Publications by authors named "I Lima"

440 Publications

Optimizing a Multi-Component Intranasal Vaccine Formulation Using a Design of Experiments Strategy.

Front Immunol 2021 25;12:683157. Epub 2021 Jun 25.

Infectious Disease Research Institute (IDRI), Seattle, WA, United States.

Amebiasis is a neglected tropical disease caused by a. Although the disease burden varies geographically, amebiasis is estimated to account for some 55,000 deaths and millions of infections globally per year. Children and travelers are among the groups with the greatest risk of infection. There are currently no licensed vaccines for prevention of amebiasis, although key immune correlates for protection have been proposed from observational studies in humans. We previously described the development of a liposomal adjuvant formulation containing two synthetic TLR ligands (GLA and 3M-052) that enhanced antigen-specific fecal IgA, serum IgG2a, a mixed IFNγ and IL-17A cytokine profile from splenocytes, and protective efficacy following intranasal administration with the LecA antigen. By applying a statistical design of experiments (DOE) and desirability function approach, we now describe the optimization of the dose of each vaccine formulation component (LecA, GLA, 3M-052, and liposome) as well as the excipient composition (acyl chain length and saturation; PEGylated lipid:phospholipid ratio; and presence of antioxidant, tonicity, or viscosity agents) to maximize desired immunogenicity characteristics while maintaining physicochemical stability. This DOE/desirability index approach led to the identification of a lead candidate composition that demonstrated immune response durability and protective efficacy in the mouse model, as well as an assessment of the impact of each active vaccine formulation component on protection. Thus, we demonstrate that both GLA and 3M-052 are required for statistically significant protective efficacy. We also show that immunogenicity and efficacy results differ in female male mice, and the differences appear to be at least partly associated with adjuvant formulation composition.
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http://dx.doi.org/10.3389/fimmu.2021.683157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268010PMC
June 2021

PD-L1 Expression Associated with Epstein-Barr Virus Status and Patients' Survival in a Large Cohort of Gastric Cancer Patients in Northern Brazil.

Cancers (Basel) 2021 Jun 22;13(13). Epub 2021 Jun 22.

Laboratory of Molecular Biology, Department of Clinical Medicine, Ophir Loyola Hospital, Belém, 66063-240 PA, Brazil.

Gastric cancer (GC) is a worldwide health problem, making it one of the most common types of cancer, in fifth place of all tumor types, and the third highest cause of cancer deaths in the world. There is a subgroup of GC that consists of tumors infected with the Epstein-Barr virus (EBV) and is characterized mainly by the overexpression of programmed cell death protein-ligand-1 (PD-L1). In the present study, we present histopathological and survival data of a thousand GC patients, associated with EBV status and PD-L1 expression. Of the thousand tumors analyzed, 190 were EBV-positive and the vast majority (86.8%) had a high relative expression of mRNA and PD-L1 protein ( < 0.0001) in relation to non-neoplastic control. On the other hand, in EBV-negative samples, the majority had a low PD-L1 expression of RNA and protein ( < 0.0001). In the Kaplan-Meier analysis, the probability of survival and increased overall survival of EBV-positive GC patients was impacted by the PD-L1 overexpression ( < 0.0001 and = 0.004, respectively). However, the PD-L1 low expression was correlated with low overall survival in those patients. Patients with GC positive for EBV, presenting PD-L1 overexpression can benefit from immunotherapy treatments and performing the quantification of PD-L1 in gastric neoplasms should be adopted as routine.
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http://dx.doi.org/10.3390/cancers13133107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268941PMC
June 2021

Validation of the Donkey Pain Scale (DOPS) for Assessing Postoperative Pain in Donkeys.

Front Vet Sci 2021 11;8:671330. Epub 2021 Jun 11.

Department of Veterinary Surgery and Animal Reproduction, School of Veterinary Medicine and Animal Science, São Paulo State University (UNESP), Botucatu, Brazil.

This study aimed to validate a scale for assessing acute pain in donkeys. Forty-four adult donkeys underwent castration after sedation with intravenous (IV) xylazine, induction with guaifenesin and thiopental IV, local anesthetic block, and maintenance with isoflurane. The scale was constructed from a pilot study with four animals combined with algetic behaviors described for equines. After content validation, the scale was evaluated in 40 other donkeys by three blinded and one reference evaluator, by means of edited videos referring to the preoperative and postoperative periods: before anesthesia, 3-4 h after recovery from anesthesia, 5-6 h after recovery from anesthesia (2 h after analgesia with flunixin-1.1 mg/kg, dipyrone-10 mg/kg, and morphine-0.2 mg/kg) IV, and 24 h after recovery. Content validity, sensitivity, specificity, and responsiveness of behaviors were investigated to refine the scale. Intra- and inter-evaluator reliabilities were investigated by the weighted kappa coefficient, criterion validity by comparing the scale with the visual analog scale (VAS), internal consistency by Cronbach's α coefficient, item-total correlation by the Spearman coefficient, and intervention point for rescue analgesic by the receiver operating characteristics curve and Youden index. The scale showed very good intra-evaluator reliability (0.88-0.96), good to moderate (0.56-0.66) inter-evaluator reliability, responsiveness for all items, good criterion validity vs. VAS (0.75), acceptable internal consistency (0.64), adequate item-total correlation, except for head position and direction, and according to the principal component analysis, good association among items. The accuracy of the point for rescue analgesic was excellent (area under the curve = 0.91). The rescue analgesic score was ≥ 4 of 11 points. The scale can diagnose and quantify acute pain in donkeys submitted to castration, as the instrument is reliable and valid, with a defined intervention analgesic score.
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http://dx.doi.org/10.3389/fvets.2021.671330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225999PMC
June 2021

Case-Ascertainment Models to Identify Adults with Obstructive Sleep Apnea Using Health Administrative Data: Internal and External Validation.

Clin Epidemiol 2021 17;13:453-467. Epub 2021 Jun 17.

ICES, Ottawa, Toronto, Ontario, Canada.

Background: There is limited evidence on whether obstructive sleep apnea (OSA) can be accurately identified using health administrative data.

Study Design And Methods: We derived and validated a case-ascertainment model to identify OSA using linked provincial health administrative and clinical data from all consecutive adults who underwent a diagnostic sleep study (index date) at two large academic centers (Ontario, Canada) from 2007 to 2017. The presence of moderate/severe OSA (an apnea-hypopnea index≥15) was defined using clinical data. Of 39 candidate health administrative variables considered, 32 were tested. We used classification and regression tree (CART) methods to identify the most parsimonious models via cost-complexity pruning. Identified variables were also used to create parsimonious logistic regression models. All individuals with an estimated probability of 0.5 or greater using the predictive models were classified as having OSA.

Results: The case-ascertainment models were derived and validated internally through bootstrapping on 5099 individuals from one center (33% moderate/severe OSA) and validated externally on 13,486 adults from the other (45% moderate/severe OSA). On the external cohort, parsimonious models demonstrated c-statistics of 0.75-0.81, sensitivities of 59-60%, specificities of 87-88%, positive predictive values of 79%, negative predictive values of 73%, positive likelihood ratios (+LRs) of 4.5-5.0 and -LRs of 0.5. Logistic models performed better than CART models (mean integrated calibration indices of 0.02-0.03 and 0.06-0.12, respectively). The best model included: sex, age, and hypertension at the index date, as well as an outpatient specialty physician visit for OSA, a repeated sleep study, and a positive airway pressure treatment claim within 1 year since the index date.

Interpretation: Among adults who underwent a sleep study, case-ascertainment models for identifying moderate/severe OSA using health administrative data had relatively low sensitivity but high specificity and good discriminative ability. These findings could help study trends and outcomes of OSA individuals using routinely collected health care data.
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http://dx.doi.org/10.2147/CLEP.S308852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216743PMC
June 2021

Biological effects induced by doses of mammographic screening.

Phys Med 2021 Jul 12;87:90-98. Epub 2021 Jun 12.

Department of Radiological Sciences (LCR), State University of Rio de Janeiro (UERJ), Pavilhão Haroldo Lisboa da Cunha, Rua São Francisco Xavier, 524, Maracanã, Rio de Janeiro, RJ CEP 20550-900, Brazil.

Purpose: Mammography is the diagnostic imaging practice used in screening to detect early lesions suspected of malignancy. It uses a low energy X-ray beam in which a low dose in the order of 2-3 mGy is delivered to patient breast cells. However, it has been speculated that it could lead to significant cell damage, when compared to conventional X-ray. We investigated the biological effects of low doses, with mean glandular doses (MGDs) of 2.5 mGy and 2.5 + 2.5 mGy, on mammary cells in vitro.

Methods: We used the non-tumorigenic cell line (MCF-10A) and two tumor cells lines (MCF-7 and MDA-MB-231). Colony formation, apoptosis, and double-strand DNA breaks (DSBs) were quantified.

Results: The selected MGD regimens did not alter the formation of colonies by any of the cell lines. MCF-7 cells exhibited a markedly increase in apoptosis, 24 h after the single-dose protocol; MCF-10A cells underwent apoptosis only after 72 h, with both irradiation regimens, while MDA-MB-231 cells (highly invasive and metastatic) were not susceptible to apoptosis. The detection of γH2AX histone in the nuclei of irradiated cells showed that the double-dose resulted in increase of DSBs, especially in tumor cell lines.

Conclusions: Although the health benefits of early breast screening remain indisputable, our future perspective is to better understand the biological basis for the effects of low dose radiation on breast cells and to investigate if and under what conditions there would be a risky situation in repeated mammography screening, in both asymptomatic and symptomatic women.
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http://dx.doi.org/10.1016/j.ejmp.2021.06.002DOI Listing
July 2021