Improving Accessibility to Patients with Interstitial Lung Disease (ILD): Barriers to Early Diagnosis and Timely Treatment in Latin America.

Delayed initiation of effective antifibrotic therapy in patients with interstitial lung diseases (ILD) may influence the progression and outcome of the disease. This study analyzes the differences in the journey of patients with ILD in the Brazilian and Mexican health systems. An evaluative study was conducted in reference centers for interstitial lung diseases in Brazil and Mexico with a panel of four specialists. The patient's journey in both countries begins when the patient seeks medical care after observing a chronic respiratory symptom. In both countries, due to diagnostic complexity, these patients arrive at ILD referral centers at an advanced stage of the disease. Once diagnosis is established, the treatment onset differs between Mexico and Brazil. In Brazil, access to antifibrotic drugs through the public health system has been a significant challenge, and their cost makes them unaffordable for most people. This situation forces medical specialists to provide only supportive care to patients until these drugs can be accessed. In Mexico, antifibrotics have been available in health sectors since 2018. Brazil and Mexico have several similarities regarding the initial journey of the patient due to diagnosis difficulties. Still, the outcome tends to be different due to a difference in access to treatment with antifibrotics. For this reason, advancing health policies that ensure proper treatment for patients with ILD is crucial for the sustainability and reliability of the health system.

Short and long effects of the COVID-19 context on oral health-related quality of life of adolescents.

AIM: To assess the immediate and late effects of the COVID-19 pandemic on the oral health-related quality of life (OHRQoL) of adolescents. DESIGN: This is a longitudinal study performed with adolescents (11-15 years old) from Southern Brazil who were evaluated before the COVID-19 outbreak, and 3 (T2) and 15 (T3) months after the beginning of the pandemic. OHRQoL was assessed using the CPQ11-14. Sociodemographic and clinical variables were also collected. Changes in OHRQoL before, 3 and 15 months after the start of the pandemic were analyzed through multilevel Poisson regression models for repeated measures. RESULTS: A total of 290 adolescents were evaluated at T1, 207 were re-evaluated at T2, and 204 at T3. Overall CPQ11-14 scores over follow-ups were 11.0 (SD 8.0) at T1, 8.3 (SD 7.8) and 12.8 (SD 8.8) at T3. Compared to T1, adolescents presented 29% lower overall CPQ11-14 scores (IRR 0.71 95% CI 0.66-0.75) at T2, and 11% higher scores at T3 (IRR 1.11 95% CI 1.05-1 0.17), especially for the emotional and social well-being domains. CONCLUSION: COVID-19 pandemic impacted the adolescents' OHRQoL differently over time, indicating a reduction in impacts immediately after the beginning and worsening over long term exposure to this scenario.

Oral health literacy and its association with oral health-related quality of life amongst pregnant women: a cross-sectional study.

PURPOSE: This study aimed to evaluate the association of oral health literacy (OHL) and oral health-related quality of life (OHRQoL) of pregnant women. METHODS: This cross-sectional study evaluated a representative sample of pregnant women assisted in public health services in southern Brazil. Demographic, socioeconomic, psychosocial and behavioural data were collected through structured questionnaires. The Oral Health Impact Profile (OHIP-14) questionnaire was used to evaluate the OHRQoL. The Brazilian Rapid Estimate of Adult Literacy in Dentistry (BREALD-30) was used to measure OHL. Dental caries and gingival bleeding were evaluated by clinical examinations. Adjusted multilevel Poisson regression models with a hierarchical approach were used to assess the associations. The results are presented as rate ratio (RR) and 95% confidence interval (95% CI). RESULTS: A total of 520 pregnant women were evaluated. Pregnant women with lower levels of OHL presented overall OHIP-14 scores 14% higher (RR 1.14; 95% CI 1.07-1.22) than their counterparts. High household income and high education level were related to low overall OHIP-14 scores. Furthermore, less dental attendance, low social support, untreated dental caries and gingival bleeding were also associated with high overall OHIP-14 scores. CONCLUSION: Our findings reinforce that health literacy levels influence patient-reported outcomes. Pregnant women with lower OHL were more likely to present poorer OHRQoL.

Clinical performance of monolithic polymer-infiltrated ceramic and lithium disilicate posterior crowns: A controlled, randomized, and double-blind clinical trial.

STATEMENT OF PROBLEM: The success rate of monolithic polymer-infiltrated ceramic posterior crowns after 1 year is unclear. PURPOSE: The purpose of this controlled, randomized, and double-blind clinical trial was to evaluate the performance of posterior complete crowns in polymer-infiltrated and lithium disilicate ceramics and to assess the impact of oral rehabilitation on esthetic satisfaction, quality of life, and periodontal health. MATERIAL AND METHODS: A total of 33 crowns were provided in 18 participants allocated to 2 groups: Control (Lithium disilicate-IPS e.max CAD; Ivoclar AG) and Experimental (Polymer-infiltrated ceramic-Vita Enamic; Vita Zahnfabrik). The crowns were evaluated before treatment (T0) and after 1 (T1), 6 (T2), and 12 (T3) months by using modified United States Public Health Service (USPHS) criteria, visual analog scales (VASs), oral impacts on daily performances (OIDP), and periodontal parameters. Survival analysis was performed by using Kaplan-Meier followed by the log-rank test (α=.05). The OIDP and USPHS data were analyzed descriptively while VASs for esthetic satisfaction and periodontal parameters were statistically evaluated by using the Mann-Whitney Friedman, and Wilcoxon post hoc tests. RESULTS: For 18 participants with a mean age of 47.2 years, 19 crowns were manufactured in lithium disilicate and 14 in polymer-infiltrated ceramic. The Kaplan-Meier test revealed similar survival rates of 92.5% for polymer-infiltrated ceramic and 94.7% for lithium disilicate (P>.05). The analysis of periodontal parameters revealed a significant increase in the bleeding on probing (BOP) for polymer-infiltrated ceramics (P=.032) but for lithium disilicate, it was not significant (P=.387). CONCLUSIONS: Survival rates between the evaluated materials were not significantly different, with acceptable clinical performance after 1 year of follow-up.

Impact of the COVID-19 pandemic on sleep bruxism among adolescents in Brazil: A longitudinal study.

AIM: To evaluate the immediate and late impact of the COVID-19 pandemic on the occurrence of possible sleep bruxism (SB) among adolescents in Brazil. DESIGN: This is a longitudinal study performed with adolescents (11-15 years old) from Southern Brazil. Baseline data were collected before the Brazilian COVID-19 outbreak (T1). Posteriorly, data were collected after 3 (T2) and 15 months under the Brazilian COVID-19 outbreak. The possible SB was evaluated by the question: 'Do you grind your teeth during your sleep?'. Sociodemographic, psychosocial and clinical variables were also collected. Changes in SB were evaluated by multilevel logistic regression models for repeated measures. RESULTS: Of the 290 adolescents assessed at T1, 182 were reassessed at both follow-ups. The prevalence of possible SB was 13% at T1, 11% at T2 and 22% at T3. There were no immediate effects of the COVID-19 pandemic on the occurrence of possible SB (T2). Adolescents had odds 2.77 times greater of presented possible SB after 15 months (T3) of COVID-19 pandemic scenarios when compared to T1. CONCLUSION: There was a considerable and late increase in the possible SB in adolescents in Brazil during the COVID-19 pandemic.

Lymphomas Affecting the Sublingual Glands: A Clinicopathological Study.

BACKGROUND: Lymphomas affecting the sublingual glands are extremely rare and very few case reports are currently available. Therefore, the aim of the current study is to describe the clinicopathological features of a series of lymphomas involving the sublingual glands. METHODS: Cases diagnosed in four pathology services were assessed and the formalin-fixed paraffin-embedded tissue blocks were retrieved for diagnosis confirmation. Clinical data were obtained from patients' medical files. RESULTS: We obtained seven cases of lymphomas in the sublingual glands, representing two follicular lymphomas, two diffuse large B cell lymphomas not otherwise specified (DLBCL NOS), two extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphomas) and one mantle cell lymphoma (MCL). In all cases the tumor cells infiltrated the glandular parenchyma, although in two of them the neoplastic cells were located more superficially and permeated the glandular acini and ducts. Clinically, the tumors presented as asymptomatic nodules and two patients (affected by DLBCL NOS and MCL) died, while the other five patients remained alive at last follow-up. CONCLUSION: Lymphomas affecting the sublingual glands are usually of the mature B cell lineage, often represent low-grade subtypes and may clinically resemble other more common lesions in the floor of the mouth like salivary gland tumors.

Biaxial flexure strength and physicochemical characterization of a CAD/CAM lithium disilicate ceramic: effect of etching time, silane, and adhesive applications.

OBJECTIVE: To evaluate the effect of different acid etching time and bonding agent (silane and/or adhesive system) on biaxial flexural strength and physico-chemical properties of a lithium disilicate ceramic. MATERIAL AND METHODS: One hundred twenty ceramic discs were made and divided into 8 groups (n = 15) according to factors "etching time" (20 and 120 s) with hydrofluoric acid (HF) and "bonding agent" (C, no bonding agent; S, silane, A, adhesive; and SA, silane + adhesive). After surface treatment, a resin cement layer was applied to the surface and all specimens were subjected to biaxial flexural strength (BFS) test with treated surfaces loaded in tension (1 mm/min). The Weibull analyses and complementary analyses were also performed. Statistical analysis was done with 2-way ANOVA and the Tukey test (α = 0.05). RESULTS: ANOVA revealed that the factors "etching time" (p = 0.0003) and "bonding agent" (p = 0.007) were statistically significant. In the overall analysis, the HF120S group (272.02 ± 35.30A MPa) presented significantly higher BFS than that of HF120C (218.45 ± 17.15CD MPa) and HF20S (228.40 ± 37.83BCDMPa). On the other hand, the HF20A group (208.92 ± 31.16D MPa) had significantly lower BFS than HF120S (272.02 ± 35.30A), HF120A (254.42 ± 26.87ABC) and HF120SA (259.30 ± 36.55AB) groups (Tukey). The Weibull modulus (m) of all groups was significantly different from each other (p = 0.000). CONCLUSIONS: Regardless of etching time, the application of silane alone is sufficient to increase the flexural strength of glass ceramic, eliminating the need for the application of adhesive systems. Moreover, if only silane or adhesive is applied, 120-s HF application should increase the flexural resistance of the lithium disilicate ceramic. CLINICAL SIGNIFICANCE: Applications of adhesive systems after silanization can be suppressed from the surface treatment protocol of glass ceramics, since it does not improve their mechanical strength.

Insights into the specificity for the interaction of the promiscuous SARS-CoV-2 nucleocapsid protein N-terminal domain with deoxyribonucleic acids.

The SARS-CoV-2 nucleocapsid protein (N) is a multifunctional promiscuous nucleic acid-binding protein, which plays a major role in nucleocapsid assembly and discontinuous RNA transcription, facilitating the template switch of transcriptional regulatory sequences (TRS). Here, we dissect the structural features of the N protein N-terminal domain (N-NTD) and N-NTD plus the SR-rich motif (N-NTD-SR) upon binding to single and double-stranded TRS DNA, as well as their activities for dsTRS melting and TRS-induced liquid-liquid phase separation (LLPS). Our study gives insights on the specificity for N-NTD(-SR) interaction with TRS. We observed an approximation of the triple-thymidine (TTT) motif of the TRS to ß-sheet II, giving rise to an orientation difference of ~25° between dsTRS and non-specific sequence (dsNS). It led to a local unfavorable energetic contribution that might trigger the melting activity. The thermodynamic parameters of binding of ssTRSs and dsTRS suggested that the duplex dissociation of the dsTRS in the binding cleft is entropically favorable. We showed a preference for TRS in the formation of liquid condensates when compared to NS. Moreover, our results on DNA binding may serve as a starting point for the design of inhibitors, including aptamers, against N, a possible therapeutic target essential for the virus infectivity.

Leiomyoma and Leiomyosarcoma (Primary and Metastatic) of the Oral and Maxillofacial Region: A Clinicopathological and Immunohistochemical Study of 27 Cases.

Smooth muscle neoplasms represent an important group of lesions which is rare in the oral cavity. Leiomyoma (LM) is benign smooth muscle/pericytic tumor usually presenting as non-aggressive neoplasm, while leiomyosarcoma (LMS) represents its malignant counterpart. The rarity of these lesions, together with its unspecific clinical presentation and a variable histopathological appearance, lead to a broad list of differential diagnoses, hampering their diagnoses. Therefore, in this study we describe the clinical and microscopic features of a series of oral and maxillofacial LMs and LMSs. A retrospective search from 2000 to 2019 was performed and all cases diagnosed as LM and LMS affecting the oral cavity and gnathic bones were retrieved. Clinical and demographic data were obtained from the patients' pathology records, while microscopic features and immunohistochemistry were reviewed and completed when necessary to confirm the diagnoses. Twenty-two LMs and five LMSs were obtained. In the LM group, males predominated, with a mean age of 45.7 years. The upper lip was the most affected site, and 18 cases were classified as angioleiomyomas and four as solid LM. In the LMS group, females predominated, with a mean age of 47.6 years. The mandible was the most affected site. Diffuse proliferation of spindle cells, with necrosis and mitotic figures, were frequent microscopic findings. LMs and LMSs were positive for α-smooth muscle actin, HHF-35 and h-caldesmon. In conclusion, oral LM/LMS are uncommon neoplasms with the latter usually presenting as metastatic disease. H&E evaluation may be very suggestive of oral LMs, but h-caldesmon staining is strongly recommended to confirm LMS diagnosis.

Nutrition Therapy Cost-Effectiveness Model Indicating How Nutrition May Contribute to the Efficiency and Financial Sustainability of the Health Systems.

BACKGROUND: Malnutrition is highly prevalent in hospitalized patients but seldom recognized and treated. Malnutrition poses several adverse events, such as increased infection rates, length of hospital stay, and mortality, as well as costs. Early nutrition interventions have been shown to decrease the associated malnutrition burdens, leading to relevant savings. Thus, this study aims to evaluate the cost-effectiveness of nutrition therapy, including oral supplements to at-risk or malnourished adult inpatients admitted to the Brazilian Public System (SUS) hospitals. METHOD: A cost-effectiveness model, encompassing a 1-year period and regarding total costs, length of hospital stay, readmissions, and mortality related to malnutrition, was developed, having the provision of early nutrition therapy as the intervention variable. The number of avoided hospitalization days, prevented hospital readmissions, and prevented deaths defined the effectiveness of the model. All the costs were estimated based on the SUS database. RESULTS: Early nutrition therapy provided to all at-risk or malnourished patients would represent cost-effectiveness of US $92.24, US $544.59, US $1848.12, and US $3698.92, for each day of hospitalization avoided, for additional patients having access to hospitalization, for preventing readmission, and for prevented death, respectively. The highest impact on savings was represented by the mean reduction in the length of hospital stay. CONCLUSION: Early oral nutrition intervention for patients malnourished or at risk of malnutrition resulted in overall reduced hospital costs. These findings provide a rationale to tackle the implementation of educational programs focusing on the care of inpatients with malnutrition or its risk.

Quercetin pentaacetate inhibits in vitro human respiratory syncytial virus adhesion.

Human respiratory syncytial virus (hRSV) is one of the main etiological agents of diseases of the lower respiratory tract and is often responsible for the hospitalization of children and the elderly. To date, treatments are only palliative and there is no vaccine available. Natural products show exceptional structural diversity and they have played a vital role in drug research. Several investigations focused on applied structural modification of natural products to improved metabolic stability, solubility and biological actions them. Quercetin is a flavonoid that presents several biological activities, including anti-hRSV role. Some works criticize the pharmacological use of Quercetin because it has low solubility and low specificity. In this sense, we acetylated Quercetin structure and we used in vitro and in silico assays to compare anti-hRSV function between Quercetin (Q0) and its derivative molecule (Q1). Q1 shows lower cytotoxic effect than Q0 on HEp-2 cells. In addition, Q1 was more efficient than Q0 to protect HEp-2 cells infected with different multiplicity of infection (0.1-1 MOI). The virucidal effects of Q0 and Q1 suggest interaction between these molecules and viral particle. Dynamic molecular results suggest that Q0 and Q1 may interact with F-protein on hRSV surface in an important region to adhesion and viral infection. Q1 interaction with F-protein showed ΔG= -14.22 kcal/mol and it was more stable than Q0. Additional, MTT and plate assays confirmed that virucidal Q1 effects occurs during adhesion step of cycle hRSV replication. In conclusion, acetylation improves anti-hRSV Quercetin effects because Quercetin pentaacetate could interact with F-protein with lower binding energy and better stability to block viral adhesion. These results show alternative anti-hRSV strategy and contribute to drug discovery and development.

Neutrophil extracellular traps possess anti-human respiratory syncytial virus activity: Possible interaction with the viral F protein.

Human respiratory syncytial virus (hRSV) is one of the main etiological agents of diseases of the lower respiratory tract, and is often responsible for the hospitalization of children and the elderly. To date, treatments are only palliative and there is no vaccine available. The airways of patients infected with hRSV exhibit intense neutrophil infiltration, which is responsible for the release of neutrophil extracellular traps (NETs). These are extracellular structures consisting of DNA associated with intracellular proteins, and are efficient in capturing and eliminating various microorganisms, including some viruses. hRSV induces the release of NETs into the lung tissue of infected individuals; however, the pathophysiological consequences of this event have not been elucidated. The objective of this study was to utilize in vitro and in silico assays to investigate the impact of NETs on hRSV infection. NETs, generated by neutrophils stimulated with phorbol myristate acetate (PMA), displayed long fragments of DNA and an electrophoretic profile suggestive of the presence of proteins that are classically associated with these structures (elastase, cathepsin G, myeloperoxidase, and histones). The presence of NETs (>2 µg/ml) in HEp-2 cell culture medium resulted in cellular cytotoxicity of less than 50%. Pre-incubation (1 h) of viral particles (multiplicity of infection (MOI) values of 0.1, 0.5, and 1.0) with NETs (2-32 µg/ml) resulted in cellular protection from virus-induced death of HEp-2 cells. Concurrently, there was a reduction in the formation of syncytia, which is related to decreased viral spread in infected tissue. Results from western blotting and molecular docking, suggest interactions between F protein of the hRSV viral envelope and BPI (bactericidal permeability-increasing protein), a microbicidal member of NETs. Interactions occurred at sites important for the neutralization and coordination of the hRSV infection/replication process. Our results showed that the presence of NETs decreases hRSV-induced cellular damage, possibly by directly affecting viral particle capture and/or interfering with the fusion activity of the F protein. These findings broaden the understanding of the role of NETs during hRSV infection.

Cost-utility of quadrivalent versus trivalent influenza vaccine in Brazil - comparison of outcomes from different static model types.

BACKGROUND: Influenza burden in Brazil is considerable with 4.2-6.4 million cases in 2008 and influenza-like-illness responsible for 16.9% of hospitalizations. Cost-effectiveness of influenza vaccination may be assessed by different types of models, with limitations due to data availability, assumptions, and modelling approach. OBJECTIVE: To understand the impact of model complexity, the cost-utility of quadrivalent versus trivalent influenza vaccines in Brazil was estimated using three distinct models: a 1-year decision tree population model with three age groups (FLOU); a more detailed 1-year population model with five age groups (FLORA); and a more complex lifetime multi-cohort Markov model with nine age groups (FLORENCE). METHODS: Analysis 1 (impact of model structure) compared each model using the same data inputs (i.e., best available data for FLOU). Analysis 2 (impact of increasing granularity) compared each model populated with the best available data for that model. RESULTS: Using the best data for each model, the discounted cost-utility ratio of quadrivalent versus trivalent influenza vaccine was R$20,428 with FLOU, R$22,768 with FLORA (versus R$20,428 in Analysis 1), and, R$19,257 with FLORENCE (versus R$22,490 in Analysis 1) using a lifetime horizon. Conceptual differences between FLORA and FLORENCE meant the same assumption regarding increased all-cause mortality in at-risk individuals had an opposite effect on the incremental cost-effectiveness ratio in Analysis 2 versus 1, and a proportionally higher number of vaccinated elderly in FLORENCE reduced this ratio in Analysis 2. DISCUSSION: FLOU provided adequate cost-effectiveness estimates with data in broad age groups. FLORA increased insights (e.g., in healthy versus at-risk, paediatric, respiratory/non-respiratory complications). FLORENCE provided greater insights and precision (e.g., in elderly, costs and complications, lifetime cost-effectiveness). CONCLUSION: All three models predicted a cost per quality-adjusted life year gained for quadrivalent versus trivalent influenza vaccine in the range of R$19,257 (FLORENCE) to R$22,768 (FLORA) with the best available data in Brazil (Appendix A).

Cost-utility of quadrivalent versus trivalent influenza vaccine in Brazil - comparison of outcomes from different static model types

ABSTRACT Background: Influenza burden in Brazil is considerable with 4.2-6.4 million cases in 2008 and influenza-like-illness responsible for 16.9% of hospitalizations. Cost-effectiveness of influenza vaccination may be assessed by different types of models, with limitations due to data availability, assumptions, and modelling approach. Objective: To understand the impact of model complexity, the cost-utility of quadrivalent versus trivalent influenza vaccines in Brazil was estimated using three distinct models: a 1-year decision tree population model with three age groups (FLOU); a more detailed 1-year population model with five age groups (FLORA); and a more complex lifetime multi-cohort Markov model with nine age groups (FLORENCE). Methods: Analysis 1 (impact of model structure) compared each model using the same data inputs (i.e., best available data for FLOU). Analysis 2 (impact of increasing granularity) compared each model populated with the best available data for that model. Results: Using the best data for each model, the discounted cost-utility ratio of quadrivalent versus trivalent influenza vaccine was R$20,428 with FLOU, R$22,768 with FLORA (versus R$20,428 in Analysis 1), and, R$19,257 with FLORENCE (versus R$22,490 in Analysis 1) using a lifetime horizon. Conceptual differences between FLORA and FLORENCE meant the same assumption regarding increased all-cause mortality in at-risk individuals had an opposite effect on the incremental cost-effectiveness ratio in Analysis 2 versus 1, and a proportionally higher number of vaccinated elderly in FLORENCE reduced this ratio in Analysis 2. Discussion: FLOU provided adequate cost-effectiveness estimates with data in broad age groups. FLORA increased insights (e.g., in healthy versus at-risk, paediatric, respiratory/non-respiratory complications). FLORENCE provided greater insights and precision (e.g., in elderly, costs and complications, lifetime cost-effectiveness). Conclusion: All three models predicted a cost per quality-adjusted life year gained for quadrivalent versus trivalent influenza vaccine in the range of R$19,257 (FLORENCE) to R$22,768 (FLORA) with the best available data in Brazil (Appendix A).

Does TGF-ß play a role in degenerative temporomandibular joint diseases? A systematic review.

OBJECTIVES: The objective of this review was to assess the literature for evidence investigating the role of TGF-ß in temporomandibular joint disease with osteoarthritis. METHOD: An electronic and manual search was carried out on the databases, MEDLINE/PubMed, Cochrane Library, Web Of Science, and EMBASE, from 1975 to December 2015 by two independent evaluators to identify clinical and laboratory trials in English. RESULTS: The search produced 693 records. Following a process of selection based on certain criteria, eight articles were included. DISCUSSION: This systematic review suggests that TGF-ß administration alone does not result in joint regeneration; other factors may be involved, such as TGF-ß receptor expression ,and TGF-ß receptor mutations that do not allow a correct transduction, resulting in TGF-ß deficiency. The anabolism induced by this growth factor is also able to neutralize the catabolic processes that are elevated in osteoarthritis. Therefore, further studies are essential to determine how the concentration of TGF-ß in the temporomandibular joints acts as a potential marker for the development of degenerative conditions.

Engineering increased thermostability in the GH-10 endo-1,4-ß-xylanase from Thermoascus aurantiacus CBMAI 756.

The GH10 endo-xylanase from Thermoascus aurantiacus CBMAI 756 (XynA) is industrially attractive due to its considerable thermostability and high specific activity. Considering the possibility of a further improvement in thermostability, eleven mutants were created in the present study via site-directed mutagenesis using XynA as a template. XynA and its mutants were successfully overexpressed in Escherichia coli Rosetta-gami DE3 and purified, exhibiting maximum xylanolytic activity at pH 5 and 65°C. Three of the eleven mutants, Q158R, H209N, and N257D, demonstrated increased thermostability relative to the wild type at 70°C and 75°C.Q158R and N257D were stable in the pH range 5.0-10.0, while WT and H209N were stable from pH 8-10. CD analysis demonstrated that the WT and the three mutant enzymes were expressed in a folded form. H209N was the most thermostable mutant, showing a Tm of 71.3°C. Molecular dynamics modeling analyses suggest that the increase in H209N thermostability may beattributed to a higher number of short helices and salt bridges, which displayed a positive charge in the catalytic core, stabilizing its tertiary structure.

Experimental evidence and molecular modeling of the interaction between hRSV-NS1 and quercetin.

Human Respiratory Syncytial Virus is one of the major causes of acute respiratory infections in children, causing bronchiolitis and pneumonia. Non-Structural Protein 1 (NS1) is involved in immune system evasion, a process that contributes to the success of hRSV replication. This protein can act by inhibiting or neutralizing several steps of interferon pathway, as well as by silencing the hRSV ribonucleoproteic complex. There is evidence that quercetin can reduce the infection and/or replication of several viruses, including RSV. The aims of this study include the expression and purification of the NS1 protein besides experimental and computational assays of the NS1-quercetin interaction. CD analysis showed that NS1 secondary structure composition is 30% alpha-helix, 21% beta-sheet, 23% turn and 26% random coils. The melting temperature obtained through DSC analysis was around 56°C. FRET analysis showed a distance of approximately 19Å between the NS1 and quercetin. Fluorescence titration results showed that the dissociation constant of the NS1-quercetin interaction was around 10(-6)M. In thermodynamic analysis, the enthalpy and entropy balanced forces indicated that the NS1-quercetin interaction presented both hydrophobic and electrostatic contributions. The computational results from the molecular modeling for NS1 structure and molecular docking regarding its interaction with quercetin corroborate the experimental data.

Passivity of conventional and CAD/CAM fabricated implant frameworks.

The objective of this research was to evaluate the passivity by measuring the passive fit and strain development of frameworks screwed on abutments, made by CAD/CAM technology, and to compare these parts with samples manufactured by conventional casting. Using CAD/CAM technology, four samples were made from zirconia (Zircad) and four samples were manufactured from cobalt-chrome (CoCrcad). The control groups were four specimens of cobalt-chrome, made by one-piece casting (CoCrci), with a total of 12 frameworks. To evaluate the passive fit, the vertical misfit at the abutment-framework interface was measured with scanning electron microscopy (250×) when only one screw was tightened. The mean strain in these frameworks was analyzed by photoelasticity test. A significant difference in the passive fit was observed between the control and sample groups. CoCrcad exhibited the best value of passive fit (48.76±13.45 µm) and CoCrci the worst (187.55±103.63 µm); Zircad presented an intermediate value (103.81±43.15 µm). When compared to the other groups, CoCrci showed the highest average stress around the implants (17.19±7.22 kPa). It was concluded that CAD/CAM-fabricated frameworks exhibited better passivity compared with conventionally fabricated frameworks. CAD/CAM-fabricated Co-Cr frameworks may exhibit better passive fit compared with CAD/CAM-fabricated zirconia frameworks. Even so, similar levels of stress were achieved for CAD/CAM-fabricated frameworks.

The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America.

Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries.