Human mobility patterns in Brazil to inform sampling sites for early pathogen detection and routes of spread: a network modelling and validation study.

BACKGROUND: Detecting and foreseeing pathogen dispersion is crucial in preventing widespread disease transmission. Human mobility is a fundamental issue in human transmission of infectious agents. Through a mobility data-driven approach, we aimed to identify municipalities in Brazil that could comprise an advanced sentinel network, allowing for early detection of circulating pathogens and their associated transmission routes. METHODS: In this modelling and validation study, we compiled a comprehensive dataset on intercity mobility spanning air, road, and waterway transport from the Brazilian Institute of Geography and Statistics (2016 data), National Transport Confederation (2022), and National Civil Aviation Agency (2017-23). We constructed a graph-based representation of Brazil's mobility network. The Ford-Fulkerson algorithm was used to rank the 5570 Brazilian cities according to their suitability as sentinel locations, allowing us to predict the most suitable locations for early detection and to track the most likely trajectory of a newly emerged pathogen. We also obtained SARS-CoV-2 genetic data from Brazilian municipalities during the early stage (Feb 25-April 30, 2020) of the virus's introduction and the gamma (P.1) variant emergence in Manaus (Jan 6-March 1, 2021), for the purposes of model validation. FINDINGS: We found that flights alone transported 79·9 million (95% CI 58·3-101·4 million) passengers annually within Brazil during 2017-22, with seasonal peaks occurring in late spring and summer, and road and river networks had a maximum capacity of 78·3 million passengers weekly in 2016. By analysing the 7 746 479 most probable paths originating from source nodes, we found that 3857 cities fully cover the mobility pattern of all 5570 cities in Brazil, 557 (10·0%) of which cover 6 313 380 (81·5%) of the mobility patterns in our study. By strategically incorporating mobility patterns into Brazil's existing influenza-like illness surveillance network (ie, by switching the location of 111 of 199 sentinel sites to different municipalities), our model predicted that mobility coverage would have a 33·6% improvement from 4 059 155 (52·4%) mobility patterns to 5 422 535 (70·0%) without expanding the number of sentinel sites. Our findings are validated with genomic data collected during the SARS-CoV-2 pandemic period. Our model accurately mapped 22 (51%) of 43 clade 1-affected cities and 28 (60%) of 47 clade 2-affected cities spread from São Paulo city, and 20 (49%) of 41 clade 1-affected cities and 28 (58%) of 48 clade 2-affected cities spread from Rio de Janeiro city, Feb 25-April 30, 2020. Additionally, 224 (73%) of the 307 suggested early-detection locations for pathogens emerging in Manaus corresponded with the first cities affected by the transmission of the gamma variant, Jan 6-16, 2021. INTERPRETATION: By providing essential clues for effective pathogen surveillance, our results have the potential to inform public health policy and improve future pandemic response efforts. Our results unlock the potential of designing country-wide clinical sample collection networks with mobility data-informed approaches, an innovative practice that can improve current surveillance systems. FUNDING: Rockefeller Foundation.

Effect of pyridoxine or cobalamin supplementation on apoptosis and cell cycle progression in a human glioblastoma cell line.

Glioblastoma is the most aggressive type of brain tumor, with current therapies failing to significantly improve patient survival. Vitamins have important effects on cellular processes that are relevant for tumor development and progression. AIM: The present study explored the effect of pyridoxine or cobalamin supplementation on the viability and cell cycle progression of human glioblastoma cell line U-87 MG. METHOD: Cell cultures were treated with increasing concentrations of pyridoxine or cobalamin for 24-72 h. After supplementation, cell viability and cell cycle progression were assessed by spectrophotometry and flow cytometry. Analysis of Bcl-2 and active caspase 3 expression in supplemented cells was performed by western blot. RESULT: The results show that pyridoxine supplementation decreases cell viability in a dose and time dependent manner. Loss of viability in pyridoxin-supplemented cells is probably related to less cell cycle progression, higher active caspase 3 expression and apoptosis. In addition, Bcl-2 expression did not appear to be altered by vitamin supplementation, but active caspase 3 expression was significantly increased in pyridoxine-, but not cobalamin-supplemented cells, furthermore, cobalamin inhibited the pyridoxine cytotoxicity in the cell viability assay when combined. CONCLUSION: The results suggest that pyridoxine supplementation promotes apoptosis in human glioblastoma-derived cells and may be useful to enhance the effect of cytotoxic therapies in vivo.

Changes in Appetite Regulation-Related Signaling Pathways in the Brain of Mice Supplemented with Non-nutritive Sweeteners.

Non-nutritive sweeteners (NNSs) are commonly used to prevent weight gain and development of metabolic diseases associated with consumption of high-energy diets. Recent studies have demonstrated that these compounds may have unwanted detrimental effects under specific circumstances in vivo. In particular, an association between NNS consumption and changes in signaling pathways involved in the hunger-satiety system in the brain has been reported. Nonetheless, the extent of alterations in brain signaling pathways associated with consumption of these compounds has not been determined. The objective of this study was to determine the effect of frequent consumption of NNSs on the expression of proteins involved in signaling pathways related to appetite control in the brain in vivo. Eight-week-old BALB/c mice were supplemented with sucrose, sucralose, or steviol glycosides in their daily drinking water for 6 weeks. Subsequently, total brain protein extracts were used to analyze the expression of total and phosphorylated JAK2, STAT5, ERK 1/2, JNK, as well as SHP-2 and POMC, by western blot. Serum concentrations of leptin and α-MSH were quantified by ELISA. Results show that consumption of NNSs promotes significant changes in these signaling pathways, reducing the expression of pSTAT5/STAT5, pERK 1/2, SHP-2, and pJNK/JNK in male mice supplemented with steviol glycosides. Furthermore, consumption of steviol glycosides induced a decrease of α-MSH in male mice. In contrast, steviol glycosides induced overexpression of pSTAT5, pERK, and SHP-2 in females. These data suggest that chronic consumption of NNSs promotes sex-specific changes in signaling pathways related to the central hunger-satiety system in vivo.

Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius.

We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)→locus coeruleus→hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 µg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 µg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 µg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 µg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 µg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS→locus coeruleus→HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning.

Estudo da refratariedade plaquetária do dia 0 ao 50, em pacientes submetidos a transplante de medula óssea / Study of the platelet refractoriness in patients submitted to bone marrow transplant from day 0 to day 50

Entre outubro de 1997 e julho de 1999 pesquisou-se a refratariedade plaquetária em 15 pacientes na fase precoce do TMO alogênico e autoplástico, com idade variando de 1 a 66 anos no Hospital São Camilo. Para esta avaliação, foram utilizados os seguintes parâmetros: evolução clínica, cálculo corrigido do incremento plaquetário (CCI), teste de microlinfocitotoxicidade dependente de complemento (CDC) e ensaios plaquetários por aderência de células vermelhas em fase sólida (SPRCA). A refratariedade plaquetária foi definida como falha de resposta a uma transfusão de dois concentrados de plaquetas ABO compatíveis, quando o cálculo corrigido do incremento plaquetário (CCI) de uma hora pós-transfusional era inferior a 7,5 ou de 24 horas < 4,5. Apenas a análise do CCI de 24 horas mostrou significância estatística. A refratariedade plaquetária foi detectada em 80,0 por cento dos casos, tendo como causa principal os fatores não imunológicos, como: anfotericina 66,66 por cento, doença veno-oclusiva hepática 53,33 por cento, febre de origem indeterminada 40,0 por cento, esplenomegalia epistaxe leve, febre, melena grave, hematêmese grave e infecção bacteriana 20,0 por cento. Melena leve, enterorragia grave, epistaxe moderada e grave 13,33 por cento, enquanto CIVD, enterorragia moderada e grave 6,66 por cento. Os fatores imunológicos foram representados pela presença da reação aguda do enxerto contra hospedeiro (aGVHD) em 33,0 por cento e infecção por citomegalovírus (CMV) em 13,33 por cento, embora a detecção de auto-anticorpos tenha sido negativa. Conclui-se que a análise do CCI pós-transfusional de 24 horas mostrou ser um método de escolha para detecção da refratariedade e de útil aplicabilidade em pacientes trombocitopênicos refratários, em particular naqueles submetidos ao TMO.

Association of Bartonella species and Coxiella burnetii infection with coronary artery disease.

Coronary artery disease is an inflammatory condition associated with several infections. We prospectively evaluated 155 consecutive patients undergoing coronary angiography for evidence of Bartonella species and Coxiella burnetii infection. All Bartonella cultures were found to be negative. Multivariable logistic regression analysis that controlled for potential confounding factors revealed no association between coronary artery disease and seropositivity to Bartonella henselae (odds ratio [OR], 0.852; 95% confidence interval [CI], 0.293-2.476), Bartonella quintana (OR, 0.425; 95% CI, 0.127-1.479), C. burnetii phase 1 (OR, undefined), and C. burnetii phase 2 (OR, 0.731; 95% CI, 0.199-2.680). The geometric mean titer (GMT) for C. burnetii phase 1 assay was slightly higher in persons with coronary artery disease than in those without such disease (P<.02). B. henselae, B. quintana, and C. burnetii seropositivity was not strongly associated with coronary artery disease. On the basis of GMTs, C. burnetii infection may have a modest association with coronary artery disease.

Assessment of pain using a computer.

Visual analogue scales are of value in the assessment of a subjective phenomenon such as pain. A method of producing such a visual scale on a computer screen is described, an audible component has also been provided on the computer to assist the patient in estimating the severity of his pain. Guidance is provided on the preparation of a programme to incorporate such a scale on a computer for use in an outpatient clinic.