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BACKGROUND: Johne's disease is a chronic wasting disease caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). Johne's disease is highly contagious and MAP infection in dairy cattle can eventually lead to death. With no available treatment for Johne's disease, genetic selection and improvements in management practices could help reduce its prevalence. In a previous study, the gene coding interleukin-10 receptor subunit alpha (IL10Rα) was associated with Johne's disease in dairy cattle. Our objective was to determine how IL10Rα affects the pathogenesis of MAP by examining the effect of a live MAP challenge on a mammary epithelial cell line (MAC-T) that had IL10Rα knocked out using CRISPR/cas9. The wild type and the IL10Rα knockout MAC-T cell lines were exposed to live MAP bacteria for 72 h. Thereafter, mRNA was extracted from infected and uninfected cells. Differentially expressed genes were compared between the wild type and the IL10Rα knockout cell lines. Gene ontology was performed based on the differentially expressed genes to determine which biological pathways were involved. RESULTS: Immune system processes pathways were targeted to determine the effect of IL10Rα on the response to MAP infection. There was a difference in immune response between the wild type and IL10Rα knockout MAC-T cell lines, and less difference in immune response between infected and not infected IL10Rα knockout MAC-T cells, indicating IL10Rα plays an important role in the progression of MAP infection. Additionally, these comparisons allowed us to identify other genes involved in inflammation-mediated chemokine and cytokine signalling, interleukin signalling and toll-like receptor pathways. CONCLUSIONS: Identifying differentially expressed genes in wild type and ILR10α knockout MAC-T cells infected with live MAP bacteria provided further evidence that IL10Rα contributes to mounting an immune response to MAP infection and allowed us to identify additional potential candidate genes involved in this process. We found there was a complex immune response during MAP infection that is controlled by many genes.
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Células Epiteliais , Mycobacterium avium subsp. paratuberculosis , Paratuberculose , Mycobacterium avium subsp. paratuberculosis/imunologia , Animais , Células Epiteliais/microbiologia , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Linhagem Celular , Bovinos , Paratuberculose/imunologia , Paratuberculose/microbiologia , Paratuberculose/genética , Feminino , Subunidade alfa de Receptor de Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/microbiologia , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologiaRESUMO
Ketosis, evidenced by hyperketonemia with elevated blood ß-hydroxybutyrate (BHB) levels, is a significant metabolic disorder of dairy cattle, typically diagnosed within the first 6 weeks post-calving when high energy levels are essential to milk production. Our study aimed to identify genetic markers linked to hyperketonemia (HYK) patterns in Holstein cows during early lactation and compare these to HYK-negative cows. We screened 964 cows for HYK using a threshold of BHB ≥1.2 mmol/L during the first 2 weeks postpartum (screening period, SP). Cows that tested negative initially were retested the following week. Cows were deemed HYK-negative (CON group) if BHB levels were below 1.2 mmol/L in both tests, while those with BHB levels exceeding this threshold at any test were treated and classified as HYK-positive (HYK+). Post-treatment, HYK+ cows were monitored for two-week follow-up period (FP) and classified based on their recovery: cured (CUR; consistently low BHB), recurrent (REC; fluctuating BHB levels), severe (SEV; high initial BHB that decreased), or chronic (CHR; persistently high BHB). Using 489 cows that were genotyped, a GWAS was conducted using GCTA software, revealing significant associations of several SNPs across different HYK patterns when compared to the CON group. These SNPs were primarily linked to genes affecting milk traits and were enriched in biological pathways relevant to protein glycosylation, inflammatory response, glucose homeostasis, and fatty acid synthesis. Our findings highlight genomic regions, potential candidate genes, and biological pathways related to ketosis, underscoring potential targets for improving health management in dairy cattle. These insights could lead to better strategies for managing ketosis through genetic selection, ultimately enhancing dairy cattle welfare and productivity. Further research with a larger number of cows is recommended to validate these findings and help confirm the implicated SNPs and genes.
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BACKGROUND: Reallocation of funding to respond the covid-19 pandemic, against a backdrop of longstanding underfunded health systems and high out of pocket expenditures for health, affected access to health services for households, especially those without social protection. These highlighted the urgency in curbing the impact of disruptions on progress towards Universal Health Coverage (UHC) goals. Strategic investments in Primary Health Care (PHC) can help spur the necessary momentum. METHODS: Under the collaborative platform of the Harmonization for Health in Africa's Health Financing Technical Working Group; UNICEF Regional Office for East and Southern Africa and WHO Regional Office for Africa convened the first PHC financing forum for 21 countries across the Eastern and Southern Africa Region. The three-day forum engaged key health and financing decision makers in constructive dialogue to identify practical actions and policy changes needed to accelerate delivery of UHC through improvements in PHC financing mechanisms and arrangements. The forum was attended by over 130 senior policy makers and technicians from governments, United Nations agencies and nonstate actors drawn from within country, regional and affiliating headquarter institutions. RESULTS: The Regional Forum engaged participants in meaningful, and constructive discussions. Five themes emerged (1) regular measurement and monitoring of PHC services and spending (2) increasing investments in PHC (3) enhancing efficiency, effectiveness, and equity of PHC spending, (4) ensuring an enabling environment to invest more and better in PHC, and (5) better partnerships for the realization of commitments. An outcome statement summarizing the main recommendations of the meeting was approved at the end of the forum, and action plans were developed by 14 government delegations to improve PHC financing within country-specific context and priorities. CONCLUSIONS AND RECOMMENDATIONS: The aims of this meeting in augmenting the political will created through the Africa Leadership Meeting (ALM), by catalyzing technical direction for increased momentum for improved health financing across all African countries was achieved. Peer exchanges offered practical approaches countries can take to improve health financing in ways that are suited to regional context providing a channel for incremental improvements to health outcomes in the countries.
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PURPOSE: Neurodevelopmental disorders, such as autism spectrum disorder (ASD), have been increasingly associated with eosinophilic gastrointestinal disorders (EGID). However, the relationship between these diseases remains unclear. We performed a systematic review with meta-analysis to address this issue. METHODS: The search was performed according to the PRISMA guidelines using descriptors for ASD and EGIDs from the MEDLINE, Embase, PsycInfo, LILACS, and Web of Science databases. Observational studies with the prevalence of ASD in any EGID were included. The study protocol was registered on the PROSPERO platform under the number CRD42023455177. RESULTS: The total dataset comprised 766,082 participants. The result of the single-arm meta-analysis showed an overall prevalence of ASD in the population with EGID of 21.59% (95% CI: 10.73-38.67). There was an association between EGID and ASD (OR: 3.44; 95% CI: 1.25-2.21), also significant when restricted only to EoE (OR: 3.70; 95% CI: 2.71-5.70). DISCUSSION: Recent studies have implicated the influence of an inadequate epithelial barrier integrity in the pathogenesis of several diseases. The role of this mechanism can be extended to situations beyond allergic reactions, including other conditions with underlying immunological mechanisms. Several diseases are potentially related to the systemic effect of bacterial translocation in tissues with defective epithelial barriers. CONCLUSION: Our meta-analysis provides evidence that supports the consideration of EGID in patients with ASD and ASD in patients with EGID. Despite its limitations, the results should also be validated by future studies, preferably using multicenter prospective designs in populations with low referral bias.
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Enterite , Eosinofilia , Gastrite , Humanos , Eosinofilia/epidemiologia , Gastrite/epidemiologia , Gastrite/imunologia , Gastrite/complicações , Prevalência , Enterite/epidemiologia , Enterite/complicações , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/complicações , Criança , Transtorno Autístico/epidemiologiaRESUMO
BACKGROUND: The objective of this study is to evaluate the diagnostic accuracy of plasma-based liquid biopsy for the detection of the BRAF V600E mutation in circulating cell-free DNA from patients with ameloblastoma. METHODS: This is a prospective diagnostic accuracy study conducted based on the Standards for Reporting Diagnostic Accuracy recommendations. The index test was the plasma-based liquid biopsy, whereas the reference standard was the conventional tissue biopsy. The target condition was the detection of BRAF V600E mutation. The study population consisted of individuals with ameloblastoma recruited from three tertiary hospitals from Brazil. A negative control group composed of three individuals with confirmed wild-type BRAF lesions were included. The participants underwent plasma circulating cell-free DNA and tumor tissue DNA isolation, and both were submitted to using competitive allele-specific TaqMan™ real-time polymerase chain reaction technology mutation detection assays. Sensitivity and specificity measures and positive and negative predictive values were calculated. RESULTS: Twelve patients with conventional ameloblastoma were included. BRAF V600E mutation was detected in 11/12 (91.66%) ameloblastoma tissue samples. However, the mutation was not detected in any of the plasma-based liquid biopsy circulating cell-free DNA samples in both ameloblastomas and negative control group. The sensitivity and specificity of plasma-based liquid biopsy for the detection of the BRAF V600E mutation in circulating cell-free DNA was 0.0 and 1.0, respectively. The agreement between index test and reference standard results was 26.66%. CONCLUSION: Plasma-based liquid biopsy does not seem to be an accurate method for the detection of the BRAF V600E mutation in circulating circulating cell-free DNA from patients with ameloblastoma, regardless of tumor size, anatomic location, recurrence status, and other clinicopathological features.
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Ameloblastoma , Ácidos Nucleicos Livres , Humanos , Ameloblastoma/diagnóstico , Ameloblastoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Prospectivos , Mutação , Ácidos Nucleicos Livres/genéticaRESUMO
BACKGROUND: Dysregulation of the MAPK pathway appears to exert a pivotal role in the pathogenesis of ameloblastomas, since BRAF p.V600E has been reported in over 65% of the tumors. Therefore, the purpose of this study was to investigate whether the BRAF p.V600E is related to biological behavior and disease-free survival in patients with conventional ameloblastomas. METHODS: This is a retrospective cohort study based on the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) recommendations. The study population consisted of individuals treated for conventional ameloblastomas. Clinical, imaging, histomorphological, immunohistochemical (Ki67 and CD138/syndecan-1), and molecular BRAF p.V600E mutation analyses were performed. Bivariate statistical analysis was performed through chi-square and Fisher's exact tests. Kaplan-Meier analysis with log-rank test and Cox proportional hazards regression were used to identify predictors of disease-free survival, with a significance level of 5%. RESULTS: Forty-one individuals were included, with a male-to-female ratio of 1.15:1. BRAF p.V600E mutation was identified in 75.6% of the tumors. No association between the BRAF mutational status and other clinical, imaging, histomorphological, and immunohistochemical variables was observed. Only the initial treatment modality was significantly associated with a better prognosis in univariate (p = 0.008) and multivariate (p = 0.030) analyses, with a hazard ratio of 9.60 (95%IC = 1.24-73.89), favoring radical treatment. CONCLUSION: BRAF p.V600E mutation emerges as a prevalent molecular aberration in ameloblastomas. Nevertheless, it does not seem to significantly affect the tumor proliferative activity, CD138/syndecan-1-mediated cell adhesion, or disease-free survival outcomes.
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Ameloblastoma , Humanos , Masculino , Feminino , Intervalo Livre de Doença , Ameloblastoma/genética , Ameloblastoma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Sindecana-1/genética , Estudos Retrospectivos , MutaçãoRESUMO
Several potential risk factors have been identified in the etiopathogenesis of febrile seizures (FS), including the type and extent of breastfeeding (BF). Given the lack of conclusive data, this study aims to systematically evaluate the evidence on the association between BF and FS. We conducted a systematic review and meta-analysis according to PRISMA guidelines. The search was conducted using descriptors for FS, BF, and formula feeding in MEDLINE, Embase, and Web of Science databases. We included observational studies that compared the incidence of FS between those who had ever breastfed and those who were formula fed. The study protocol was registered on the PROSPERO platform under the number CRD42023474906. A total of 1,893,079 participants from 8 datasets were included. Our main analysis showed no significant association of any type of BF on the incidence of FS compared with formula-fed children (OR: 0.84; CI: 0.67-1.04; I2 = 78%; Cochran's Q = 0.0001), although meta-regression showed that BF was associated with a lower incidence of FS in preterm infants. Our secondary outcome showed a significantly reduced incidence of FS in children who received BF exclusively (OR: 0.80; CI: 0.65-0.99; I2 = 70%; Cochran's Q = 0.02). Conclusion: There was no significant reduction in the incidence of FS in those who were breastfed compared to formula feeding. However, our meta-regression analysis indicated an association between BF and a lower incidence of FS in preterm infants. Additionally, children who exclusively received BF had a significantly reduced incidence of FS. These findings should be further investigated in prospective cohorts. What is Known: ⢠Breastfeeding can modify risk factors for febrile seizures, such as susceptibility to viral and bacterial infections, micronutrient deficiencies, and low birth weight. ⢠However, studies have shown conflicting results regarding the impact of breastfeeding on febrile seizures. What is New: ⢠When comparing any breastfeeding pattern with no breastfeeding, there is no significant difference in the incidence of febrile seizures. ⢠When comparing exclusive breastfeeding with no breastfeeding, there may be a decrease in the occurrence of febrile seizures.
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Aleitamento Materno , Convulsões Febris , Humanos , Aleitamento Materno/estatística & dados numéricos , Convulsões Febris/epidemiologia , Convulsões Febris/prevenção & controle , Convulsões Febris/etiologia , Lactente , Recém-Nascido , Incidência , Fatores de Risco , Fórmulas Infantis , Recém-Nascido Prematuro , Fatores de ProteçãoRESUMO
INTRODUCTION: Baseline cardiovascular (CV) risk stratification is recommended in all cancer patients. Integrating all clinical information (personal/family history, ECG and echocardiogram) can properly identify high-risk patients. We aimed to evaluate the concealed inherited CV conditions detected in mandatory CV screening performed at a Cardio-Oncology Unit. METHODS: retrospective study of all consecutive cancer patients referred to the Cardio-Oncology Unit for CV evaluation (2020-2023). Inherited CV conditions diagnosis and genetic testing was performed according to guidelines. RESULTS: 1984 cancer patients underwent CV screening. Sanger sequencing was indicated in 1 patient, excluding the genetic family disease. NGS sequencing was performed in 11 cancer patients with normal left ventricular ejection fraction (LVEF): 2 due to aortic syndrome evaluation (identifying 1 vascular Ehrler-Danlos syndrome due to COL3A1 p.Arg242Ter), 4 channelopathies (2 Long QT syndrome and 2 Brugada's), 4 hypertrophic cardiomyopathies and 1 non-dilated left ventricular cardiomyopathy (NDLVC). Among the 12 patients with reduced LVEF, one was diagnosed with NDLVC, and chemotherapy-induced dilated cardiomyopathy was only ascribable in 3 of them. CONCLUSION: Integrating clinical information at mandatory baseline CV toxicity risk cardio-oncology evaluation, can identify high-risk cancer patients with concealed inherited conditions. Keeping an "inherited cardiovascular disease-oriented mindset" to implement opportunist screenings is encouraged.
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Cardiomiopatias , Cardiomiopatia Dilatada , Doenças Cardiovasculares , Neoplasias , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Volume Sistólico , Cardio-Oncologia , Estudos Retrospectivos , Função Ventricular Esquerda , Neoplasias/diagnóstico , Neoplasias/genéticaRESUMO
BACKGROUND: Neonatal herpes simplex virus (HSV) infection is rare and has significant morbimortality rates. Approximately 85% of newborns are infected intrapartum, and risk factors for mother-to-child transmission include vaginal delivery, primary maternal infection, and prolonged rupture of membranes. Neonatal HSV can manifest with isolated mucocutaneous lesions, neurological involvement, or disseminated disease. In general, herpetic infection can cause blepharoconjunctivitis or keratitis. We report a rare case of congenital herpes with ophthalmologic manifestations and multisystemic involvement. CASE PRESENTATION: A preterm infant, born at 32 weeks and 2 days, with presumed neonatal infection developed intestinal and respiratory complications, as well as hyperemic lesions on the left nostril and oral mucosa. An ophthalmological assessment was requested and brought up the suspicion of HSV infection, indicating empirical treatment with endovenous acyclovir. Later, a new ocular examination was suggestive of panuveitis. Afterward, serum IgM antibodies to HSV-1 and HSV-2 were positive. Proper antiviral therapy led to an improvement in the condition. DISCUSSION: Neonatal herpes is associated with a high risk of persistent skin lesions, long-term neurological disability and other lasting sequelae. It is essential to consider HSV infection in cases of neonatal conjunctivitis, especially in patients with an epithelial defect and no improvement after initial treatment with topical or systemic antibiotics. CONCLUSIONS: In the management of neonatal HSV, early diagnosis is essential for the timely initiation of antiviral therapy. Our report highlights that ocular assessment can be crucial in the correct diagnostic investigation of this condition.
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Doenças Fetais , Herpes Simples , Complicações Infecciosas na Gravidez , Feminino , Humanos , Recém-Nascido , Gravidez , Antivirais/uso terapêutico , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Recém-Nascido Prematuro , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/tratamento farmacológicoRESUMO
Interleukins 6 and 17 act in bone resorption in the presence of infections of endodontic origin for host defense. Genetic polymorphisms may be associated with increased bone loss, represented by areas of large periapical lesions. This study aimed to verify the frequency of interleukin 6 and 17 gene polymorphism in patients with asymptomatic apical periodontitis or chronic apical abscess and to verify the existence of correlations between periapical lesion area with age, gender, and presence of the polymorphism, in the studied population, in the state of Pernambuco. A population consisting of thirty diagnosed individuals was included. The area of the lesions was measured in mm². Genomic DNA was extracted and genotyping was performed by Polymerase Chain Reaction Restriction Fragment Length Polymorphism for interleukin 6 (rs 1800795) and interleukin 17 (rs 2275913). Fisher's exact, chi-square, and odds ratio tests were used. A logistic regression analysis was also performed using sex, age, and the presence of polymorphism as covariates, in addition to linear regression to test the relationship between age and lesion area. All tests used a significance level of 0.05% (p ≤0.05%). There was no statistical significance in the occurrence of large areas of periapical lesions correlated with age, sex, and diagnosis, nor in the distribution of alleles in the polymorphism of interleukins 6 and 17 in the studied groups. The frequency of homozygous and heterozygous polymorphism was high. The polymorphism of these interleukins is not correlated with the increase in the areas of asymptomatic periapical inflammatory lesions.
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Interleucina-17 , Interleucina-6 , Periodontite Periapical , Humanos , Estudos Transversais , Interleucina-6/genética , Interleucinas/genética , Periodontite Periapical/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Interleucina-17/genéticaRESUMO
Mycotoxins are secondary metabolites produced by a variety of fungi that contaminate animal food and feeds and are capable of inducing a wide range of toxicities. Predictive in vitro models represent valuable substitutes for animal experiments to assess the toxicity of mycotoxins. The complexities of the interactions between epithelial and innate immune cells, vital for upholding barrier integrity and averting infections, remain inadequately understood. In the current study, a co-culture model of bovine epithelial cells (MAC-T) and macrophages (BoMac) was used to investigate the impact of exposure to Fusarium mycotoxins, namely deoxynivalenol (DON), zearalenone (ZEN), enniatin B (ENB), and beauvericin (BEA), on the inflammatory response elicited by the bacterial lipopolysaccharide (LPS) endotoxin. The MAC-T cells and BoMac were seeded on the apical side of a Transwell membrane and in the lower chamber, respectively, and mycotoxin exposure on the apical side of the membrane was carried out with the different mycotoxins (LC20; concentrations that elicited 20% cytotoxicity) for 48 h followed by an LPS immunity challenge for 24 h. The culture supernatants were collected from the basolateral compartment and these samples were submitted for cytokine/chemokine multiplex analysis. RNA-Seq analysis was performed using total RNA extracted from the MAC-T cells to acquire a more detailed insight into their cellular functions. The multiplex analysis indicated that IFN-γ, IL-1α, IL-8, and MCP-1 were significantly induced post-DON treatment when compared to control cells, and levels of IL-1α and IL-8 were enhanced significantly in all mycotoxin-treated groups post-LPS challenge. Analysis of the sequencing results showed that there were 341, 357, and 318 differentially expressed MAC-T cell genes that were up-regulated in the DON, ENB, and BEA groups, respectively. Gene ontology and pathway analysis revealed that these DEGs were significantly enriched in various biological processes and pathways related to inflammation, apoptosis signaling, and Wnt signaling. These results provide a comprehensive analysis of the co-culture cytokine/chemokine production and MAC-T cells' gene expression profiles elicited by Fusarium mycotoxins, which further contributes to the understanding of early endotoxemia post-mycotoxin exposure.
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Fusarium , Micotoxinas , Tricotecenos , Animais , Bovinos , Micotoxinas/toxicidade , Fusarium/metabolismo , Tricotecenos/toxicidade , Tricotecenos/metabolismo , Técnicas de Cocultura , Lipopolissacarídeos/farmacologia , Interleucina-8 , Células Epiteliais/metabolismo , Endotoxinas , MacrófagosRESUMO
BACKGROUND: Primary healthcare (PHC) is a crucial strategy for achieving universal health coverage. Ethiopia is working to improve its primary healthcare system through the Optimization of Health Extension Program (OHEP), which aims to increase accessibility, availability and performance of health professionals and services. Measuring current accessibility of healthcare facilities and workforce availability is essential for the success of the OHEP and achieving universal health coverage in the country. METHODS: In this study we use an innovative mixed geospatial approach to assess the accessibility and availability of health professionals and services to provide evidence-based recommendations for the implementation of the OHEP. We examined travel times to health facilities, referral times between health posts and health centers, geographical coverage, and the availability and density of health workers relative to the population. RESULTS: Our findings show that the accessibility and availability of health services in Somali region of Ethiopia is generally low, with 65% of the population being unable to reach a health center or a health post within 1 h walking and referral times exceeding 4 h walking on average. The density of the health workforce is low across Somali region, with no health center being adequately staffed as per national guidelines. CONCLUSIONS: Improving accessibility and addressing healthcare worker scarcity are challenges for implementing the primary care roadmap in Ethiopia. Upgrading health posts and centers, providing comprehensive services, and training healthcare workers are crucial. Effective outreach strategies are also needed to bridge the gap and improve accessibility and availability.
Access to primary healthcare, which encompasses essential healthcare services and often the initial point of contact between individuals and the healthcare system, is crucial for addressing the health needs of a population. In Ethiopia, ongoing efforts to reform the primary healthcare system aim to increase geographic access to health services and improve the availability of healthcare workers. This study focuses on the Somali region of Ethiopia and finds that 65% of the population is unable to reach a health center within 1 h of walking, and none of the health centers meet national and international staffing guidelines. These results play an important role in identifying areas where mobile outreach, involving trained service providers traveling to communities with limited access to healthcare facilities, can bridge gaps in healthcare accessibility and availability. Furthermore, the findings inform the implementation of primary healthcare reforms.
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The MB-pol many-body potential accurately predicts many properties of water, including cluster, liquid phase, and vapor-liquid equilibrium properties, but its high computational cost can make applying it in large-scale simulations quite challenging. In order to address this limitation, we developed a "deep potential" neural network (DPMD) model based on the MB-pol potential for water. We find that a DPMD model trained on mostly liquid configurations yields a good description of the bulk liquid phase but severely underpredicts vapor-liquid coexistence densities. By contrast, adding cluster configurations to the neural network training set leads to a good agreement for the vapor coexistence densities. Liquid phase densities under supercooled conditions are also represented well, even though they were not included in the training set. These results confirm that neural network models can combine accuracy and transferability if sufficient attention is given to the construction of a representative training set for the target system.
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Abstract Interleukins 6 and 17 act in bone resorption in the presence of infections of endodontic origin for host defense. Genetic polymorphisms may be associated with increased bone loss, represented by areas of large periapical lesions. This study aimed to verify the frequency of interleukin 6 and 17 gene polymorphism in patients with asymptomatic apical periodontitis or chronic apical abscess and to verify the existence of correlations between periapical lesion area with age, gender, and presence of the polymorphism, in the studied population, in the state of Pernambuco. A population consisting of thirty diagnosed individuals was included. The area of the lesions was measured in mm². Genomic DNA was extracted and genotyping was performed by Polymerase Chain Reaction Restriction Fragment Length Polymorphism for interleukin 6 (rs 1800795) and interleukin 17 (rs 2275913). Fisher's exact, chi-square, and odds ratio tests were used. A logistic regression analysis was also performed using sex, age, and the presence of polymorphism as covariates, in addition to linear regression to test the relationship between age and lesion area. All tests used a significance level of 0.05% (p ≤0.05%). There was no statistical significance in the occurrence of large areas of periapical lesions correlated with age, sex, and diagnosis, nor in the distribution of alleles in the polymorphism of interleukins 6 and 17 in the studied groups. The frequency of homozygous and heterozygous polymorphism was high. The polymorphism of these interleukins is not correlated with the increase in the areas of asymptomatic periapical inflammatory lesions.
Resumo As interleucinas 6 e 17 atuam na reabsorção óssea na presença de infecções de oriegem endodôntica para defesa do hospedeiro. Polimorfismos genéticos podem estar associados ao aumento da perda óssea, representada por áreas de lesões periapicais grandes. O objetivo deste estudo foi verificar a frequência do polimorfismo dos genes interleucina 6 e 17 em pacientes com periodontite apical assintomática ou abscesso apical crônico e verificar a existência de correlações entre área de lesão periapical com idade, sexo e presença do polimorfismo, na população estudada, no estado de Pernambuco. Foi incluída uma população constituída por trinta indivíduos diagnosticados. A áreas da lesões foram medidas em mm². O DNA genômico foi extraído e a genotipagem realizada por Polimorfismo de Comprimento de Fragmento de Restrição de Reação em Cadeia da Polimerase para interleucina 6 (rs 1800795) e interleucina 17 (rs 2275913). Os testes exato de Fisher, qui-quadrado e odds ratio foram utilizados. Uma análise de regressão logística também foi realizada usando sexo, idade e presença de polimorfismo como covariável, além de regressão linear para testar a relação da idade e área da lesão. Todos os testes utilizaram um nível de significância de 0,05% (p ≤0.05%). Não houve significância estatística na ocorrência das áreas grandes de lesões periapicais correlacionadas com idade, sexo e diagnóstico nem nas distribuições de alelos no polimorfismo das interleucinas 6 e 17 nos grupos estudados. A frequência de polimorfismo homozigoto e heterozigoto foi alta. O polimorfismo dessas interleucinas não está correlacionado ao aumento das áreas das lesões inflamatórias periapicais assintomáticas.
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BACKGROUND: Bartter's syndrome (BS) is a group of salt-wasting tubulopathies characterized by hypokalemia, metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism, and low or normal blood pressure. Loss-of-function variants in genes encoding for five proteins expressed in the thick ascending limb of Henle in the nephron, produced different genetic types of BS. AIM: Clinical and genetic analysis of families with Antenatal Bartter syndrome (ABS) and with Classic Bartter syndrome (CBS). METHODS: Nine patients from unrelated non-consanguineous Mexican families were studied. Massive parallel sequencing of a gene panel or whole-exome sequencing was used to identify the causative gene. RESULTS: Proband 1 was homozygous for the pathogenic variant p.Arg302Gln in the SLC12A1 gene encoding for the sodium-potassium-chloride NKCC2 cotransporter. Proband 3 was homozygous for the nonsense variant p.Cys308* in the KCNJ1 gene encoding for the ROMK potassium channel. Probands 7, 8, and 9 showed variants in the CLCKNB gene encoding the chloride channel ClC-Kb: proband 7 was compound heterozygous for the deletion of the entire gene and the missense change p.Arg438Cys; proband 8 presented a homozygous deletion of the whole gene and proband 9 was homozygous for the nonsense mutation p.Arg595*. A heterozygous variant of unknown significance was detected in the SLC12A1 gene in proband 2, and no variants were found in SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, and MAGED2 genes in probands 4, 5, and 6. CONCLUSIONS: Genetic analysis identified loss-of-function variants in the SLC12A1, KCNJ1, and CLCNKB genes in four patients with ABS and in the CLCNKB gene in two patients with CBS.
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Síndrome de Bartter , Humanos , Feminino , Gravidez , Síndrome de Bartter/genética , Homozigoto , Deleção de Sequência , Heterozigoto , Mutação , Antígenos de Neoplasias , Proteínas Adaptadoras de Transdução de Sinal , Canais de Cloreto/genéticaRESUMO
Excessive noise in the work environment has been associated with extra-auditory symptoms, which can have harmful long-term effects on individuals. The purpose of this study was to identify noise levels in neonatal intensive care units and investigate their impact on the occurrence of stress among healthcare professionals, using cortisol levels as a biomarker for Burnout Syndrome. This descriptive, observational, and cross-sectional study was conducted in four public teaching hospitals in Fortaleza, Ceará, Brazil. Sound pressure levels in the environment were measured, and questionnaires were administered to collect sociodemographic data and assess perceptions of the work environment and Burnout symptoms. Saliva samples were collected at the beginning and end of work shifts for cortisol quantification. The average sound pressure ranged from 59.9 to 66.4 dB(A), exceeding the recommended levels set by Brazilian and international legislation. Among the 256 participants, the average age was 39.4 years, with 95% being female. The majority (70.9%) were nurses, and 22.7% were physicians. There was no significant association found between noise and Burnout Syndrome, nor with changes in cortisol levels. However, a significant association was observed between the perception of excessive noise and the sensation of a stressful work shift (p = 0.012). All evaluated professionals displayed symptoms of Burnout. The high sound pressure levels indicated that the assessed environments did not meet the recommended standards for acoustic comfort, and this was associated with the participants' perception of stressful work shifts. While Burnout symptoms were evident in our participants, it was not possible to confirm a correlation with high noise levels.
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BACKGROUND AND AIMS: In the presence of malignant dysphagia in non-surgical candidates, a self-expanding metal stent (SEMS) represents a safe and effective approach. Recently, a through-the-scope (TTS) SEMS was launched. The aim of our study was to assess the feasibility and safety of the TTS versus over-the-wire (OTW) SEMS in patients with malignant dysphagia. METHODS: This single-center retrospective cohort study included patients with malignant dysphagia undergoing esophageal TTS and OTW-SEMS from 2012 to May-2022. The primary outcomes were the technical and the clinical success of the SEMS placement. Secondary outcomes included adverse events, patency, and survival. Patients were prospectively followed until death or loss of follow-up. RESULTS: A total of 98 patients were enrolled, including 34 patients in the TTS group and 64 patients in the OTW group. TTS and OTW SEMS placement were feasible in 33 (97.1%) and 64 (100%) procedures , respectively (p=0.118). Overall, 32 patients (94.1%) in the TTS group and 62 patients (96.9%) in the OTW group showed an improvement in Ogilvie score (p=0.432). Recurrent dysphagia occurred in 30 patients, 12 in TTS group and 18 in OTW group, due to migration (4 vs. 5), stent deformation (1 vs. 1), tissue ingrowth (5 vs. 5) and overgrowth (2 vs. 7). No patient died from a stent-related cause. Median survival was 123 days (IQR: 59-209) in TTS group and 113 days (IQR: 73-271) in OTW group (p=0.349). CONCLUSIONS: Placement of esophageal TTS and OTW stents resulted in similar technical and clinical outcomes, stent patency and survival in patients with malignant dysphagia.
Assuntos
Transtornos de Deglutição , Neoplasias Esofágicas , Humanos , Estudos Retrospectivos , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Estudos de Viabilidade , Resultado do Tratamento , Stents/efeitos adversos , Estudos de Coortes , Cuidados Paliativos/métodos , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/cirurgiaRESUMO
Computational studies of liquid water and its phase transition into vapor have traditionally been performed using classical water models. Here, we utilize the Deep Potential methodology-a machine learning approach-to study this ubiquitous phase transition, starting from the phase diagram in the liquid-vapor coexistence regime. The machine learning model is trained on ab initio energies and forces based on the SCAN density functional, which has been previously shown to reproduce solid phases and other properties of water. Here, we compute the surface tension, saturation pressure, and enthalpy of vaporization for a range of temperatures spanning from 300 to 600 K and evaluate the Deep Potential model performance against experimental results and the semiempirical TIP4P/2005 classical model. Moreover, by employing the seeding technique, we evaluate the free energy barrier and nucleation rate at negative pressures for the isotherm of 296.4 K. We find that the nucleation rates obtained from the Deep Potential model deviate from those computed for the TIP4P/2005 water model due to an underestimation in the surface tension from the Deep Potential model. From analysis of the seeding simulations, we also evaluate the Tolman length for the Deep Potential water model, which is (0.091 ± 0.008) nm at 296.4 K. Finally, we identify that water molecules display a preferential orientation in the liquid-vapor interface, in which H atoms tend to point toward the vapor phase to maximize the enthalpic gain of interfacial molecules. We find that this behavior is more pronounced for planar interfaces than for the curved interfaces in bubbles. This work represents the first application of Deep Potential models to the study of liquid-vapor coexistence and water cavitation.
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Background: Antitumor antibody, or targeted immunotherapy, has revolutionized cancer treatment and markedly improved patient outcomes. A prime example is the monoclonal antibody (mAb) trastuzumab, which targets human epidermal growth factor receptor 2 (HER2). However, like many targeted immunotherapies, only a subset of patients benefit from trastuzumab long-term. In addition to tumor-intrinsic factors, we hypothesize that host genetics may influence subsequent immune activation. Methods: To model the human population, we produced F1 crosses of genetically heterogeneous Diversity Outbred (DO) mice with BALB/c mice (DOCF1). Distinct DOCF1 mice were orthotopically implanted with the BALB/c-syngeneic TUBO mammary tumor line, which expresses the HER2 ortholog rat neu. Treatment with anti-neu mAb clone 7.16.4 began once tumors reached â¼200 mm 3 . Genetic linkage and quantitative trait locus (QTL) effects analyses in R/qtl2 identified loci associated with tumor growth rates. Locus validation was performed with BALB/c F1 crosses with recombinant-inbred Collaborative Cross (CC) strains selected for therapy-associated driver genetics (CCxCF1). The respective roles of natural killer (NK) cells and macrophages were investigated by selective depletion in vivo. Ex vivo macrophage antibody-dependent phagocytosis (ADCP) assays were evaluated by confocal microscopy using 7.16.4-opsonized E2Crimson-expressing TUBO tumor cells. Results: We observed a divergent response to anti-tumor antibody therapy in DOCF1 mice. Genetic linkage analysis detected a locus on chromosome 10 that correlates to a robust response to therapy, which was validated in CCxCF1 models. Single-cell RNA sequencing of tumors from responder and non-responder models identified key differences in tumor immune infiltrate composition, particularly within macrophage (Mφ) subsets. This is further supported by ex vivo analysis showing Mφ ADCP capacity correlates to in vivo treatment outcomes in both DOCF1 and CCxCF1 models. Conclusions: Host genetics play a key regulatory role in targeted immunotherapy outcomes, and putative causal genes are identified in murine chromosome 10 which may govern Mφ function during ADCP.