decrease in varicella cases and 30% reduction in varicella-related deaths compared to NV strategy. QQVa led to a net saving in societal cost around €13 billion compared to NV as the cost of vaccination was more than offset by the savings that resulted from the reduced burden of illness. CONCLUSION: Varicella vaccination has a major impact on reducing varicella incidence, prevalence, and societal costs. This analysis supports the policy for universal varicella vaccination in Italy as the NV strategy was the most expensive and resulted in the poorest outcomes. QQVa offers the greatest benefits at the lowest cost and should be considered as a potential priority strategy for Italian population.

Molecular dynamics simulation of sucrose- and trehalose-coated carboxy-myoglobin.

We performed a room temperature molecular dynamics (MD) simulation on a system containing 1 carboxy-myoglobin (MbCO) molecule in a sucrose-water matrix of identical composition (89% [sucrose/(sucrose + water)] w/w) as for a previous trehalose-water-MbCO simulation (Cottone et al., Biophys J 2001;80:931-938). Results show that, as for trehalose, the amplitude of protein atomic mean-square fluctuations, on the nanosecond timescale, is reduced with respect to aqueous solutions also in sucrose. A detailed comparison as a function of residue number evidences mobility differences along the protein backbone, which can be related to a different efficacy in bioprotection. Different heme pocket structures are observed in the 2 systems. The joint distribution of the magnitude of the electric field at the CO oxygen atom and of the angle between the field and the CO unit vector shows a secondary maximum in sucrose, absent in trehalose. This can explain the CO stretching band profile (A substates distribution) differences evidenced by infrared spectroscopy in sucrose- and trehalose-coated MbCO (Giuffrida et al., J Phys Chem B 2004;108:15415-15421), and in particular the appearance of a further substate in sucrose. Analysis of hydrogen bonds at the protein-solvent interface shows that the fraction of water molecules shared between the protein and the sugar is lower in sucrose than in trehalose, in spite of a larger number of water molecules bound to the protein in the former system, thus indicating a lower protein-matrix coupling, as recently observed by Fourier transform infrared (FTIR) experiments (Giuffrida et al., J Phys Chem B 2004;108:15415-15421).

Improvement of diabetic autonomic gustatory sweating by botulinum toxin type A.

Fourteen diabetic subjects with gustatory sweating were treated by intracutaneous injections of botulinum toxin type A into the affected facial skin areas. In all subjects, sweating (measured by Minor starch iodine test) ceased within 4 days, with the maximal follow-up time lasting 24 weeks. This therapeutic approach, which could be used to reduce the severity of diabetic gustatory sweating, appears to be long lasting, adverse effect free, and minimally invasive.

Supratentorial atrophy in spinocerebellar ataxia type 2: MRI study of 20 patients.

There have been only few studies of brain magnetic resonance imaging (MRI) in spinocerebellar ataxia (SCA) type 2. We investigated 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects using MRI. Our data confirm that olivopontocerebellar atrophy (OPCA) is the typical pattern in SCA2. We found no significant correlation between infratentorial atrophy, disease duration, or the number of CAG repeats in our SCA2 patients, but there was supratentorial atrophy in 12 patients, with a significant correlation between supratentorial atrophy and disease duration. OPCA appears to represent the "core" of the SCA2: however, central nervous system involvement is not limited to pontocerebellar structures. We therefore consider central nervous system degeneration in SCA2 as a widespread atrophy. MRI is helpful in diagnosing SCA, but it is not diagnostic in the absence of clinical and molecular studies. We suggest that serial MRI may play a role in evaluating "in vivo" the progressive steps of neurodegeneration in SCA2, for a better comprehension of the pathophysiology of this disorder.

Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families.

Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 +/- 3.3 in 85 expanded alleles, with a range of 34-52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range -3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy.

Swellable microparticles containing Suprofen: evaluation of in vitro release and photochemical behaviour.

Suprofen, an anti-inflammatory drug was incorporated in polymer networks based on biocompatible macromolecules, such as alpha,beta-polyasparthydrazide (PAHy) and alpha,beta-poly(N-hydroxyethyl)-DL-aspartamide (PHEA) crosslinked by glutaraldehyde or gamma-rays, respectively. Swelling tests carried out in aqueous media showed that pH value affects the swelling degree of the prepared hydrogels. In vitro release tests were performed in simulated gastrointestinal fluids (pH 1/6.8) using the pH variation method and in phosphate-buffered saline, pH 7.4. Experimental data indicated that Suprofen was released in a sustained way both from PAHy and PHEA microparticles. Further, incorporation of Suprofen in PAHy and PHEA networks provided a significant reduction of the drug photosensitizing activity, as evidenced by in vitro hemolysis tests.

Central motor conduction to lower limb after transcranial magnetic stimulation in spinocerebellar ataxia type 2 (SCA2).

OBJECTIVES: To evaluate central motor conduction to lower limbs in spinocerebellar ataxia type 2 (SCA2). METHODS: Transcranial magnetic stimulation was performed to study the corticospinal tracts of 18 patients with SCA2. RESULTS: Central motor conduction time (CMCT) to lower limbs and thresholds were abnormal in 8 patients (44%); CMCT and thresholds were significantly correlated with disease duration and disability. CONCLUSIONS: Corticospinal tract involvement is more frequent than previously reported in SCA2. Prolonged CMCT and increased threshold should not be used to differentiate between various type of autosomal dominant cerebellar ataxia. Similar to that reported in Friedreich's ataxia, we suggest that examining central motor conduction to the lower limbs may assist in evaluating the progressive steps of neurodegeneration in SCA2.

Molecular mechanism of photosensitization. XI. Membrane damage and DNA cleavage photoinduced by enoxacin.

The photosensitizing activity of enoxacin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- 1,8-naphthyridine-3-carboxilic acid (ENX), toward membranes and DNA has been studied, taking into account human erythrocyte photohemolysis, unilamellar liposome alterations and plasmid pBR322 DNA photocleavage. Hydroxyl radicals and an aromatic carbene generated from ENX photodefluorination seem to be the active intermediates involved in the photosensitization process. The steady-state photolysis products do not participate in the process. The mechanism of photosensitization responsible for the membrane damage depends on the oxygen concentration and follows a different path with respect to that operative for DNA cleavage. Between oxygenated radicals, the hydroxyl seems the species mainly responsible for membrane damage, whereas DNA cleavage is mainly produced by the carbene intermediate. A molecular mechanism of the photosensitization induced by ENX is proposed.

pH effects on the spectroscopic and photochemical behavior of enoxacin: a steady-state and time-resolved study.

The spectroscopic and photochemical behavior of Enoxacin (ENX), 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- 1,8-naphthyridine-3-carboxylic acid, has been investigated in aqueous solutions between pH 3.5 and pH 12. The absorption and emission properties of ENX are strongly affected by pH. The fluorescence quantum yield, 4 x 10(-3) at pH 3.5, increases by a factor of two on going to neutral pH while a strong reduction is observed at alkaline pH. The photodegradation quantum yield also depends on pH, being maximum in neutral conditions (ca 0.04). Nanosecond flash photolysis experiments confirm that the yield of absorbing transients is maximum at neutral pH while it decreases to zero at acid and alkaline pH. These results indicate that both the dissociation of the carboxylic group and the protonation of the piperazinyl residues are key steps for the formation of the photochemically active form of ENX. Loss of F by heterolytic cleavage of the C-F bond is proposed to occur from the triplet state of the zwitterion with formation of a carbocation. A path for the evolution of this intermediate to the final product is also proposed.

Molecular mechanism of drug photosensitization. IX. Effect of inorganic ions on DNA cleavage photosensitized by naproxen.

Photocleavage of DNA induced by naproxen and the correlated protective effect by some inorganic ions have been considered. The presence of a DNA complex is suggested and only associated naproxen seems to be responsible for the cleavage, for which the quantum yield of single strand breaks was calculated. The inorganic ions I-, Mn2+, Co2+ and Cu2+ decrease naproxen-photoinduced DNA cleavage. Iodide acts by a heavy atom mechanism, thus inhibiting naproxen photolysis and decreasing the amount of free radicals responsible for the photocleavage both in aerobic and anaerobic conditions. Metallic ions protect only within a range of concentrations, as for higher amounts damaging processes are observed. The protective efficiency of cations decreases with the increase of free drug concentration in the bulk of the solution, due to their involvement in the scavenging of naproxen radicals generated by photolysis of the free drug. In the presence of EDTA the cations show a better protective action. The most likely hypothesis is an inhibiting effect on the damaging processes via a redox cycle. The different behaviors of copper and of the two other cations can be justified by the influence of redox potentials of free and complexed metals and by the superoxide dismutase-like activity of copper.

Molecular mechanism of drug photosensitization. 7. Photocleavage of DNA sensitized by suprofen.

Ultraviolet-A irradiation of a suprofen (2-[4-2(2-thenoyl) phenyl]propionic acid) (SPF) buffered solution (pH 7.4) in the presence of supercoiled pBR322 DNA leads to single strand breaks with the formation of an open circular form and subsequent linearization of the plasmid. On the basis of agarose gel electrophoresis data of samples irradiated in an air-saturated solution or in an oxygen-modified atmosphere, and the effects of sodium azide, D20, mannitol, copper(II), superoxide dismutase, 2-H-propanol, deferoxamine and surfactants, we suggest a photosensitization mechanism involving singlet oxygen and free radicals. The higher rate of photocleavage in nitrogen compared to that in an air-saturated solution and the results obtained from oxygen consumption measurements support the hypothesis that both the type I and type II photosensitization mechanisms are operative and that oxygen quenches the excited state of the irradiated drug. The photosensitization model applied was in agreement with that previously applied to cell membrane SPF photoinduced damage. Interaction of the drug with DNA, studied through circular dichroism and fluorescence anisotropy, probably occurs through a surface binding mode. The experimental techniques used for assessing the photodamaging activity of this drug may be useful for screening of phototoxic compounds in the environment and for determining the active species involved.

Molecular mechanisms of photosensitization induced by drugs. XII. Photochemistry and photosensitization of rufloxacin: an unusual photodegradation path for the antibacterials containing a fluoroquinolone-like chromophore.

The UVA irradiation of 9-fluoro-2,3-dihydro-10-4'-methyl-1' -piperazinyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzo-thiazine-6-carboxylic acid, rufloxacin, a fluoroquinolone antibacterial that shows photosensitizing properties toward biological substrates, leads to formation of two main steady photoproducts characterized by a decarboxylation process and an opening of the piperazinyl ring, respectively. The deprotonation of the 10-piperazinyl group and the dissociation of the 6-carboxyl group of rufloxacin are strictly pH dependent. The photosensitizing activity was tested toward membranes as biological targets. Red blood cell hemolysis and lipid peroxidation were considered as markers of photosensitization. Ultraviolet A-induced damage is strongly influenced by the presence of oxygen, it is triggered by transient species, such as singlet oxygen and free radicals, photogenerated via rufloxacin irradiation, whereas no drug photoproduct is involved in the photosensitization process.

The photochemistry of flutamide and its inclusion complex with beta-cyclodextrin. Dramatic effect of the microenvironment on the nature and on the efficiency of the photodegradation pathways.

The photochemistry of the anticancer drug flutamide (FM), 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide, in homogeneous media and in the beta-cyclodextrin (beta-CD) cavity has been investigated. The photoreactivity of the free molecule has been rationalized on the basis of an intramolecular nitro to nitrite rearrangement followed by cleavage of the nitrite intermediate. The twisted geometry of the nitro group with respect to the aromatic plane plays a key role in triggering such a photoprocess. Incorporation of FM in the beta-CD cavity leads to dramatic effects on both the efficiency and the nature of the photochemical deactivation pathways of the guest molecule. A 20-fold increase in the FM photodecomposition quantum yield and the formation of photoproducts originated by both reduction of the nitro group and cleavage of the amide bond were observed in the presence of the macrocycle. Such a behavior cannot be attributed exclusively to the micropolarity of beta-CD and/or to its role as a reactant. The induced circular dichroism spectra and the nature of the photoproducts formed in these experimental conditions provide indications that the photoreactivity in the beta-CD microenvironment could likely be mediated by structural changes of FM upon complexation.