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Publication
Journal: The Gerontologist
February/23/2022
Publication
Journal: Health and Social Work
February/23/2022
Publication
Journal: Research
February/23/2022
Abstract
Chagas disease (CD), caused by Trypanosoma cruzi, occurs in several countries in Latin America and non-endemic countries. Heterogeneity among T. cruzi population has been the Achilles' heel to find a better treatment for CD. In this study, we characterized the biochemical parameters and mitochondrial bioenergetics of epimastigotes differentiated from eight T. cruzi isolates (I1-I8) obtained from Brazilian CD patients. Molecular analysis of parasites DTUs grouped all of them as TcII. The profile of the growth curves in axenic cultures was distinct among them, except for I1 and I3 and I2 and I4. Doubling times, growth rates, cell body length, and resistance to benznidazole were also significantly different among them. All the isolates were more glucose-dependent than other T. cruzi strains adapted to grow in axenic culture. Mitochondrial bioenergetics analysis showed that each isolate behaved differently regarding oxygen consumption rates in non-permeabilized and in digitonin-permeabilized cells in the presence of a complex II-linked substrate. When complex IV-linked respiratory chain substrate was used to provide electrons to the mitochondrial respiratory chain (MRC), similarity among the isolates was higher. Our findings show that TcII epimastigotes derived from patients' trypomastigotes displayed their own characteristics in vitro, highlighting the intra-TcII diversity, especially regarding the functionality of mitochondrial respiratory complexes II and IV. Understanding T. cruzi intraspecific biological features help us to move a step further on our comprehension regarding parasite's survival and adaptability offering clues to improve the development of new therapies for CD.
Keywords: Chagas disease; Mitochondrial bioenergetics; Trypanosoma cruzi.
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Journal: ESC heart failure
February/23/2022
Abstract
Aims: Available upper reference levels (URLs) in older adults for N-terminal pro brain natriuretic peptide (NT-proBNP), an established biomarker for heart failure, are mainly based on small samples. We aimed to identify NT-proBNP URL in a population-based reference sample of individuals aged ≥65 years.
Methods and results: We analysed established NT-proBNP predictors using quantile regression among 2459 participants of two-independent population-based cohorts located in Germany, the Activity and Function in the Elderly Study (ActiFE, n = 1450) and the Study of Health in Pomerania (SHIP-TREND-0, n = 1009). Based on predictors a reference population of 441 subjects (ActiFE, n = 227; SHIP-TREND-0, n = 214) without history of diabetes, cardiovascular, or pulmonary diseases and with systolic blood pressure (BP) <140 mmHg, diastolic BP ≥60 and ≤90 mmHg, haemoglobin in men ≥14 and ≤18 g/dL and in women ≥12 and ≤16 g/dL, GFR ≥60 mL/min/1.73 m2 , CRP <5 mg/L, BMI ≥18 and ≤33 kg/m2 , and hs-cTnI <40 ng/L were built with NT-proBNP median levels and 97.5% quantiles reported stratified by sex and age. In a secondary analysis the URL among 97 SHIP-TREND-0 participants with a left ventricular ejection fraction (LVEF) ≥50 and no diastolic dysfunction were estimated. The median age in the identified reference sample was 70 years, with 41.9% and 40.2% male participants in ActiFE and SHIP-TREND-0, respectively. We observed an age-dependent increment of NT-proBNP levels with higher values in women compared to men. Notably, NT-proBNP levels were >125 ng/L in 165 participants (37.4%), with NT-proBNP URL (97.5% quantiles) equal to 663, 824, 592, and 697 ng/L in men, and 343, 463, 2641, 1276 ng/L in women for ages 65-69, 70-74, 75-79, and 80+ years, respectively. In the secondary analysis with a LVEF ≥50 and no diastolic dysfunction (35 men and 62 women) NT-proBNP levels >125 ng/L were still observed in 38 (39.2%) participants.
Conclusions: This reference sample of apparently healthy asymptomatic older adults showed an age-related increment of NT-proBNP levels with URL markedly higher than the European Society of Cardiology recommended cut-off of 125 ng/L for the diagnosis of heart failure in ambulatory settings. Identifying URL in those ≥80 years remains complex. Our results attempt to provide a frame for the further investigation of age-specific NT-proBNP cut-offs in older adults. Considering the demographic changes, further evaluation of NT-proBNP URL in larger samples of older adults followed by the validation of age-specific cut-off values for the identification of heart failure in those 65 years or older are urgently needed.
Keywords: NT-proBNP; Older adults; Reference levels.
Publication
Journal: Journal of Child Psychology and Psychiatry and Allied Disciplines
February/23/2022
Abstract
Background: Adolescence is a critical period for social and emotional development. We sought to examine the impacts of Covid-19 and related social restrictions and school closures on adolescent mental health, particularly among disadvantaged, marginalised, and vulnerable groups.
Methods: We analysed four waves of data - 3 pre-Covid-19 (2016-2019) and 1 mid-Covid-19 (May-Aug 2020; n, 1074; 12-18 years old, >80% minority ethnic groups, 25% free school meals) from REACH (Resilience, Ethnicity, and AdolesCent Mental Health), an adolescent cohort based in inner-London, United Kingdom. Mental health was assessed using validated measures at each time point. We estimated temporal trends in mental distress and examined variations in changes in distress, pre- to mid-Covid-19, by social group, and by pre- and mid-pandemic risks.
Results: We found no evidence of an overall increase in mental distress midpandemic (15.9%, 95% CI: 13.0, 19.4) compared with prepandemic (around 18%). However, there were variations in changes in mental distress by subgroups. There were modest variations by social group and by pre-Covid risks (e.g., a small increase in distress among girls (b [unstandardised beta coefficient] 0.42 [-0.19, 1.03]); a small decrease among boys (b - 0.59 [-1.37, 0.19]); p for interaction .007). The most notable variations were by midpandemic risks: that is, broadly, increases in distress among those reporting negative circumstances and impacts (e.g., in finances, housing, social support and relationships, and daily routines) and decreases in distress among those reporting positive impacts.
Conclusions: We found strong evidence that mental distress increased among young people who were most negatively impacted by Covid-19 and by related social restrictions during the first lockdown in the United Kingdom.
Keywords: Covid-19; adolescence; cohort; mental distress.
Publication
Journal: IBRO Neurosci Rep
February/23/2022
Abstract
Medial amygdala processes social/reproductive chemosensory input, and its projections to preoptic and hypothalamic areas evoke appropriate behavioral and physiological responses. We and others have shown that different chemosensory signals elicit differential responses in medial amygdala subregions and in adjacent main intercalated nucleus (mICN). The largely GABAergic mICN receives no direct chemosensory input but, as we show, mICN has functional circuit connections with medial amygdala that could be responsible both for mICN chemosensitivity and for a feedforward inhibitory effect on posterior medial amygdala; which, in turn would affect chemosignal response. mICN is subject to inhibition by dopamine and is probably regulated by neuropeptides and input from frontal cortex. Thus, mICN is in position to modify chemosensory processing in medial amygdala and behavioral responses to social signals, according to internal brain state. Patch-clamp recordings from neurons in each relevant nucleus in horizontal brain-slices, with electrical stimulation in adjacent nuclei, reveal multiple functional connections between medial amygdala subregions and mICN. We highlight a triangular circuit which may underlie mICN chemosensitivity and its potential for modifying chemosensory information transmitted to basal forebrain. Anterior medial amygdala, which receives most of the chemosensory input, connects to posterior medial amygdala directly and both areas send information on to basal forebrain. Anterior medial amygdala can also modulate posterior medial amygdala indirectly via the mICN side-loop, which also provides a pathway for modulation by cortical input or, when inhibited by dopamine, could allow a more automatic response - as proposed for other amygdala circuits with similar ICN side loops.
Keywords: Dopamine; Electrical stimulation; GABA; Glutamate; Male Hamster; Whole-cell slice-recording.
Publication
Journal: Biofilm
February/23/2022
Abstract
Treatment of staphylococcal infections is difficult due to multidrug resistance with their persister forms posing an added threat of recalcitrant infections. Antibiotic combinations are widely studied as an alternative strategy to combat them; therefore, they merit further investigation into their effect on the number of persister cells. In the present study, the fractional inhibitory concentrations of antibiotic combinations ciprofloxacin-daptomycin, ciprofloxacin-vancomycin, daptomycin-tobramycin, and tobramycin-vancomycin (checkerboard assay) were determined against two previously studied clinical (S48 and J6) and one standard (NCIM 5021) isolate of Staphylococcus aureus. They showed synergistic effects with a 2 to 256-fold reduction in MICs. All combinations also resulted in inhibition and disruption of biofilms in a concentration-dependent manner. All antibiotic combinations, except ciprofloxacin-daptomycin, showed total biofilm inhibition at 100X MICs. Similarly, antibiotic combination at 100X MIC showed 77-97% disruption of preformed biofilms. Time-kill assays performed at a 100X MIC combination against stationary-phase cells showed a two to six log10 reduction in CFU followed by a plateau indicating the presence of persisters. Significant differences were observed in persister cell fraction remaining after treatment with antibiotic combinations compared to monotherapies (p < 0.05) and therefore merit further investigation in clinical use for treatment against persisters.
Keywords: Biofilm; Drug combination; Drug tolerance; Staphylococcus aureus.
Publication
Journal: Oral Diseases
February/23/2022
Abstract
Objectives: To evaluate the prognostic and locoregional metastatic features of carcinoma ex pleomorphic adenoma of submandibular gland (SMG-CXPA) and improve the understanding of this uncommon condition.
Patients and methods: We retrospectively reviewed patients who were diagnosed with SMG-CXPA. The survival data of SMG-CXPA patients were statistically analyzed using Cox regression and Kaplan-Meier method. The associations between cervical metastasis and clinicopathological parameters were evaluated using chi-squared test. Additionally, two different histological categories (histological grade and invasiveness) and their combination were evaluated with the Kaplan-Meier method and receiver operating characteristic curves.
Results: In total, 86 patients were diagnosed: 38 clinically node-negative, 31 pathologically node-negative and 17 node-positive patients. Clinical tumor stage and histological grade were two independent prognostic factors for SMG-CXPA. There were significant correlations between sex, tumor size, clinical tumor stage, clinical lymph node stage, histological grade, invasiveness, malignant components, perineural invasion and no specific criteria exist for the clinical outcome.
Conclusion: SMG-CXPA is a high-grade malignancy with an unfavorable prognosis. Elective neck dissection should be performed in SMG-CXPA patients with a risk of locoregional metastasis. Histological grade seems to be a more valuable predictor of lymph node involvement than invasiveness.
Keywords: carcinoma ex pleomorphic adenoma; locoregional metastasis; prognosis; salivary gland tumor; submandibular gland.
Publication
Journal: Journal of Digital Imaging
February/23/2022
Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer worldwide, and it is characterized by the production of immature malignant cells in the bone marrow. Computer vision techniques provide automated analysis that can help specialists diagnose this disease. Microscopy image analysis is the most economical method for the initial screening of patients with ALL, but this task is subjective and time-consuming. In this study, we propose a hybrid model using a genetic algorithm (GA) and a residual convolutional neural network (CNN), ResNet-50V2, to predict ALL using microscopy images available in ALL-IDB dataset. However, accurate prediction requires suitable hyperparameters setup, and tuning these values manually still poses challenges. Hence, this paper uses GA to find the best hyperparameters that lead to the highest accuracy rate in the models. Also, we compare the performance of GA hyperparameter optimization with Random Search and Bayesian optimization methods. The results show that GA optimization improves the accuracy of the classifier, obtaining 98.46% in terms of accuracy. Additionally, our approach sheds new perspectives on identifying leukemia based on computer vision strategies, which could be an alternative for applications in a real-world scenario.
Keywords: Convolutional neural networks; Fine-tuning; Genetic algorithm; Hyperparameter optimization; Leukemia classification.
Publication
Journal: Science and Engineering Ethics
February/23/2022
Abstract
Relying on data collected by the Zurich Survey of Academics (ZSoA), a unique representative online survey among academics in Germany, Austria, and Switzerland (DACH region), this paper replicates Johann and Mayer's (Minerva 57(2):175-196, 2019) analysis of researchers' perceptions of scientific authorship and expands their scope. The primary goals of the study at hand are to learn more about (a) country differences in perceptions of scientific authorship, as well as (b) the influence of perceived publication pressure on authorship perceptions. The results indicate that academics in Switzerland interpret scientific authorship more leniently than their colleagues in Germany and Austria. The findings further indicate that, as perceived pressure to publish increases, researchers are more likely to belong to a group of academics who hold the view that any type of contribution/task justifies co-authorship, including even those contributions/tasks that do not justify co-authorship according to most authorship guidelines. In summary, the present study suggests that action is required to harmonize regulations for scientific authorship and to improve the research culture.
Keywords: Austria; Authorship perceptions; Germany; Pressure to publish; Science studies; Scientific authorship; Switzerland.
Publication
Journal: Journal of Dermatology
February/23/2022
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Journal: Small
February/23/2022
Abstract
Oxide perovskite ceramics are cornerstone materials of electronic devices, but they easily break under bending. Such brittle failure phenomenon limits their applications in emerging flexible electronics. Here, the authors propose a scalable approach of sol-gel electrospinning to synthesize flexible perovskite Li0.35 La0.55 TiO3 (LLTO) nanofibers (NFs) by reducing grain sizes and pore defects in the NFs. The strategy is to precisely control crystal nucleation and growth by forming homogeneous nuclei in the sol before electrospinning and to construct soft twin and amorphous grain boundaries by controlling calcination temperatures. Ball-milling the sol promotes the formation of numerous LLTO nuclei and thus effectively refines grains, while using gradient calcination temperatures from 200 to 900 °C creates intricate soft grain boundaries. The individual LLTO NF shows ceramic toughness with an elastic modulus of ≈40 GPa and the NF film demonstrates silk-like softness with a large elastic strain of 1.51%. Moreover, the LLTO film shows superior fatigue resistance and it maintains structure well after repeated tensile-buckling cycles at 40% strain. The proposed strategy facilitates to develop flexible oxide perovskite ceramic films with appealing applications.
Keywords: electrospinning; flexible oxide perovskite nanofibers; grain refinement; homogeneous crystal nucleation; twin grain boundaries.
Publication
Journal: Statistics in Medicine
February/23/2022
Abstract
As a fundamental component of health care, disease screening is of highly importance. Oftentimes, two screening tests for a specific disease are compared in order to determine an optimal screening policy, for example, the digital rectal examination (DRE) and serum prostate specific antigen (PSA) level for screening prostate cancer. Ideally, if a gold standard test is given to each individual being screened to establish their true disease status, the difference in accuracy measures between two tests can be evaluated. In practice, however, it is common that only individuals who test positive on at least one screening test are to receive gold standard tests, which are often invasive and cannot be applied to those with negative results on both tests due to ethical reasons. Under such circumstances, estimates of the differences in accuracy measures between two tests cannot be determined, thus the inference problem within this framework is challenging. In this article, using sensitivity and specificity as measures of test accuracy, we show that their difference between two tests is interval-identified, as bounded by estimable sharp bounds. Here, we develop the asymptotic normality for the estimators of the bounds and construct confidence intervals for the difference by utilizing the method for solving inference problem for partially identified parameters. The performance of constructed confidence intervals for the difference and their sharp bounds are evaluated via simulation studies. We also apply the proposed method to the prostate cancer example to compare the accuracy of DRE and PSA.
Keywords: partial identification; screen-positive studies; sharp bounds; test accuracy.
Publication
Journal: Vascular
February/23/2022
Abstract
Introduction: Left renal vein stenting (LRVS) for the treatment of anterior nutcracker syndrome (NCS) has been associated with a significant risk of stent migration into the inferior vena cava or right ventricle.
Surgical technique: A hybrid technique is reported for the treatment of NCS to prevent stent migration. The first part of the procedure consists of LRVS at the level of the aortomesenteric compression. The second part consists of laparoscopic stent exofixation through a transperitoneal direct approach. The left renal vein is exposed in order to visualise the stent meshes through the venous wall. Stent exofixation in performed with a simple transfixing polypropylene stitch, reinforced with a Teflon pledget.
Discussion: The hybrid treatment of anterior NCS combining laparoscopic stent exofixation with left renal vein stenting is a simple and low morbidity technique. Further follow up data are needed to evaluate its potential benefit in reducing the risk of left renal vein stent migration.
Keywords: Laparoscopic stent exofixation; Left renal vein stenting; Nutcracker syndrome; Stent migration.
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Publication
Journal: Environmental Science and Pollution Research
February/23/2022
Abstract
CO2 contributes a lot to the greenhouse effect. The total CO2 emissions of the two countries, China and the USA, as the world's top two economies, have exceeded 40% of the total global carbon emissions. In this context, the exploration of the evolution of carbon emissions from energy consumption in China and the USA and the comparison of the characteristics of carbon emission drivers in different periods play a significant role in the policy formulation and climate change cooperation between China and the USA. In this study, the BP structural breakpoint test was used to divide the carbon emission stages of China and the USA from 1970 to 2019. The generalized Divisia index model (GDIM) was developed to decompose the growth of carbon emissions in China and the USA into eight items, GDP, carbon intensity of GDP, energy use, carbon intensity of energy, population, carbon emissions per capita, GDP per capita, and energy intensity, and to analyze the characteristics and cumulative contribution of carbon emission drivers at each stage. Based on the stage and cumulative characteristics of carbon emissions between China and the USA, the USA should take the initiative to assume the legal responsibility of carbon emissions and further deepen the cooperation with other countries in the field of climate change. China should transform the economic growth mode, optimize the energy structure, and improve the efficiency of resource utilization to help achieve the peaking carbon emissions and the carbon neutrality smoothly.
Keywords: Carbon emissions; Comparative study; Driving factors; GDIM; Stage characteristics; The BP structural breakpoint test.
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Publication
Journal: Environmental Science and Pollution Research
February/23/2022
Abstract
Climate change resulting from a rapid increase in greenhouse gas (GHG) emissions is adversely affecting humanity. If the GHG emission continues to rise at the current pace, humanity will face severe consequences and reverse all the progress made. This paper, therefore, uses relevant data from 14 developing countries in Asia from 1990 to 2018 to examine the potential impact of environmental innovation on CO2 emissions by controlling globalization, urbanization, and economic growth. The number of environmental-related technology patents is used as a measure of environmental innovation. We employed a panel long-run regression model - FMOLS, PCSE, and FGLS to estimate the elasticity of CO2 emissions. For causal association among variables, we used Dumitrescu-Hurlin Granger causality tests. Our results show that renewable energy consumption and globalization have a significant impact in reducing CO2 emissions, while environmental technology innovations play a meager role in reducing emissions and only when economic growth support those type of investment. Furthermore, we found urbanization, oil consumption, and economic growth is detrimental to the environment, which is also evident in past studies. Therefore, countries should invest in renewable energy and environmental innovation aligned with the growth to reduce GHG emissions.
Keywords: CO2 emissions; Decarbonization; Developing Asia economies; Environmental innovation; Environmental technology; Globalization; Renewable energy.
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Journal: STAR Protoc
February/23/2022
Abstract
The protocol describes step-by-step sample preparation, data acquisition, and segmentation of cellular organelles with soft X-ray tomography. It is designed for microscopes built to perform full-rotation data acquisition on specimens in cylindrical sample holders, such as the XM-2 microscope at the Advanced Light Source, LBNL; however, it might be generalized for similar sample holder designs for both synchrotron and table-top microscopes. For complete details on the use and execution of this profile, please refer to Loconte et al. (2021).
Keywords: Cell Biology; Microscopy; Single Cell.
Publication
Journal: European Urology
February/23/2022
Related with
Publication
Journal: International Forum of Allergy and Rhinology
February/23/2022
Abstract
Keywords: COVID-19; Follow up; Olfactory Dysfunction; Smell.
Publication
Journal: Vascular
February/23/2022
Related with
Publication
Journal: Journal of Nephrology
February/23/2022
Abstract
Background: Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adults. The Kidney Disease Improving Global Outcomes guidelines recommend rituximab or cyclophosphamide and steroids, or calcineurin inhibitor-based therapy. However, there have been few or no head-to-head comparisons of the relative efficacy and safety of different immunosuppression regimens. We conducted a network meta-analysis to evaluate the comparative efficacy and safety of available immunosuppression strategies compared to cyclophosphamide in adults with idiopathic membranous nephropathy.
Methods: We performed a systematic search of MEDLINE, Embase and CENTRAL for randomized controlled trials in the treatment of adults with idiopathic membranous nephropathy. The primary outcome was complete remission. Secondary outcomes were kidney failure, partial remission, estimated glomerular filtration rate, doubling of serum creatinine, proteinuria, serious adverse events, discontinuation of treatment, serious infection and bone marrow suppression.
Results: Cyclophosphamide had uncertain effects on inducing complete remission when compared to rituximab (OR 0.35, CI 0.10-1.24, low certainty evidence), mycophenolate mofetil (OR 1.81, CI 0.69-4.71, low certainty), calcineurin inhibitor (OR 1.26, CI 0.61-2.63, low certainty) or steroid monotherapy (OR 2.31, CI 0.62-8.52, low certainty). Cyclophosphamide had a higher probability of inducing complete remission when compared to calcineurin inhibitor plus rituximab (OR 4.45, CI 1.04-19.10, low certainty). Compared to other immunosuppression strategies, there was limited evidence that cyclophosphamide had different effects on other pre-specified outcomes.
Conclusions: The comparative effectiveness and safety of immunosuppression strategies compared to cyclophosphamide is uncertain in adults with idiopathic membranous nephropathy.
Keywords: Calcineurin inhibitor; Cytotoxic agents; Membranous nephropathy; Network meta-analysis; Rituximab.
Publication
Journal: Journal of Nuclear Cardiology
February/23/2022
Abstract
Objective: Evaluate the impact of 82-Rubidium positron emission tomography (PET) myocardial perfusion imaging (MPI) availability on patient management presenting at the emergency department (ED) with chest pain (CP).
Methods: This is a single-center retrospective study of clinical databases. Patients presenting with CP with a non-definitive suspicion of acute coronary syndrome (ACS) at the ED between April 2016 and February 2020 were divided into 2 groups based on PET availability. The proportion of invasive coronary angiography (ICA) without significant coronary artery disease (CAD), length of stay (LoS), and additional downstream testing were evaluated.
Results: There were 21,242 ED visits for CP without definitive ACS: 5,492 when PET is not available and 15,750 when PET is available. When PET is available, proportion of patients undergoing a MPI study was greater (20.7% vs 17.6%, P<0.0001), proportion of ICA without significant CAD was similar (18.5% vs 21.4%, P=0.24), and median ED LoS was shorter (16.6 vs 18.1 hours, P=0.03). Patients undergoing SPECT MPI had significantly more downstream testing (8.9% vs 6.4%, P=0.003) and a higher rate of coronary angiogram without significant CAD (21.2% vs 14.2%, P=0.09) compared to those who underwent PET MPI.
Conclusion: Availability of PET MPI was associated with an increased number of MPI referral from the ED, similar rates of ICA without significant CAD, decreased LoS, and fewer downstream testing.
Objetivo: Evaluar el impacto de la tomografía por emisión de positrones (PET) con 82-Rubidio y la disponibilidad de imágenes de perfusión miocárdica (MPI) en el manejo de los pacientes que se presentan en el servicio de urgencias (ED) con dolor torácico (CP). MéTODOS: Este es un estudio retrospectivo de bases de datos clínicas de un solo centro. Pacientes que presentaron CP con sospecha no definitiva de síndrome coronario agudo (ACS) en el ED entre abril de 2016 y febrero de 2020, se dividieron en 2 grupos según la disponibilidad de PET. Se evaluó la proporción de angiografía coronaria invasiva (ICA) sin enfermedad arterial coronaria (CAD) significativa, la duración de la estancia (LoS) y las pruebas posteriores adicionales.
Resultados: Hubo 21,242 visitas al ED por CP sin ACS definitivo: 5,492 cuando no se dispone de PET y 15.750 cuando se dispone de PET. Cuando se dispone de PET, la proporción de pacientes sometidos a estudio de MPI fue mayor (20.7% vs 17.6%, p=0.03). Los pacientes que se sometieron a SPECT MPI tuvieron significativamente más pruebas posteriores (8.9 % frente a 6.4 %, p = 0.003) y una tasa más alta de angiografía coronaria sin CAD significativa (21.2 % frente a 14.2 %, p = 0.09) en comparación con los que se sometieron a PET MPI. CONCLUSIóN: La disponibilidad de PET MPI se asoció con un mayor número de referencias de MPI desde el ED, tasas similares de ICA sin CAD significativa, disminución de LoS y menos pruebas posteriores.
Keywords: Chest pain; Myocardial perfusion imaging; Positron emission tomography; Rb-82; Rubidium-82.
Publication
Journal: Journal of Antimicrobial Chemotherapy
February/23/2022
Abstract
Objectives: To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii.
Methods: Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time-kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice.
Results: Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time-kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 μM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy.
Conclusions: These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.
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Journal: Journal of Diabetes Investigation
February/23/2022
Abstract
Aims/introduction: We evaluated the effect of co-administration of esaxerenone and a sodium-glucose cotransporter 2 (SGLT2) inhibitor on the magnitude of serum potassium elevation in Japanese patients with diabetic kidney disease.
Materials and methods: We conducted a prespecified subanalysis of data from two phase 3 studies: a multicenter, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes and microalbuminuria (J308); and a multicenter, single-arm, open-label trial in patients with type 2 diabetes and macroalbuminuria (J309). Changes in serum potassium levels during the studies and other measures were evaluated according to SGLT2 inhibitor use.
Results: In both studies, time course changes in serum potassium levels, and incidence rates of serum potassium elevation were lower in patients with co-administration of SGLT2 inhibitor in both the placebo and esaxerenone groups than those without the inhibitor. In contrast, time course changes and mean percent changes from baseline in urinary albumin-to-creatinine ratio (UACR), the proportion of patients with albuminuria remission, and time course changes in blood pressure did not change with or without SGLT2 inhibitor, while UACR and blood pressure were reduced with esaxerenone. The blood glucose-lowering effect of SGLT2 inhibitor was not affected by esaxerenone.
Conclusions: In Japanese patients with type 2 diabetes and albuminuria treated with esaxerenone, concomitant use of SGLT2 inhibitor reduced the magnitude of serum potassium elevation without any change of its antihypertensive and albuminuria-suppressing effects. Co-administration of esaxerenone and SGLT2 inhibitor may be a beneficial treatment option for patients with diabetic kidney disease.
Keywords: esaxerenone; potassium; sodium-glucose transporter 2 inhibitor.
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