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Background: Considering that peripheral blood biomarkers are prognostic predictors for several human tumors, this study aimed to comparatively analyze the association of hematological alterations with the incidence of epithelial dysplasia (ED) and oral squamous cell carcinoma (OSCC) in male and female mice treated with 4-nitroquinoline-N-oxide (4NQO) and ethanol (EtOH)., Methods: 120 C57Bl/6J mice (60 males and 60 females) were allocated to four groups (n = 15). They were treated firstly either with 5 mg/mL propylene glycol (PPG) or 100 μg/mL 4NQO in the drinking water for 10 weeks, followed by sterilized water (H 2 O) or 8% EtOH (v/v) for 15 weeks, as follows: PPG/H 2 O, PPG/EtOH, 4NQO/H 2 O, and 4NQO/EtOH (CEUA-UFU, #020/21). After killing, tongues were collected for histopathological analysis of ED and OSCC. Blood samples were processed for complete blood count and calculation of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII)., Results: The incidence of OSCC in females from the 4NQO/EtOH group (60%) was lower when compared to males (93%). Neutrophils, NLR, and SII increased from control animals (PPG/H 2 O and PPG/EtOH) to ED and OSCC-bearing male and female mice (4NQO/H 2 O and 4NQO/EtOH), while lymphocytes decreased. Females from the 4NQO/H 2 O group with ED also had higher neutrophils, NRL, and SII values than females with normal tongues., Conclusion: The low incidence of 4NQO- and ethanol-induced OSCC in females indicates that the sex bias in OSCC may not be associated with extrinsic risk factors alone. Neutrophil and lymphocyte counts, NRL, and SII were significantly altered during multistep carcinogenesis and thus could be explored as biomarkers for ED and OSCC development., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bovine viral diarrhea virus (BVDV) is a widespread pathogen of cattle and other mammals that causes major economic losses in the livestock industry. N4-TSC and 6NO 2 -TSC are two thiosemicarbazones derived from 1-indanone that exhibit anti-BVDV activity in vitro. These compounds selectively inhibit BVDV and are effective against both cytopathic and non-cytopathic BVDV-1 and BVDV-2 strains. We confirmed that N4-TSC acts at the onset of viral RNA synthesis, as previously reported for 6NO 2 -TSC. Moreover, resistance selection and characterization showed that N4-TSC R mutants were highly resistant to N4-TSC but remained susceptible to 6NO 2 -TSC. In contrast, 6NO 2 -TSC R mutants were resistant to both compounds. Additionally, mutations N264D and A392E were found in the viral RNA-dependent RNA polymerase (RdRp) of N4-TSC R mutants, whereas I261 M was found in 6NO 2 -TSC R mutants. These mutations lay in a hydrophobic pocket within the fingertips region of BVDV RdRp that has been described as a "hot spot" for BVDV non-nucleoside inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chikungunya fever is a mosquito-borne disease caused by Chikungunya virus (CHIKV). Treatment of CHIKV infections is currently supportive and does not limit viral replication or symptoms of persistent chronic arthritis. Although there are multiple compounds reported as antivirals active against CHIKV in vitro, there are still no effective and safe antivirals. Thus, active research aims at the identification of new chemical structures with antiviral activity. Here, we report the screen of the Pandemic Response Box library of small molecules against a fully infectious CHIKV reporter virus. Our screening approach successfully identified previously reported CHIKV antiviral compounds within this library and further expanded potentially active hits, supporting the use of reporter-virus-based assays in high-throughput screening format as a reliable tool for antiviral drug discovery. Four molecules were identified as potential drug candidates against CHIKV: MMV1634402 (Brilacidin) and MMV102270 (Diphyllin), which were previously shown to present broad-spectrum antiviral activities, in addition to MMV1578574 (Eravacycline), and the antifungal MMV689401 (Fluopicolide), for which their antiviral potential is uncovered here., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the context of continuous emergence of SARS-CoV-2 variants of concern (VOCs), one strategy to prevent the severe outcomes of COVID-19 is developing safe and effective broad-spectrum vaccines. Here, we present preclinical studies of a RBD vaccine derived from the Gamma SARS-CoV-2 variant adjuvanted with Alum. The Gamma-adapted RBD vaccine is more immunogenic than the Ancestral RBD vaccine in terms of inducing broader neutralizing antibodies. The Gamma RBD presents more immunogenic B-cell restricted epitopes and induces a higher proportion of specific-B cells and plasmablasts than the Ancestral RBD version. The Gamma-adapted vaccine induces antigen specific T cell immune responses and confers protection against Ancestral and Omicron BA.5 SARS-CoV-2 challenge in mice. Moreover, the Gamma RBD vaccine induces higher and broader neutralizing antibody activity than homologous booster vaccination in mice previously primed with different SARS-CoV-2 vaccine platforms. Our study indicates that the adjuvanted Gamma RBD vaccine is highly immunogenic and a broad-spectrum vaccine candidate., (© 2024. The Author(s).)

Purpose: To evaluate the effect of tooth brushing and dentifrice fluoride (F-) concentration on changes in color and translucency (ΔE00 and ΔT00, respectively), surface gloss (GS), surface roughness (Sa), and microstructure of a glazed CAD/CAM ceramic., Materials and Methods: Ceramic blocks (e.max/CAD) were sectioned into rectangular plates (14 x 12 x 1 mm), and one surface of each sample was glazed. Samples were divided into three groups according to the F- concentration in the dentifrice (0, 1,100, and 5,000 μg/g) and were then subjected to 60,000 tooth brushing cycles. Luminosity and color were measured using a spectrophotometer at baseline and after every 20,000 cycles to obtain their ΔE00 and ΔT00 values. Another set of samples was prepared to measure the GS with a gloss meter and the Sa with a confocal laser microscope. The GS and Sa results were subjected to analysis of variance, Tukey test, and Dunnett test (α = .05)., Results: After 60,000 tooth brushing cycles, all of the variables were clinically acceptable, and there were no significant differences in the ΔE00, ΔT00, GS, or Sa among the fluoridated dentifrices. The GS values decreased significantly as the number of tooth brushing cycles increased., Conclusion: The ΔE00, ΔT00, GS, and Sa values were all clinically acceptable after the glazed e.max/CAD ceramic had been subjected to 60,000 tooth brushing cycles with dentifrices containing up to 5,000 μg/g of F-.

Mayaro virus (MAYV), the etiologic agent of Mayaro fever, leads patients to severe myalgia and arthralgia, which can have a major impact on public health in all the countries where the virus circulates. The emergence and dissemination of new viruses have led the scientific community to develop new in vivo models that can help in the fight against new diseases. So far, mice have been the most used animal model in studies with MAYV and have proved to be an adequate model for recapitulating several aspects of the disease observed in humans. Mice are widely used in in vivo research and, therefore, are well known in the scientific community, which has allowed for different strains to be investigated in the study of MAYV. In this review, we summarize the main studies with MAYV using mice as an experimental model and discuss how they can contribute to the advancement of the understanding of its pathogenesis and the development of new drugs and vaccines.

Objectives: The purpose of this study was to evaluate the effect of build orientation of 3D-printed provisional resins (3DRs) on gloss (Gs), surface roughness (Sa), maximum profile valley depth (Rv), and color difference (∆E 00 )., Methods: PMMA CAD/CAM blocks (Vita Temp/Vita) were sectioned and served as a Control. Four 3DRs (Cosmos-SLA/Yller, Cosmos-DLP/Yller, PriZma-Bioprov/Makertech, Nanolab/Wilcos) were obtained as discs (15-mm diameter, 2.5-mm thickness) in three orientations (0°, 45°, and 90°) using different 3D printers (Form 2/Formlabs, P30/Straumann, Hunter/Flashforge, W3D/Wilcos, respectively). Samples were then cleaned with isopropyl alcohol prior to post-curing in specific post-curing units. Half of the samples' surface was covered with an adhesive tape and submitted to 10,000 toothbrushing (TB) cycles. The Gs and Sa at the brushed and not brushed surfaces were evaluated with a glossmeter (Novo-curve) and a laser confocal microscope (OLS5000) (n = 10), which also obtained the Rv and 3D representative images of the interface between not brushed and brushed surfaces. Electron microscopy images of the surface of some samples was also performed (n = 3). On another set of samples (n = 5), the coordinates of luminosity and color were obtained with a spectrophotometer (Easyshade V) at baseline and after 16.7 h and 200 h of UVB aging, to calculate the ∆E 00 using CIEDE:2000 formula. Additionally, 3DRs photoinitiators were identified using a minispectrometer (USB2000 +) (n = 5). Data of Gs and Sa were submitted to three-way-, Rv to two-way-, and ∆E 00 to mixed-ANOVA tests, followed by Tukey's test (α = 0.05). For all variables, results from experimental groups were compared to control using Dunnett's test (α = 0.05). Student's t-test was used to compare the control at different TB cycles (Gs, Sa) or aging periods (∆E 00 ) (α = 0.05)., Results: Build orientation of 3DRs did not influence any of the variables studied. The 10,000 TB cycles resulted in a decrease in Gs and increase in Sa for all resins tested. The control showed higher Gs after 10,000 TB cycles than Cosmos-SLA and Nanolab resins. Compared to all 3DRs, Control presented lower ∆E 00 after 200 h of UVB aging. All 3DRs presented higher ∆E 00 than the clinically acceptable after 200 h of UVB aging. Lucirin® TPO was identified in all 3DRs, although PriZma might also present other photoinitiators and Nanolab might present Irgacure 369., Significance: Alterations in build orientation are very useful and frequently performed in the day-today of 3D-printing, thus its effect in the optical properties and in the topography of 3D-printed restorations is very relevant. For the evaluated 3D-printed provisional resins, build orientation did not influence any of the variables studied (Gs, Sa, Rv, and ∆E 00 ), even after toothbrushing cycles and UVB aging., Competing Interests: Declaration of Competing Interest The authors have no financial interest in the companies whose materials are included in this article. No conflict of interest to declare., (Copyright © 2023 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2 vaccine protection has encountered waning of immune response and breakthrough infections. The hybrid immune response generated by the combination of vaccination and infection was shown to offer higher and broader protection. Here, we present a seroprevalence study of anti-SARS-CoV-2 spike/RBD IgG in 1,121 health care workers immunized with Sputnik V and a follow-up of humoral response at 2 and 24 weeks postvaccination (wpv), including neutralizing antibody response (NAT) against ancestral, Gamma, and Delta variants. The first seroprevalence study showed that among 122 individuals with one dose, 90.2% were seropositive versus 99.7% seropositivity among volunteers with the complete two-dose regimen. At 24 wpv, 98.7% of the volunteers remained seropositive, although antibody levels decreased. IgG levels and NAT were higher in individuals that had acquired COVID-19 previous to vaccination than in naive individuals at 2 and 24 wpv. Antibody levels dropped over time in both groups. In contrast, IgG levels and NAT increased after vaccine breakthrough infection. At 2 wpv, 35/40 naive individuals had detectable NAT against SARS-CoV-2 Gamma and 6/40 against Delta. In turn, 8/9 previously infected individuals developed a neutralizing response against SARS-CoV-2 Gamma and 4/9 against Delta variants. NAT against variants followed a trajectory similar to NAT against ancestral SARS-CoV-2, and breakthrough infection led to an increase in NAT and complete seroconversion against variants. In conclusion, Sputnik V-induced humoral response persisted at 6 months postvaccination, and hybrid immunity induced higher levels of anti-S/RBD antibodies and NAT in previously exposed individuals, boosted the response after vaccination, and conferred wider breadth of protection. IMPORTANCE Since December 2020, Argentina has begun a mass vaccination program. The first vaccine available in our country was Sputnik V, which has been approved for use in 71 countries with a total population of 4 billion people. Despite all the available information, there are fewer published studies on the response induced by Sputnik V vaccination compared to that of other vaccines. Although the global political context has paralyzed the verification by the WHO of the efficacy of this vaccine, our work aims to add new clear and necessary evidence to Sputnik V performance. Our results contribute to general knowledge of the humoral immune response developed by vaccines based on viral vector technology, highlighting the higher immune protection conferred by hybrid immunity and reinforcing the importance of completing vaccination schedules and booster doses to maintain adequate antibody levels., Competing Interests: The authors declare no conflict of interest.

Echocardiography is commonly used in veterinary clinical practice for many species but is not as easily applied in non-sedated marine mammals. Additionally, Doppler echocardiography provides further information on hemodynamics, estimation of cardiac output, characterization of flow patterns, and diastolic function. However, its applications in marine mammals have not been as widely explored either. The present report aimed to characterize the left ventricle structure and function of the Southern Sea Lion (Otaria flavescens) through a Doppler echocardiography study. Data were obtained from a healthy animal trained for different veterinary examination routines. This communication constitutes the first report of Doppler echocardiography with stroke volume, and cardiac output measurement in pinnipeds, and the first report of measurement of myocardial performance index in aquatic mammals. This data brought initial information about in vivo structure and function of the heart of the Southern Sea Lion that can be safely and effectively evaluated with the use of transthoracic Doppler echocardiography. Our data have both clinical and research implications for future studies evaluating diseases of the cardiopulmonary system in pinnipeds, and cardiovascular physiology investigation in diving mammals., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Evaluate the effect of thickness of high-translucency (HT) CAD/CAM materials on irradiance and beam profile from a blue light-emitting diode light-curing unit (LCU) and on the degree of conversion (DC) and maximum polymerization rate (Rp max ) of a light-cured resin cement (LCC)., Material and Methods: The direct output from the LCU, the light transmission and irradiance ratio (IR) through one conventional composite and nine HT CAD/CAM materials (0.5, 1.0, 1.5, or 2.0-mm thick; n = 5) were measured with a integrating sphere coupled to a spectrometer. The light beam was assessed with a beam profiler camera. The DC at 600 s and the Rp max of one LCC was determined using a Fourier transform infrared spectrometer (n = 5). Data were analyzed by ANOVA followed by Tukey's tests, and Dunnett's test was also used for irradiance data (α = 0.05)., Results: A significant decrease in irradiance through all materials occurred as thickness increased. Thin CAD/CAM materials improved light homogeneity, which decreased with the increase in thickness. The DC of the LCC directly exposed to light was the same as when exposed to 45%, 25%, 15%, or 5% IRs. Rp max decreased with the decrease in IR., Conclusions: Although the HT CAD/CAM materials reduced the irradiance from the LCU, minor effects were observed in the LCC's DC., Clinical Significance: Despite the light attenuation of blue light through different CAD/CAM materials that were up to 2-mm thick, the degree of conversion of one brand of light-cured resin cement was clinically acceptable when the LCU was used for 30 s., (© 2022 Wiley Periodicals LLC.)

Purpose: This study evaluated the effects of 3D-printing build orientation on accuracy, flexural modulus (FM), flexural strength (FS), and microhardness of selected, commercial 3D-printed provisional resins (3DRs)., Material and Methods: PMMA CAD/CAM provisional material (Vita Temp/Vita) served as Control. Four 3DRs (Cosmos-SLA/Yller, Cosmos-DLP/Yller, PriZma-Bioprov/Makertech, Nanolab/Wilcos) were used in three printing orientations (0°, 45°, and 90°). Printed samples were cleaned with isopropyl alcohol prior to post-curing in specific post-curing units. For each group, 20 bar-shaped samples (25 × 2x2 mm) and ten disc-shaped samples (15-mm diameter, 2.5-mm thick) were obtained. The dimensions of bar samples were measured and the mean percent errors were compared to the reference (digital) values to obtain "accuracy" (n = 20). Samples were then aged in distilled water at 37 °C and half were submitted to a three-point bend test in a universal testing machine after 24 h and the other half after 1 year (n = 10). Disc samples were polished prior to microhardness evaluation (n = 10). Microstructure and elemental composition of filler particles in the 3DRs were analyzed using scanning electron microscopy (SEM) and energy dispersive x-ray spectroscopy (EDS) (n = 3). Accuracy and microhardness were submitted to two way-, and FM and FS to three way-ANOVA, followed by Tukey's tests. Results of experimental groups were compared to a milled PMMA Control using Dunnett's tests, and Student's t-tests compared FM and FS to Control at different aging periods (α = 0.05)., Results: Except for Cosmos-DLP, the 90° orientation demonstrated the best overall accuracy in all dimensions evaluated. The overall accuracy of Cosmos-SLA was not significantly different from Control and higher than other 3DRs. The FM of all 3DRs was lower than Control, regardless of orientation and aging period. After 1 year of aging, FS of 45°-Cosmos-SLA and all orientations of PriZma were not different from Control, while 90°-Cosmos-SLA was higher. Build orientation had no influence on microhardness of the 3DRs: Nanolab was the only resin harder than Control. Very few nanometric spherical filler particles were found in Cosmos-SLA, Cosmos-DLP, and PriZma, while Nanolab presented higher number of particles having irregular shapes and sizes., Conclusions: In general, although build orientation did not influence microhardness results, the 90° -orientation resulted in the best overall accuracy for most 3DRs. After 1-year water storage, Cosmos-SLA printed vertically showed the highest FS, while the PMMA Control obtained the highest FM for both aging periods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The aim of this study was to make the first characterization of the electrocardiogram (ECG) of the Burmeister porpoise (Phocoena sipinipinnis). A total of three ECGs were made in one, wild juvenile female (body weight = 32.5 kg, Lt = 1.45 m), temporarily held in captivity for rehabilitation at Mar del Plata Aquarium (Argentina). For ECG recordings, the animal was removed from its pool on a stretcher under constant veterinary supervision. A traditional six-lead system in the frontal plane was used, with the typical four "extremities" electrodes positioned bilaterally. ECGs were readable and all waves were detectable. The QRS complexes were characterized by Q wave absence in all leads. The ECG characteristically displayed distinctly defined STs, with a T wave clearly differentiated from the QRS complex. An STs elevation was detected in leads II and III. The mean electrical axis was -79°, meaning a cranial left axis orientation. The animal showed normal sinus rhythm and heart rate (HR) showed a continuous oscillation between tachycardia and bradycardia. Mean HR from all recordings was 147.02 ± 24.95 bpm (range = 71-176, n = 178). Evidence of the occurrence of respiratory sinus arrhythmia was detected through HR variations and RR interval differences, which suggested an adequate cardiovascular system compensation to handling conditions. This study has reported ECG amplitude and duration measurements of a potentially healthy specimen, which represents the starting point for the determination of normal ECG values for this species. Also, it has confirmed that ECG is a valuable noninvasive tool for rapid cardiac health assessment in small cetaceans., (© 2022 Wiley Periodicals LLC.)

Objectives: To evaluate the effect of post-curing times on the color change, flexural strength (FS), modulus (FM) and microhardness at different depths of four 3D printed resins., Materials and Methods: A characterization of the light emitted by 3D-resin post-curing unit (Wash and Cure 2.0, Anycubic) was performed. The tested 3D printed resins were Cosmos Temp3D (COS), SmartPrint BioTemp (SM) Resilab3D Temp (RES) and Prizma3D BioProv (PRI) were evaluated under five different post-curing conditions (no post-curing or 5-, 10-, 15, and 20 min of post-curing). For color change analysis, 10 mm diameter x 1 mm thick discs (n = 7) were printed, and the luminosity, color and translucency were measured before post-curing as control, and repeatedly after 5 min cycles of post-curing until a total of 20 min was reached for ΔE 00 [CIED2000 (1:1:1)] calculation. For FS and FM, 25 × 2×2 mm (n = 10, for each post-curing time) 3D printed bars were subjected to a 3-point being test. Knoop microhardness (KHN) was measured transversally on 5 × 5×5 mm blocks (n = 10, for each post-curing time). Color results were analyzed by one-way repeated measures ANOVA (factor: color change). FS and FM were analyzed by two-way ANOVA (factors: Material*Post-Curing Time). KHN was analyzed individually for each material by two-way ANOVA (factors: Depth*Post-Curing Time)., Results: The post-curing time significantly influenced the ΔE 00, FS, FM and KHN of all the evaluated materials. COS and SMA presented ΔE 00 values above the acceptability threshold after 5 and 10 min of post-curing, respectively. The FS of RES reached a plateau after 5 min of post-curing, and for PRI and SMA, the FS stabilized after 10 min of post-curing. The post-curing process improved the KHN of the tested materials, and longer exposure periods were associated to higher KHN values at all the evaluated depths., Significance: A fine adjustment of the post-curing time is crucial to produce adequate mechanical properties in 3D-printed restorative resins, while minimizing the color alterations on the restorations. For the evaluated resins, 5-10 min of post-curing will result in adequate mechanical properties, without affecting the acceptability in the color of the material. However, the results are material-dependent, and evaluation of each specific resin is advised., (Copyright © 2022 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.)

The appearance and spread of parasitic diseases around the world aroused the interest of the scientific community to discover new animal models for improving the quality and specificity of surveys. Calomys callosus is a rodent native to South America, an easy handling model, with satisfactory longevity and reproducibility. C. callosus is susceptible to toxoplasmosis and can be used as experimental model for the study the pathogenesis, treatment, vertical transmission, and ocular toxoplasmosis. C. callosus can also be used to study cutaneous and visceral leishmaniasis, as the animals present cutaneous lesions, as well as parasites in the organs. C. callosus has epidemiological importance in Chagas disease, and since it is a Trypanosoma cruzi natural host in which rodents show high parasitemia and lethality, they are also effective as a model of congenital transmission. In the study of schistosomiasis, Schistosoma mansoni was proven to be a C. callosus natural host; thus, this rodent is a great model for fibrosis, hepatic granulomatous reaction, and celloma associated with lymphomyeloid tissue (CALT) during S. mansoni infection. In this review, we summarize the leading studies of parasitic diseases that used C. callosus as a rodent experimental model, describing the main uses and characteristics that led them to be considered an effective model.

Objectives: To evaluate the biaxial flexural strength (BFS), flexural modulus (BFM), and Knoop microhardness (KHN) of incremental and bulk-filled resin-based composites (RBCs) using extended curing exposure times., Materials and Methods: Disc specimens (n = 8; 6-mm diameter) were fabricated using three stacked molds (0.5-mm thick for the top and bottom molds, and a 1-mm-thick center mold for the conventional and 3-mm thick for the bulk-fill RBCs). Conventional (Tetric EvoCeram/TCE and Filtek Z250/FIZ) and bulk-fill RBCs (Tetric EvoCeram Bulk Fill/TBF and Filtek One Bulk Fill Restorative/FOB) were evaluated. The stacked RBC-filled molds were light-cured for (1) the manufacturer-recommended exposure (MRE) duration; (2) 50%, and (3) 100% extension of the MRE. The BFS, BFM, and KHN of the top and bottom discs were measured. BFS and BFM were analyzed by three-way ANOVA (material*curing time*depth) and Tukey's post hoc (α = 0.05). KHN was analyzed by two-way ANOVA (curing time*depth) and Tukey's post hoc (α = 0.05)., Results: Extending the exposure duration did not change the BFS and BFM on the top of the RBCs, but the BFS and KHN increased at the bottom of bulk-fill RBCs. For the conventional RBCs, TCE showed the highest increase on BFS at the bottom, going from 53.6 MPa at T1 to 69.9 at T3. Among the bulk-fill RBCs, FOB presented the highest increase on the bottom BFS (T1: 101.0 ± 19.9 MPa, T3: 147.6 ± 12.9 MPa). For all RBCs and exposure times, BFS and KHN were lower at the bottom. Only FIZ and FOB reached a bottom-to-top hardness ratio of 80%, at T3 and T2., Conclusion: A significant increase on the BFS and KHN on the bottom of bulk-fill RBCs can be observed when the time of exposure to the curing light is double the MRE. However, extended exposure does not eliminate differences on the BFS and KHN between the shallow and deep regions of RBCs. TCE and TBF failed to reach an acceptable B/T hardness ratio at all evaluated exposure times., Clinical Relevance: Mechanical properties of RBCs can be affected by insufficient polymerization, specially at deeper regions of the increment. Therefore, clinicians should consider applying twice the MRE to curing-light to polymerize the maximal increment thickness of bulk-fill RBCs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the influence of shades of a multilayered zirconia on light transmission, resin cement degree of conversion, and shear bond strength of resin cement., Materials and Methods: The light transmission through opaque (OPQ) and translucent (TNS) regions of Katana UTML zirconia (Kuraray Noritake Dental) were evaluated for using a spectroradiometer (n = 5). Degree of conversion of dual-cure resin cement (Panavia V5, Kuraray Noritake Dental) was measured after light-activation through OPQ or TNS regions and direct exposure. Composition of the zirconia was analyzed with energy dispersive x-ray spectroscopy (EDS). Shear bond strength (SBS) was evaluated on the OPQ and TNS regions after 24 h and 1 year from specimen preparation (n = 15)., Results: The OPQ region produced higher irradiance loss (95.1%) than TNS one (92.9%), and lower degree of conversion (52.4%) than TNS (71.2%) at 24 h post-light activation. EDS analysis did not show differences on the microstructure of the OPQ and TNS regions. There were no significant differences on the SBS between zirconia regions. For both zirconia regions, a significant reduction on the SBS occurred after aging, being 31.7% for OPQ and 38% for TNS., Conclusion: Both OPQ and TNS regions affected the light transmission through the multilayered zirconia. The OPQ region yielded the highest light attenuation and the lowest degree of conversion of resin cement. Different regions of the zirconia did not influence the SBS. Clinical significance Although opaque and translucent regions of the multilayered zirconia reduced the light transmission from LED curing unit and the degree of conversion of resin cement, the regions did not affect the resin cement adhesion., (© 2021 Wiley Periodicals LLC.)

In this work, we evaluated recombinant receptor binding domain (RBD)-based vaccine formulation prototypes with potential for further clinical development. We assessed different formulations containing RBD plus alum, AddaS03, AddaVax, or the combination of alum and U-Omp19: a novel Brucella spp. protease inhibitor vaccine adjuvant. Results show that the vaccine formulation composed of U-Omp19 and alum as adjuvants has a better performance: it significantly increased mucosal and systemic neutralizing antibodies in comparison to antigen plus alum, AddaVax, or AddaS03. Antibodies induced with the formulation containing U-Omp19 and alum not only increased their neutralization capacity against the ancestral virus but also cross-neutralized alpha, lambda, and gamma variants with similar potency. Furthermore, the addition of U-Omp19 to alum vaccine formulation increased the frequency of RBD-specific geminal center B cells and plasmablasts. Additionally, U-Omp19+alum formulation induced RBD-specific Th1 and CD8 + T-cell responses in spleens and lungs. Finally, this vaccine formulation conferred protection against an intranasal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge of K18-hACE2 mice., Competing Interests: LC, KP and JC are inventors of a patent related to U-Omp19 “Adjuvant for vaccines, vaccines that comprise it and uses thereof” PCT/ES2010/070667. The owner of this patent is the National Research Council CONICET. The existence of the patent did not have any role in experimental design, data collection and analysis, decision to publish, or preparation of this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a shared affiliation, with no collaboration, with several of the authors, namely, PP, IM, AV, and MS, at the time of review., (Copyright © 2022 Coria, Saposnik, Pueblas Castro, Castro, Bruno, Stone, Pérez, Darriba, Chemes, Alcain, Mazzitelli, Varese, Salvatori, Auguste, Álvarez, Pasquevich and Cassataro.)

Objectives: To compare the operative time and presence of air voids on Class II restorations fabricated by dental practitioners with 1 to 5 years of experience using incremental and bulk-filling techniques., Method and Materials: Four techniques were evaluated: incremental, bulk-filling, bulk-filling with heated composite, and snowplow technique. Standardized mandibular first molars with a MOD (mesial, occlusal, and distal) cavity were used. Voluntary operators made two restorations using each technique and the time required for each restoration was recorded. The restorations were scanned by micro-computed tomography to calculate the volume of the restoration occupied by air voids. The "operative time" and "volume of air voids" were analyzed individually by two-way ANOVA and Tukey HSD post hoc (α = .05) for the factors operator and insertion technique. A correlation between "operative time" and "volume of air voids" was evaluated using Pearson coefficient (α = .05)., Results: The incremental technique required significantly longer time, yet no differences were observed between the bulk-filling techniques. There were no significant differences between techniques regarding the volume of air voids. A significant, but weak, and inverse linear correlation (P = .0059; r = -.29; r2 = 8.41%) was found between the operative time and volume of air voids., Conclusion: There were no significant differences in the volume of air voids among the evaluated techniques, although bulk-filling techniques required a shorter operative time. Hence, implementing bulk-filling techniques by dental schools and restorative dental practitioners with different levels of expertise may reduce chair time and produce a volume of air voids similar to the incremental technique.

Challenges in measuring early childhood development (ECD) at scale have been documented, yet little is known about the specific difficulties related to questionnaire design and question interpretation. The purpose of this paper is to discuss the challenges of measuring ECD at scale in the context of household surveys and to show how to overcome them. The paper uses examples from the cognitive interviewing exercises that were conducted as part of the methodological work to develop a measure of ECD outcomes, the ECDI2030. It describes the methodological work carried out to inform the selection and improvement of question items and survey implementation tools as a fundamental step to reduce and mitigate systematic measurement error and improve data quality. The project consisted of a total of five rounds of testing, comprising 191 one-on-one, in-depth cognitive interviews across six countries (Bulgaria, India, Jamaica, Mexico, Uganda, and the USA). Qualitative data analysis methods were used to determine matches and mismatches between intention of items and false positives or false negative answers among subgroups of respondents. Key themes emerged that could potentially lead to systematic measurement error in population-based surveys on ECD: (1) willingness of child to perform task versus ability of child to perform task; (2) performing task versus performing task correctly; (3) identifying letters or numbers versus recognizing letters or numbers; (4) consistently performing task versus correctly performing task; (5) applicability of skills being asked versus observability of skills being asked; and (6) language production versus language comprehension. Through an iterative process of testing and subsequent revision, improvements were made to item wording, response options, and interviewer training instructions. Given the difficulties inherent in population-level data collection in the context of global monitoring, this study's findings confirm the importance of cognitive testing as a crucial step in careful, culturally relevant, and sensitive questionnaire design and as a means to reduce response bias in cross-cultural contexts.

Objective: To evaluate the influence of surface treatment on roughness (SA), topography, and shear bond strength (SBS) of computer-aided designer and manufacture (CAD/CAM) zirconia-reinforced lithium silicate (ZLS) and feldspathic (FEL) glass-ceramics., Materials and Methods: FEL and ZLS specimens were submitted to 5% or 10% hydrofluoric acid (HF) or self-etching ceramic primer (MEP) and different application times (20, 40, and 60 s), or to sandblasting (Control, 20 s). Resin cement cylinders were bonded to the specimens and tested in shear (n = 10) after 24 h and 16-months of water storage. SA and topography were evaluated by atomic force (AFM, n = 10) and scanning electron microscopy. Data were analyzed by ANOVA and Bonferroni test (α = 0.05)., Results: Sandblasting promoted the highest SA for ZLS, but 10% HF (40, 60 s) promoted higher SBS at 16 months. 10% HF produced the highest SA for FEL, but sandblasting and 5% HF (20 s) maintained SBS after 16 months, without differences from 10% HF (20 s) (p > 0.05). Overall, MEP produced lower SA and SBS among groups (p < 0.05). HF displayed greater morphological changes on FEL., Conclusion: 10% HF (40 s) provided better results for ZLS, while 5% or 10% HF (20 s) was suitable for FEL., Clinical Significance: Surface treatments influenced SA, topography, and SBS of materials. HF etching is the surface treatment of choice for both CAD/CAM glass-ceramics., (© 2021 Wiley Periodicals LLC.)

Background: Bulk-fill materials can facilitate the restorative procedure mainly for deep and wide posterior cavities. The purpose of this study was to evaluate flexural strength (biaxial flexural strength [BFS]) and microhardness (Knoop microhardness [KHN]) at different depths of bulk-fill materials., Methods: Five bulk-fill materials were tested: two light-curable composite resins, one dual-cure composite, one bioactive restorative, and a high-viscosity glass ionomer. A conventional composite was used as control. BFS and KHN were tested at different depths. Data was analyzed by two- and one-way ANOVAs, respectively and Tukey's post-hoc (α=0.05)., Results: The high-viscosity glass ionomer material presented the lowest BFS at all depths. KHN for the two light-curable and the dual-cure bulk-fill resin composites was reduced following an increase in restoration depth, while the conventional composite, the bioactive material, and the high-viscosity glass ionomer were not affected., Conclusion: There are differences in the properties of the tested materials at 4 mm depth, showing that the studied properties of some materials vary according to the cavity depth, although the results are material dependent., Clinical Significance: Mechanical properties of light-cured, bulk-fill materials may be affected by inadequate polymerization. Clinicians should consider complementary strategies to achieve adequate polymerization at high-increment depths., (© 2021 Wiley Periodicals LLC.)

Bovine viral diarrhea virus (BVDV) belongs to the Pestivirus genus ( Flaviviridae ). In spite of the availability of vaccines, the virus is still causing substantial financial losses to the livestock industry. In this context, the use of antiviral agents could be an alternative strategy to control and reduce viral infections. The viral RNA-dependent RNA polymerase (RdRp) is essential for the replication of the viral genome and constitutes an attractive target for the identification of antiviral compounds. In a previous work, we have identified potential molecules that dock into an allosteric binding pocket of BVDV RdRp via a structure-based virtual screening approach. One of them, N -(2-morpholinoethyl)-2-phenylquinazolin-4-amine [ 1 , 50% effective concentration (EC 50 ) = 9.7 ± 0.5 μM], was selected to perform different chemical modifications. Among 24 derivatives synthesized, eight of them showed considerable antiviral activity. Molecular modeling of the most active compounds showed that they bind to a pocket located in the fingers and thumb domains in BVDV RdRp, which is different from that identified for other non-nucleoside inhibitors (NNIs) such as thiosemicarbazone (TSC). We selected compound 2-[4-(2-phenylquinazolin-4-yl)piperazin-1-yl]ethanol ( 1.9 ; EC 50 = 1.7 ± 0.4 μM) for further analysis. Compound 1.9 was found to inhibit the in vitro replication of TSC-resistant BVDV variants, which carry the N264D mutation in the RdRp. In addition, 1.9 presented adequate solubility in different media and a high-stability profile in murine and bovine plasma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Fernández, Castro, Rosas, Fidalgo, Adler, Battini, España de Marco, Fabiani, Bruno, Bollini and Cavallaro.)

Objective: To evaluate the effects of human saliva decontamination protocols on bond strength of resin cement to zirconia (Y-PSZ), wettability, and microbial decontamination., Materials and Methods: Zirconia plates were sandblasted and divided into (a) not contaminated, (b) contaminated with human saliva and: (c) not cleaned, (d) cleaned with air-water spray, (e) cleaned with 70% ethanol, (f) cleaned with Ivoclean, or (g) cleaned with nonthermal atmospheric plasma (NTAP). The wettability and microbial decontamination of the surfaces were determined after saliva contamination or cleaning. Monobond Plus (Ivoclar Vivadent) was applied after cleaning, followed by Variolink LC (Ivoclar Vivadent). The samples were stored 1 week before shear bond strength (SBS) testing, and data (SBS and wettability) were analyzed by one-way analysis of variance and Tukey test (α = .05)., Results: Saliva contamination reduced SBS to zirconia compared to not contaminated. Both Ivoclean and NTAP produced higher SBS compared to not cleaned and were not significantly different from the not contaminated. Ivoclean produced the highest contact angle, and NTAP the lowest. With the exception of using just water-spray, all cleaning protocols decontaminated the specimens., Conclusions: Both Ivoclean and NTAP overcame the effects of saliva contamination, producing an SBS to zirconia comparable to the positive control., Clinical Significance: Dental ceramics should be cleaned prior to resin cementation to eliminate the effects of human saliva contamination, and Ivoclean and NTAP are considered suitable materials for this purpose., (© 2020 Wiley Periodicals LLC.)

Purpose: To investigate the effects of 1-year water storage and surface treatments on shear bond strength (SBS) of two composite cements bonded to resin matrix CAD-CAM ceramics (RMCs) and on the mechanical properties of RMCs., Materials and Methods: Three types of RMCs were tested: 1. polymer-infiltrated hybrid ceramic (PIHC, Enamic, VITA Zahnfabrik); 2. resin nanoceramic (RNC, Lava Ultimate, 3M Oral Care); and 3. flexible hybrid ceramic (FHC, Cerasmart, GC). One indirect laboratory composite (ILC, Epricord, Kuraray Noritake) was used as control. For each material, 60 plates (14 x 7 x 1 mm) were prepared for the SBS test and submitted to three different surface treatments: following manufacturer's instructions, non-thermal atmospheric plasma application (30 s), and plasma + bonding agent. Two composite cements were tested: RelyX Ultimate (3M Oral Care) and Panavia V5 (Kurarary Noritake). Two resin cylinders (1.5 mm diameter x 1.5 mm height) were bonded to each plate (n = 10), with one tested after 24-h storage in distilled water and the other after 1 year of storage in distilled water. Twenty rectangular bars (12 x 2 x 1 mm) of each indirect material were prepared and submitted to the 3-point flexural test after 24-h or 1-year water storage to determine the elastic modulus (EM) and flexural strength (FS) (n = 10). Fractured samples were also examined with SEM and energy dispersive x-ray spectroscopy (EDS). SBS data were analyzed by four-way ANOVA, and EM and FS data by two-way ANOVA, followed by Tukey's post-hoc test (α = 0.05)., Results: Groups treated in accordance with manufacturer's instructions exhibited higher SBS than did plasma and plasma + bonding agent groups for all indirect materials, composite cements, and storage periods tested. In general, RelyX Ultimate displayed higher mean SBS than did Panavia V5, except for some groups of ILC where manufacturer's instructions were followed. After 1-year storage in water, all groups exhibited a significant reduction in SBS, except for some groups that following manufacturer's instructions. ILC showed the lowest values of EM and FS. Among the CAD-CAM materials, FHC exhibited the lowest EM and highest FS means, while PIHC possessed the highest EM and lowest FS means for both storage periods., Conclusions: In general, following the respective manufacturer's instructions yielded the best bond strength results. For most materials, 1-year water storage decreased bond strength of composite cements to RMCs, as well as their FS, while increasing their EM. Microstructure and composition influenced the mechanical properties studied.

Bovine viral diarrhea virus (BVDV) is a pestivirus whose infection in cattle is globally distributed. The use of antivirals could complement vaccination as a tool of control and reduce economic losses. The RNA-dependent RNA polymerase (RdRp) of the virus is essential for its genome replication and constitutes an attractive target for the identification of antivirals. With the aim of obtaining selective BVDV inhibitors, the crystal structure of BVDV RdRp was used to perform a virtual screening. Approximately 15,000 small molecules from commercial and in-house databases were evaluated and several structurally different compounds were tested in vitro for antiviral activity. Interestingly, of twelve evaluated compounds, five were active and displayed EC 50 values in the sub and low-micromolar range. Time of drug addition experiment and measured intracellular BVDV RNA showed that compound 7 act during RNA synthesis. Molecular Dynamics and MM/PBSA calculation were done to characterize the interaction of the most active compounds with RdRp, which will allow future ligand optimization. These studies highlight the use of in silico screening to identify a new class of BVDV inhibitors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Orbital compartment syndrome (OCS) is a rare condition characterized by increased intraorbital pressure and hypoperfusion of critical neural structures. It is usually associated with external ophthalmoplegia. We report a case of postoperative OCS following a frontotemporal craniotomy and review pertinent literature., Case Description: A 3-year-old female patient presented with a 3-year history of refractory epilepsy and diagnosis of right frontobasal cortical dysplasia. She underwent an elective frontotemporal craniotomy to allow resection of dysplastic cortex. The intraoperative period was uneventful. Postoperatively, following removal of operating fields, we noticed proptosis and right periorbital swelling. A diagnosis of orbital compartment syndrome was made. At the pediatric intensive care unit, the patient underwent an emergency right lateral canthotomy with wide inferior and superior cantholysis. Nowadays she is in the fourth month of postoperative follow-up. There is still slight and almost indistinguishable exophthalmos, but her extrinsic eye movement ranges and reaction to light are normal., Discussion: OCS is a rare ophthalmologic emergency characterized by an acute rise in orbital pressure and may result in complete irreversible blindness if not rapidly treated. The frontotemporal or "pterional" craniotomy exposure requires a myocutaneous flap to be retracted anteriorly and inferiorly near the orbit. There may be orbital compression due to this flap leading to potential harmful complications. Attention to factors such as direct ocular pressure from skin flaps, congestion from head positioning, and adequate intraoperative eye protection may reduce the risk or allow faster management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Oral mucositis (OM) is the most common debilitating complication among patients undergoing hematopoietic stem cell transplantation (HSCT). Photobiomodulation therapy (PBM) has shown beneficial effects in the treatment of OM, but few studies have evaluated its biological effects. This study evaluated the effect of PBM on the reduction of OM severity in patients undergoing HSCT and its relation to the modulation of the inflammatory response. Fifty-one patients were randomly assigned to two groups: PBM [submitted to PBM from admission (AD) to D+7] (n = 27) and control (n = 24) [received oral hygiene]. OM severity was assessed daily using the WHO scale. Saliva samples were collected on AD, D+7, and hospital discharge (HD) to measure CXCL8/interleukin 8, using cytometric bead array analysis and nitrite (NO) and myeloperoxidase (MPO) using colorimetric methods. PBM significantly reduced the severity of OM from D+7 to D+11 (p < 0.05). All non-interventional patients (controls) who developed grade 2 or higher OM induced an increase of CXCL8 in saliva (n = 14) on D+7. PBM led to a decrease in CXCL8 on D+7 in 85% of patients, while 70.8% of patients in the control group presented an increase in this chemokine (p = 0.007). NO decreased from AD to D+7 in the PBM group (p > 0.05). MPO significantly decreased on D+7 in both groups (p < 0.05). PBM brought about a reduction in the severity of OM in patients undergoing HSCT, and this reduction was associated with a decrease in CXCL8 salivary levels.

A series of N 4 -arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N 4 position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC 50 =2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis. In a previous study, the thiosemicarbazone of 5,6-dimethoxy-1-indanone (5,6-TSC) was characterized as a non-nucleoside inhibitor (NNI) of the BVDV RNA-dependent RNA polymerase. In the present work, cross-resistance assays were performed with the most active compounds. Such studies were carried out on 5,6-TSC resistant BVDV (BVDV-TSC r T1) carrying mutations in the viral polymerase. This BVDV mutant was also resistant to compound 15. Molecular docking studies and MM/PBSA calculations were performed to assess the most active derivatives at the 5,6-TSC viral polymerase binding site. The differences in the interaction pattern and the binding affinity of derivative 15 either to the wild type or BVDV-TSC r T1 polymerase were key factors to define the mode of action of this compound., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Primary breast lymphoma is a rare disease and accounts for 0.5% of cases of breast cancer. Most primary breast lymphomas develop from B cells, and the involvement of T cells is rare. Anaplastic large cell lymphoma (ALCL) is a recently discovered T-cell lymphoma associated with breast implants. Only a few cases have been reported to date. It is believed that the incidence of ALCL is increasing because of the increasing number of breast implants. The clinical presentation is variable and can manifest as a palpable mass in the breast or armpit, breast pain, or capsular contracture. Because of the rarity of the disease and the lack of knowledge to date, clinical diagnosis is often delayed, with consequent delays in treatment. The cause and pathogenesis have not been fully elucidated, and there are no evidence-based guidelines for diagnosis, treatment, or follow-up of this disease. We present a review of cases of patients with silicone breast implants, including ALCL, a rare type of breast cancer that is still under study, and silicone-induced granuloma of breast implant capsule and its differential diagnosis, and discuss if a silicone-induced granuloma of breast implant capsule could be the precursor of the disease., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Social support networks are crucial for the health of older adults; however, personal characteristics and time of life may diminish the protective effect of social support., Objective: to determine if the presence of social support networks were associated with cognitive impairment among Mexican adults aged 50 or older and if this relationship was different based on age., Method: This study analyzed data from the National Representation Survey performed in Mexico, Study on Global Ageing (SAGE) wave 1. Cognitive function was evaluated by a standardized test, social support was evaluated through latent class analysis (LCA). The LCA was run to obtain three subgroups of different Social Support Levels (SSL): low, medium, and high. Logistic regression models, stratified by age, were performed to analyze the association between SSL and cognitive function., Results: For respondents ages 71-80 y/o, there was an inverse relationship with cognitive impairment for those with medium (OR 0.23, p=0.020) and high (OR 0.07, p=0.000) SSL in comparison with low SSL. While social support helped to improve cognitive function in older adults aged 71-80, this same association was not observed in adults of other ages. Those younger than 70 y/o may not need such a strong support network as a result of being more self-sufficient. After 80, social networks were not enough to help diminish the negative impact of cognitive impairment., Conclusion: Social support could improve the cognitive function of adults ages 71 and 80; suggesting there could be a window of opportunity to improve cognitive functioning for this group., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Child and maternal health outcomes have notably improved in Mexico since 1990, whereas rising adult mortality rates defy traditional epidemiological transition models in which decreased death rates occur across all ages. These trends suggest Mexico is experiencing a more complex, dissonant health transition than historically observed. Enduring inequalities between states further emphasise the need for more detailed health assessments over time. The Global Burden of Diseases, Injuries, and Risk Factors Study 2013 (GBD 2013) provides the comprehensive, comparable framework through which such national and subnational analyses can occur. This study offers a state-level quantification of disease burden and risk factor attribution in Mexico for the first time., Methods: We extracted data from GBD 2013 to assess mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) in Mexico and its 32 states, along with eight comparator countries in the Americas. States were grouped by Marginalisation Index scores to compare subnational burden along a socioeconomic dimension. We split extracted data by state and applied GBD methods to generate estimates of burden, and attributable burden due to behavioural, metabolic, and environmental or occupational risks. We present results for 306 causes, 2337 sequelae, and 79 risk factors., Findings: From 1990 to 2013, life expectancy from birth in Mexico increased by 3·4 years (95% uncertainty interval 3·1-3·8), from 72·1 years (71·8-72·3) to 75·5 years (75·3-75·7), and these gains were more pronounced in states with high marginalisation. Nationally, age-standardised death rates fell 13·3% (11·9-14·6%) since 1990, but state-level reductions for all-cause mortality varied and gaps between life expectancy and years lived in full health, as measured by HALE, widened in several states. Progress in women's life expectancy exceeded that of men, in whom negligible improvements were observed since 2000. For many states, this trend corresponded with rising YLL rates from interpersonal violence and chronic kidney disease. Nationally, age-standardised YLL rates for diarrhoeal diseases and protein-energy malnutrition markedly decreased, ranking Mexico well above comparator countries. However, amid Mexico's progress against communicable diseases, chronic kidney disease burden rapidly climbed, with age-standardised YLL and DALY rates increasing more than 130% by 2013. For women, DALY rates from breast cancer also increased since 1990, rising 12·1% (4·6-23·1%). In 2013, the leading five causes of DALYs were diabetes, ischaemic heart disease, chronic kidney disease, low back and neck pain, and depressive disorders; the latter three were not among the leading five causes in 1990, further underscoring Mexico's rapid epidemiological transition. Leading risk factors for disease burden in 1990, such as undernutrition, were replaced by high fasting plasma glucose and high body-mass index by 2013. Attributable burden due to dietary risks also increased, accounting for more than 10% of DALYs in 2013., Interpretation: Mexico achieved sizeable reductions in burden due to several causes, such as diarrhoeal diseases, and risks factors, such as undernutrition and poor sanitation, which were mainly associated with maternal and child health interventions. Yet rising adult mortality rates from chronic kidney disease, diabetes, cirrhosis, and, since 2000, interpersonal violence drove deteriorating health outcomes, particularly in men. Although state inequalities from communicable diseases narrowed over time, non-communicable diseases and injury burdens varied markedly at local levels. The dissonance with which Mexico and its 32 states are experiencing epidemiological transitions might strain health-system responsiveness and performance, which stresses the importance of timely, evidence-informed health policies and programmes linked to the health needs of each state., Funding: Bill & Melinda Gates Foundation, Instituto Nacional de Salud Pública., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution., Methods: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol., Findings: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa., Interpretation: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks., Funding: Bill & Melinda Gates Foundation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The current standard of care of the infection by hepatitis C virus (HCV) is effective in a limited number of patients and the high cost hinders therapy affordability and compliance. In this context, the research of new direct-acting antiviral agents (DAAs) for a more effective and long-lasting therapy is an urgent need and an area of active investigation. In an effort to develop novel DAAs, a series of 1-indanone thiosemicarbazones (TSCs) was synthesized and fully characterized. However, the high self-aggregation tendency and extremely poor aqueous solubility of these antiviral candidates often preclude their reliable biological evaluation in vitro. To maintain constant TSC concentrations over the biological assays, different TSC/cyclodextrin complexes were produced. In the present work, we report for the first time the cytotoxicity and antiviral activity of 5,6-dimethoxy TSC inclusion complexes with hydroxypropyl-β-cyclodextrin on bovine viral diarrhea virus (BVDV) as HCV surrogate model. Results showed a potent suppression of the virus replication, with greater activity for the inclusion complexes than the free compound.

The present study aimed to study the effects of exercise training (ET) performed by rats on a 10-week high-fructose diet on metabolic, hemodynamic, and autonomic changes, as well as intraocular pressure (IOP). Male Wistar rats receiving fructose overload in drinking water (100 g/L) were concomitantly trained on a treadmill for 10 weeks (FT group) or kept sedentary (F group), and a control group (C) was kept in normal laboratory conditions. The metabolic evaluation comprised the Lee index, glycemia, and insulin tolerance test (KITT). Arterial pressure (AP) was measured directly, and systolic AP variability was performed to determine peripheral autonomic modulation. ET attenuated impaired metabolic parameters, AP, IOP, and ocular perfusion pressure (OPP) induced by fructose overload (FT vs F). The increase in peripheral sympathetic modulation in F rats, demonstrated by systolic AP variance and low frequency (LF) band (F: 37±2, 6.6±0.3 vs C: 26±3, 3.6±0.5 mmHg2), was prevented by ET (FT: 29±3, 3.4±0.7 mmHg2). Positive correlations were found between the LF band and right IOP (r=0.57, P=0.01) and left IOP (r=0.64, P=0.003). Negative correlations were noted between KITT values and right IOP (r=-0.55, P=0.01) and left IOP (r=-0.62, P=0.005). ET in rats effectively prevented metabolic abnormalities and AP and IOP increases promoted by a high-fructose diet. In addition, ocular benefits triggered by exercise training were associated with peripheral autonomic improvement.

Objective: To aprehend the social representations about the solvability in mental health care with users of the Family Health Strategy and professionals of family health teams and of the Center for Psychosocial Care., Method: A qualitative study using semi-structured interviews for data collection, and the Alceste software for analysis. This software uses the Hierarchical Descending Classification based on the examination of lexical roots, considering the words as units and providing context in the corpus., Results: The representations emerge in two opposing poles: the users require satisfaction with care and the professionals realize the need for improvement of health actions. Although the matricial support in mental health and the home visits are developed, the barriers related to investment in health, continuing education and organization of care persist., Conclusion: The different representations enable improvements in customer service, solvability of care and aggregate knowledge and practices in the expanded perspective of health needs in the family, social and therapeutic context.

Bovine viral diarrhea virus (BVDV) is the prototype Pestivirus. BVDV infection is distributed worldwide and causes serious problems for the livestock industry. The thiosemicarbazone of 5,6-dimethoxy-1-indanone (TSC) is a non-nucleoside polymerase inhibitor (NNI) of BVDV. All TSC-resistant BVDV variants (BVDV-TSCr T1-5) present an N264D mutation in the NS5B gene (RdRp) whereas the variant BVDV-TSCr T1 also presents an NS5B A392E mutation. In the present study, we carried out twenty passages of BVDV-TSCr T1-5 in MDBK cells in the absence of TSC to evaluate the stability of the resistance. The viral populations obtained (BVDV R1-5) remained resistant to the antiviral compound and conserved the mutations in NS5B associated with this phenotype. Along the passages, BVDV R2, R3 and R5 presented a delay in the production of cytopathic effect that correlated with a decrease in cell apoptosis and intracellular accumulation of viral RNA. The complete genome sequences that encode for NS2 to NS5B, Npro and Erns were analyzed. Additional mutations were detected in the NS5B of BVDV R1, R3 and R4. In both BVDV R2 and R3, most of the mutations found were localized in NS5A, whereas in BVDV R5, the only mutation fixed was NS5A V177A. These results suggest that mutations in NS5A could alter BVDV cytopathogenicity. In conclusion, the stability of the resistance to TSC may be due to the fixation of different compensatory mutations in each BVDV-TSCr. During their replication in a TSC-free medium, some virus populations presented a kind of interaction with the host cell that resembled a persistent infection: decreased cytopathogenicity and viral genome synthesis. This is the first report on the stability of antiviral resistance and on the evolution of NNI-resistant BVDV variants. The results obtained for BVDV-TSCr could also be applied for other NNIs.

Purpose: To evaluate macular edema after uncomplicated phacoemulsification with implantation of intraocular lens by spectral domain optical coherence tomography (OCT)., Methods: Prospective study was conducted in 62 eyes of patients underwent phacoemulsification with implantation of intraocular lens. Patients were evaluated before surgery and after surgery at day 1, week 1, week 2 and week 4. Visual acuity (VA), anterior chamber cells and 200 x 200 macular cube optical coherence tomography were measured., Results: After phacoemulsification there was an improvement in visual acuity, decreasing inflammation, and increased macular thickness and macular volume. There was one case of cystoid macular edema. There was a weak inverse correlation between visual acuity and central macular thickness, and between visual acuity and macular volume. We observed a week direct correlation between inflammation and macular volume., Conclusion: Subclinical macular edema develops even after uncomplicated cataract surgery in patients not predisposed. The spectral domain optical coherence tomography was able to detect small increases in macular thickness in the study period.

Objective: This study sought to compare the effects and outcomes of two ophthalmic viscosurgical devices, 1.6% hyaluronic acid/4.0% chondroitin sulfate and 2.0% hydroxypropylmethylcellulose, during phacoemulsification., Methods: This prospective, randomized clinical trial comprised 78 eyes (39 patients) that received phacoemulsification performed by the same surgeon using a standardized technique. Patients were randomly assigned to receive either 1.6% hyaluronic acid/4.0% chondroitin sulfate or 2.0% hydroxypropylmethylcellulose on the first eye. The other eye was treated later and received the other viscoelastic agent. Preoperative and postoperative examinations (5, 24 and 48 hours; 7 and 14 days; 3 and 6 months) included measurements of the total volume of the ophthalmic viscosurgical device, ultrasound and washout times to completely remove the ophthalmic viscosurgical device, intraocular pressure, central corneal thickness and best-corrected visual acuity. The corneal endothelial cell count was measured at baseline and at six months postoperatively. ClinicalTrials.gov: NCT01387620., Results: There were no statistically significant differences between groups in terms of cataract density or ultrasound time. However, it took longer to remove 2.0% hydroxypropylmethylcellulose than 1.6% hyaluronic acid/ 4.0% chondroitin sulfate, and the amount of viscoelastic material used was greater in the 2.0% hydroxypropylmethylcellulose group. In addition, the best-corrected visual acuity was significantly better in the hyaluronic acid/ chondroitin sulfate group, but this preferable outcome was only observed at 24 hours after the operation. There were no statistically significant differences between the two ophthalmic viscosurgical devices regarding the central corneal thickness or intraocular pressure measurements at any point in time. The corneal endothelial cell count was significantly higher in the hyaluronic acid/chondroitin sulfate group., Conclusion: The ophthalmic viscosurgical device consisting of 1.6% hyaluronic acid/4.0% chondroitin sulfate was more efficient during phacoemulsification and was easier to remove after IOL implantation than 2.0% hydroxypropylmethylcellulose. In addition, the corneal endothelial cell count was significantly higher following the use of hyaluronic acid/chondroitin sulfate than with hydroxypropylmethylcellulose, which promoted an improved level of corneal endothelium protection.

Systemic injection of pilocarpine in rodents induces status epilepticus (SE) and reproduces the main characteristics of temporal lobe epilepsy (TLE). Different mechanisms are activated by SE contributing to cell death and immune system activation. We used BALB/c nude mice, a mutant that is severely immunocompromised, to characterize seizure pattern, neurochemical changes, cell death and c-Fos activation secondarily to pilocarpine-induced SE. The behavioral seizures were less severe in BALB/c nude than in BALB/c wild type mice. However, nude mice presented more tonic-clonic episodes and higher mortality rate during SE. The c-Fos expression was most prominent in the caudate-putamen, CA3 (p<0.05), dentate gyrus, entorhinal cortex (p<0.001), basolateral nucleus of amygdala (p<0.01) and piriform cortex (p<0.05) of BALB/c nude mice than of BALB/c. Besides, nude mice subjected to SE presented high number of Fluorojade-B (FJB) stained cells in the piriform cortex, amygdala (p<0.05) and hilus (p<0.001) in comparison with BALB/c mice. A significant increase in the level of glutamate and GABA was found in the hippocampus and cortex of BALB/c mice presenting SE in comparison to controls. However, the level of glutamate was higher in the brains of BALB nude mice than in the brains of BALB/c wild type mice, while the levels of GABA were unchanged. These results indicate that the brains of immunodeficient nude mice are more vulnerable to the deleterious effects of pilocarpine-induced SE as they present intense activation, increased glutamate levels and more cell death., (Published by Elsevier B.V.)

In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV).

The antiviral activities of lamivudine (3TC; 2',3'-dideoxy-3'-thiacytidine) and six 5'-O-carbonates of 3TC were determined by inhibition of hepatitis B virus (HBV) replication in HepG2 2.2.15 cells. HBV DNA in cell supernatants was quantified by real-time polymerase chain reaction (PCR). The results showed that 3TC-Etha was six times more active than 3TC and that 3TC-Buta, 3TC-Hexa and 3TC-Octa were approximately three times more active than 3TC. In contrast, 3TC-Penta and 3TC-Metha showed anti-HBV activity similar to that of the parent compound 3TC. In conclusion, 5'-O-carbonates of 3TC appear to be promising candidates as anti-HBV compounds. This modification could optimise the use of 3TC, a well-tolerated, effective and inexpensive drug, in monotherapy or combined therapy for chronic HBV infections as well as human immunodeficiency virus (HIV)/HBV co-infections., (Copyright © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Viruses belonging to the Flaviviridae family cause clinically significant diseases in humans and animals. This family includes three genera: Pestivirus [including bovine viral diarrhea virus (BVDV)], Flavivirus [including yellow fever virus (YFV), dengue virus, and West Nile virus (WNV)], and Hepacivirus [including hepatitis C virus (HCV)]. BVDV is responsible for major losses in cattle, causing a range of clinical manifestations, and is also a problematic contaminant in the laboratory. Noncytopathic BVDV infection can remain unnoticed and infect laboratory cell lines through its presence in contaminated bovine serum used in cell culture. BVDV is considered to be a valuable surrogate virus model for identifying and characterizing antiviral agents to be used against HCV. In some aspects of viral replication, BVDV is more advantageous than the currently used HCV replicon systems. In this review, we report the design, synthesis, and activity against BVDV of a series of compounds assayed until now.

We evaluated the effects of vincristine on the gastrointestinal (GI) motility of awake rats and correlated them with the course of vincristine-induced peripheral neuropathy. Vincristine or saline was injected into the tail vein of male Wistar rats (180-250 g) on alternate days: 50 microg/kg (5 doses, N = 10), 100 microg/kg (2, 3, 4 and 5 doses, N = 49) or 150 microg/kg (1, 2, or 5 doses, N = 37). Weight and stool output were measured daily for each animal. One day after completing the vincristine treatment, the animals were fasted for 24 h, gavage-fed with a test meal and sacrificed 10 min later to measure gastric emptying (GE), GI transit and colon weight. Sensory peripheral neuropathy was evaluated by hot plate testing. Chronic vincristine treatments with total cumulative doses of at least 250 microg/kg significantly decreased GE by 31-59% and GI transit by 55-93%. The effect of 5 doses of vincristine (150 microg/kg) on GE did not persist for more than 1 week. Colon weight increased after 2 and 5 doses of vincristine (150 microg/kg). Fecal output decreased up to 48 h after the fifth dose of vincristine (150 microg/kg). Vincristine decreased the heat pain threshold 1 day after 5 doses of 50-100 microg/kg or after 3-5 doses of 150 microg/kg. This effect lasted for at least 2 weeks after the fifth dose. Chronic intravenous vincristine treatment delayed GE and GI transit of liquid. This effect correlated with the peak increase in colon weight but not with the pain threshold changes.

Identification of new therapeutic agents for the treatment of viral diseases represents an area of active investigation. In an effort to develop new antiviral compounds, a series of 1-indanone thiosemicarbazone derivatives were synthesized. These derivatives were structurally characterized using several spectroscopic techniques and evaluated against bovine viral diarrhoea virus as a surrogate model for hepatitis C virus. Thiosemicarbazone 2m showed potent anti-bovine viral diarrhoea virus activity with a higher selectivity index (SI=80.29) than that of ribavirin (SI=11.64). This result determines the potentiality of these thiosemicarbazones as antiviral agents for the treatment of infections caused by other highly related members of Flaviviridae family, as hepatitis C virus.

Suprofen (SPF) is a non-steroidal anti-inflammatory drug (NSAID), which belongs to the 2-arylpropionic acids subclass. As a result of their chiral characteristics, these compounds have shown a marked enantioselective behaviour with a high degree of interspecies variation. They are mainly eliminated by glucuronidation. Plasma, biliary and urine disposition of SPF was investigated in the cat after intravenous administration of the racemate (dose 2 mg/kg). Both enantiomers exhibited similar disposition profiles in plasma with no evidence of chiral inversion. During bile sampling time, recovered acylglucuronides of R (-) and S (+) SPF were less than 1% of the total dose administered. Only free SPF was recovered in the urine, representing 0.12% of the administered racemic SPF dose. The results indicate that neither chiral inversion nor glucuronidation predominate in SPF disposition in cats., (Copyright Harcourt Publishers Ltd.)

To clarify the relationship between people who have committed homicide and been convicted (murderers) and homicide victims, and between murderers and suicide victims, their profiles were compared in Portugal from 1970 to 1987. Correlations were found between the age group, marital status and occupation of murderers and homicide victims. Murderers and suicide victims were only correlated by occupation. Since 1983, there has been a trend towards an increasing prevalence of murderers among younger people and single people, and of homicide victims among older people. The correlation between murderers and suicide victims can be explained by alcoholism, and murderers tend to kill their relatives and peers as a result of conflict situations. The emerging trend towards young people murdering old and defenceless people points towards a colder and financially motivated killer, perhaps increasingly among young drug addicts.

The greater incidence of suicide among males could be ascribed to the distinct roles still attributed to each sex. Progress towards female independence could reduce this different incidence. We analysed the following in Portugal: male and female suicide rates; profiles; and male/female suicide ratio before (1955-1969) and after the development of a movement for women's independence (1970-85). Concomitant with progress towards female independence there is a significant rise in female suicide and a decrease in male/female suicide ratio. The highest rates are among professional/technical women living in urban areas. In professional groups there is significant correlation between deaths caused by suicide and by liver cirrhosis. It is concluded that alcoholism often leads to suicide; in women, taboos about alcoholism and suicide explain a higher incidence of suicide among culturally freer professional groups; female independence will catalyse a rise in alcoholism, which together with other factors resulting from that independence will lead to a predictable increase of suicide among Portuguese women and a reduced difference in rates of suicide between the sexes.

Our purpose has been to verify whether and in what way female autonomy may contribute to change the importance of variables once seeming to influence the suicide of Portuguese women. The suicide rates in both sexes in Portugal and the district and city of Lisbon (the capital of the district) was surveyed from 1950 to 1968 and from 1969 to 1983, over the decades of the 1950's, 60's and 70's and the period 1980-83 and related to age, seasons, marital status, and number of children of married women. Since 1977, female suicide rates have risen significantly in Portugal and the district of Lisbon, both in total and in age groups which are professionally active; unmarried, and married and childless women achieve more. The rising trend of suicides in spring and summer is confirmed and resembles the male seasonal variation. The growing independence of Portuguese women is still not widely reflected in their suicide rates, but it seems plausible to anticipate that, without the reality of children, women's rates would gradually approach those of men.