Metabolic Profile and Cardiovascular Risk in a Population of Renal transplant recipients

Introduction. Cardiovascular disease is more common in renal transplant recipients (RTRs) than in the general population, and is the major cause of both graft loss and patient death in RTRs. Objectives. This study aimed to characterize the cardiovascular risk factors, calculate the 7-year risk for major adverse cardiac events and the 7-year risk for death in a population of RTRs using a cardiovascular risk calculator, and determine the main cardiovascular risk factors associated with increased prediction of major adverse cardiac event (MACE) and death. Patients. This is a retrospective review of clinical data from 121 RTRs who are in follow-up programs at our institution, and who had a functioning and stable graft for longer than 6 months. Results. Among 121 adult patients followed at our institution (59.5% males, mean age of 49.6 13.8 years, mean times for functioning grafts were 105 73.5 mo), 86.8% had hypertension, 19.8% had diabetes, 24.8% were current or former smokers, 61.9% had increased body mass index, and 71% had dyslipidemia. The 7-year risk for MACE was more than 10% in 38 (31.4%) patients with age, diabetes, and smoke being independent risk predictors. The 7-year risk for death was more than 10% in 56 (46.3%) patients with age, diabetes, blood pressure, smoking, and male gender being independent risk predictors. Conclusion. There is a high prevalence of cardiovascular risk factors in a population of RTRs, and there is increased risk for MACE and death. Accurate risk prediction is important for physician decision support and patient education, promoting improved cardiovascular health of RTRs, and thus prolonging the survival of both patients and graft.info:eu-repo/semantics/publishedVersio

Increase of Antimicrobial Consumption in a Tertiary Care Hospital during the First Phase of the COVID-19 Pandemic

Background: The COVID-19 pandemic poses novel challenges in antimicrobial consumption metrics and stewardship strategies. COVID-19 patients became the major cause of hospital admission during the first wave of the pandemic, often leading to an antimicrobial prescription upon admission or treatment for superinfections. The aim of this study was to understand how antimicrobial consumption was impacted at the beginning of the pandemic in a tertiary care hospital, a reference center for COVID-19. Materials and Methods: A retrospective before-and-after study was done. Descriptive statistics of discharges, patient-days, and antimicrobial use indicators (defined daily doses (DDD)/100 discharges, DDD/100 patient-days) for various groups were calculated for the first three months of the pandemic (March, April, and May 2020) as a quarterly value, and for each year in 2011–2019, and their annual percentage changes were used to estimate 95% confidence intervals. The indicators were compared to patient type (medical/surgical), type of admission (urgent/elective), and age groups using Spearman’s correlation coefficient. Results: Statistically significant increases occurred in 2020 for total antibacterials, macrolides, cephalosporins, amoxicillin/clavulanic acid, carbapenems, meropenem, and third-generation cephalosporins, while a reduction was seen in cefazolin/cefoxitin. A correlation was found between antibacterial consumption and patient or admission type. In 2020, unlike in pre-pandemic years, there was a different impact in DDD/100 discharges and DDD/100 patient-days due to increased lengths-of-stay and longer antimicrobial therapy. Conclusions: The COVID-19 pandemic led to an increase in antimicrobial consumption with a different impact in DDD/100 discharges and DDD/100 patient-days. This highlights the need to use both indicators simultaneously to better understand the causes of antimicrobial consumption variation and improve the design of effective antimicrobial stewardship interventions.This research received no external funding

Determination of the absolute configuration of bioactive indole-containing pyrazino[2,1-b]quinazoline-3,6-diones and study of their in vitro metabolic profile

In recent decades, fungi-derived naturally occurring quinazolines have emerged as potential drug candidates. Nevertheless, most studies are conducted for bioactivity assays, and little is known about their absorption, distribution, metabolism, and elimination (ADME) properties. To perform metabolic studies, the synthesis of the naturally occurring quinazolinone, fiscalin B (1), and its chloro derivative, 4-((1H-indol-3-yl)methyl)-8,10-dichloro-1-isobutyl-1,2-dihydro-6H-pyra-zino[2,1-b]quinazoline-3,6(4H)-dione (2), disclosed as an antibacterial agent, was performed in a gram scale using a microwave-assisted polycondensation reaction with 22% and 17% yields, respec-tively. The structure of the non-natural (+)-fiscalin B was established, for the first time, by X-ray crystallography as (1R,4S)-1, and the absolute configuration of the naturally occurring fiscalin B (- )-1 was confirmed by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra as (1S,4R)-1. In vitro metabolic studies were monitored for this class of natural products for the first time by ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS). The metabolic characteristics of 1 and 2 in human liver microsomes indicated hydration and hydroxylation mass changes introduced to the parent drugs.This research was supported by national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF) and COMPETE under the Strategic Funding of CIIMAR UIDB/04423/2020 (Group of Natural Products and Medicinal Chemistry-CIIMAR) and LAQV-REQUIMTE (UIDB/50006/2020) and the project PTDC/SAU-PUB/28736/2017 (Reference: POCI-01–0145-FEDER-028736), as well as CHIRALBIOACTIVE-PI-3RL-IINFACTS-2019. This work is also a result of the project ATLANTIDA (Reference: NORTE-01-0145-FEDER-000040), supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement and through the European Regional Development Fund (ERDF). Additionally, this research was supported by the Agency for the Improvement of Higher Education Personnel (CAPES) (Finance Code 001), National Council for Scientific and Technological Development (CNPq) (Grant Number 406064/2018-05), São Paulo Research Foundation (FAPESP) (Grant Number: 2020/05965-8 and Ph.D. scholarships 2018/03035-3 and 2019/15040-4)

The adaptive immune landscape of the colorectal adenoma–carcinoma sequence

Background. The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma–carcinoma sequence (ACS). Methods. We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). Results. The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. Conclusions. The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.This research was funded by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the projects “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and “O papel dos Tregs na resposta imune ao cancro” (PTDC/MED-PAT/32462/2017)

Network model of immune responses reveals key effectors to single and co-infection dynamics by a respiratory bacterium and a gastrointestinal helminth

Co-infections alter the host immune response but how the systemic and local processes at the site of infection interact is still unclear. The majority of studies on co-infections concentrate on one of the infecting species, an immune function or group of cells and often focus on the initial phase of the infection. Here, we used a combination of experiments and mathematical modelling to investigate the network of immune responses against single and co-infections with the respiratory bacterium Bordetella bronchiseptica and the gastrointestinal helminth Trichostrongylus retortaeformis. Our goal was to identify representative mediators and functions that could capture the essence of the host immune response as a whole, and to assess how their relative contribution dynamically changed over time and between single and co-infected individuals. Network-based discrete dynamic models of single infections were built using current knowledge of bacterial and helminth immunology; the two single infection models were combined into a co-infection model that was then verified by our empirical findings. Simulations showed that a T helper cell mediated antibody and neutrophil response led to phagocytosis and clearance of B. bronchiseptica from the lungs. This was consistent in single and co-infection with no significant delay induced by the helminth. In contrast, T. retortaeformis intensity decreased faster when co-infected with the bacterium. Simulations suggested that the robust recruitment of neutrophils in the co-infection, added to the activation of IgG and eosinophil driven reduction of larvae, which also played an important role in single infection, contributed to this fast clearance. Perturbation analysis of the models, through the knockout of individual nodes (immune cells), identified the cells critical to parasite persistence and clearance both in single and co-infections. Our integrated approach captured the within-host immuno-dynamics of bacteria-helminth infection and identified key components that can be crucial for explaining individual variability between single and co-infections in natural populations

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT