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We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies. PAPERCLIP: VIDEO ABSTRACT.
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Simulação por Computador , Modelos Neurológicos , Neocórtex/citologia , Neurônios/classificação , Neurônios/citologia , Córtex Somatossensorial/citologia , Algoritmos , Animais , Membro Posterior/inervação , Masculino , Neocórtex/fisiologia , Rede Nervosa , Neurônios/fisiologia , Ratos , Ratos Wistar , Córtex Somatossensorial/fisiologiaRESUMO
Understanding the intracellular dynamics of brain cells entails performing three-dimensional molecular simulations incorporating ultrastructural models that can capture cellular membrane geometries at nanometer scales. While there is an abundance of neuronal morphologies available online, e.g. from NeuroMorpho.Org, converting those fairly abstract point-and-diameter representations into geometrically realistic and simulation-ready, i.e. watertight, manifolds is challenging. Many neuronal mesh reconstruction methods have been proposed; however, their resulting meshes are either biologically unplausible or non-watertight. We present an effective and unconditionally robust method capable of generating geometrically realistic and watertight surface manifolds of spiny cortical neurons from their morphological descriptions. The robustness of our method is assessed based on a mixed dataset of cortical neurons with a wide variety of morphological classes. The implementation is seamlessly extended and applied to synthetic astrocytic morphologies that are also plausibly biological in detail. Resulting meshes are ultimately used to create volumetric meshes with tetrahedral domains to perform scalable in silico reaction-diffusion simulations for revealing cellular structure-function relationships. Availability and implementation: Our method is implemented in NeuroMorphoVis, a neuroscience-specific open source Blender add-on, making it freely accessible for neuroscience researchers.
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Simulação por Computador , Neurônios , Neurônios/ultraestrutura , Neurônios/citologia , Modelos Neurológicos , Humanos , Animais , Astrócitos/citologia , Astrócitos/ultraestruturaRESUMO
The world has been dealing with the SARS-COV-2 pandemic since December 2019 and a lot of effort has focused on tracking the spread of the virus by gathering information regarding testing statistics and generating viral genomic sequences. Unfortunately, there is neither a single comprehensive resource with global historical testing data nor a centralized database with summary statistics of the identified genomic variants. We merged different pre-aggregated historical testing data and complemented them with our manually extracted ones, which consist of 6852 historical test statistics from 76 countries/states unreported in any other dataset, at the date of submission, making our dataset the most comprehensive to date. We also analyzed all publicly deposited SARS-CoV-2 genomic sequences in GISAID and annotated their variants. Both datasets can be accessed through our interactive dashboard which also provides important insights on different outbreak trends across countries and states. The dashboard is available at https://bioinfo.lau.edu.lb/gkhazen/covid19 . A daily updated version of the datasets can be downloaded from github.com/KhazenLab/covid19-data.
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COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , Surtos de Doenças , Genoma Viral , Genômica , Humanos , SARS-CoV-2/genéticaRESUMO
BACKGROUND: Finding combinations of homotypic or heterotypic genomic sites obeying a specific grammar in DNA sequences is a frequent task in bioinformatics. A typical case corresponds to the identification of cis-regulatory modules characterized by a combination of transcription factor binding sites in a defined window size. Although previous studies identified clusters of genomic sites in species with varying genome sizes, the availability of a dedicated and versatile tool to search for such clusters is lacking. RESULTS: We present fcScan, an R/Bioconductor package to search for clusters of genomic sites based on user defined criteria including cluster size, inter-cluster distances and sites order and orientation allowing users to adapt their search criteria to specific biological questions. It supports GRanges, data frame and VCF/BED files as input and returns data in GRanges format. By performing clustering on vectorized data, fcScan is adapted to search for genomic clusters in millions of sites as input in short time and is thus ideal to scan data generated by high throughput methods including next generation sequencing. CONCLUSIONS: fcScan is ideal for detecting cis-regulatory modules of transcription factor binding sites with a specific grammar as well as genomic loci enriched for mutations. The flexibility in input parameters allows users to perform searches targeting specific research questions. It is released under Artistic-2.0 License. The source code is freely available through Bioconductor (https://bioconductor.org/packages/fcScan) and GitHub (https://github.com/pkhoueiry/fcScan).
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Genômica/métodos , Elementos Reguladores de Transcrição , Análise de Sequência de DNA/métodos , Software , Sítios de Ligação , Análise por Conglomerados , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: Lebanon hosts a heterogeneous population coming from underdeveloped and developing countries, resulting in increasing incidences of tuberculosis over the past years. The genetic heterogeneity and lineages associated with tuberculosis, along with their resistance determinants have not been studied at the genomic level previously in the region. METHODS: Isolates were recovered from the American University of Beirut Medical Center (AUBMC). Antimicrobial susceptibility profiles were determined using the MGIT automated system for the first-line drugs at AUBMC, while second-line drug susceptibility was tested at Mayo Clinic Laboratories. Whole Genome Sequencing (WGS) was performed to classify mycobacterial lineages and highlight single nucleotide mutations causing resistance to both 1st line and 2nd line antimicrobials. wgSNP analysis provided insights on the phylogeny of the isolates along with spoligotyping and core genomic SNVs, IS6110 insertion sites, and variable number tandem repeats (VNTR). RESULTS: The analyzed isolates carry distinct resistance determinants to isoniazid, rifampicin, ethambutol, quinolones, and streptomycin. The isolates belonged to different lineages including the Euro/American lineage (Lineage 4) (53.8%), M. bovis (15.4%) and Delhi/Central Asia (Lineage 1) (15.4%), Beijing/East Asia (Lineage 2) (7.7%), and East Africa/Indian Ocean lineage (Lineage 3) (7.7%) showing great phylogenetic differences at the genomic level. CONCLUSIONS: The population diversity in Lebanon holds an equally diverse and uncharacterized population of drug resistant mycobacteria. To achieve the WHO "END-TB" milestones of 2025 and 2035, Lebanon must decrease TB incidences by 95% in the next decade. This can only be done through WGS-based patient centered diagnosis with higher throughput and genomic resolution to improve treatment outcomes and to monitor transmission patterns.
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Variação Genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto , Técnicas de Tipagem Bacteriana , Feminino , Genótipo , Humanos , Isoniazida/uso terapêutico , Líbano/epidemiologia , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Mutação , Mycobacterium tuberculosis/classificação , Filogenia , Polimorfismo de Nucleotídeo Único , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologiaRESUMO
The present study aimed to examine the vulnerability to eating disorders (ED) among 949 Lebanese female young adults as well as its association with stress, anxiety, depression, body image dissatisfaction (BID), dysfunctional eating, body mass index, religious affiliation (Christian, Muslim, Druze or Other), religiosity and activity level. Results showed that anxiety had the greatest effect on increasing the predisposition to ED, followed by stress level, BID, depression and restrained eating. Affiliating as Christian was found to significantly decrease the vulnerability to developing an ED. Furthermore, the interaction of anxiety with intrinsic religiosity was found to have a protective role on reducing ED. The current study emphasized a buffering role of intrinsic religiosity against anxiety and ED vulnerability.
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Suscetibilidade a Doenças , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Adolescente , Adulto , Ansiedade , Cristianismo , Estudos Transversais , Feminino , Humanos , Islamismo , Líbano , Fatores de Risco , Inquéritos e Questionários , Adulto JovemRESUMO
The Lebanese American University Interprofessional Education (LAU IPE) Steps Framework consists of a five-step workshop-based series that is offered throughout the curriculum of health and social care students at an American university in Lebanon. The aim of the present study was to report students' perceptions of their readiness for interprofessional learning before and after completing the IPE steps, their evaluations of interprofessional learning outcomes, as well as their satisfaction with the learning experience as a whole. A longitudinal survey design was used: questionnaires were completed by students before IPE exposure and after each step. The results showed that before IPE exposure, students' perceptions of their readiness for interprofessional learning were generally favourable, with differences across genders (stronger professional identity in females compared to males) and across professions (higher teamwork and collaboration in pharmacy and nutrition students compared to other professions and lower patient centredness in nursing students compared to others). After participation in the IPE steps, students showed enhanced readiness for interprofessional learning and differences between genders and professions decreased. Participants were satisfied with the learning experience and assessment scores showed that all IPE learning outcomes were met. The LAU IPE Steps Framework may be of value to other interprofessional education course developers.
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Atitude do Pessoal de Saúde , Pessoal de Saúde/educação , Relações Interprofissionais , Estudantes de Ciências da Saúde/psicologia , Competência Clínica , Comportamento Cooperativo , Feminino , Humanos , Líbano , Estudos Longitudinais , Masculino , Assistência Centrada no Paciente/organização & administração , Percepção , Fatores SexuaisRESUMO
BACKGROUND: The role of inflammation in coronary artery disease (CAD) pathogenesis is well recognized. Moreover, smoking inhalation increases the activity of inflammatory mediators through an increase in leukotriene synthesis essential in atherosclerosis pathogenesis. AIM: The aim of this study is to investigate the effect of "selected" genetic variants within the leukotriene (LT) pathway and other variants on the development of CAD. METHODS: CAD was detected by cardiac catheterization. Logistic regression was performed to investigate the association of smoking and selected susceptibility variants in the LT pathway including ALOX5AP, LTA4H, LTC4S, PON1, and LTA as well as CYP1A1 on CAD risk while controlling for age, gender, BMI, family history, diabetes, hyperlipidemia, and hypertension. RESULTS: rs4769874 (ALOX5AP), rs854560 (PON1), and rs4646903 (CYP1A1 MspI polymorphism) are significantly associated with an increased risk of CAD with respective odds ratios of 1.53703, 1.67710, and 1.35520; the genetic variant rs9579646 (ALOX5AP) is significantly associated with a decreased risk of CAD (OR 0.76163). Moreover, a significant smoking-gene interaction is determined with CYP1A1 MspI polymorphism rs4646903 and is associated with a decreased risk of CAD in current smokers (OR 0.52137). CONCLUSION: This study provides further evidence that genetic variation of the LT pathway, PON1, and CYP1A1 can modulate the atherogenic processes and eventually increase the risk of CAD in our study population. Moreover, it also shows the effect of smoking-gene interaction on CAD risk, where the CYP1A1 MspI polymorphism revealed a decreased risk in current smokers.
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Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Inflamação/complicações , Inflamação/genética , Fumar/efeitos adversos , Fumar/genética , Idoso , Alelos , Arildialquilfosfatase/genética , Estudos Transversais , Citocromo P-450 CYP1A1/genética , Feminino , Variação Genética , Humanos , Leucotrienos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
A main underlying pathology of coronary artery disease is the deposition of cholesterol in the arteries supplying blood to the heart that leads to stenosis and myocardial infarction. We tested if dyslipidemia is a risk factor for coronary artery disease in the Lebanese population, and studied the role of the total cholesterol/HDL cholesterol (TC/HDL-C) ratio as a biological marker of coronary artery disease. We recruited 6,180 Lebanese patients undergoing cardiac catheterization. We conducted a cross-sectional association study between TC/HDL-C ratio and the number and type of vessels occluded in catheterized patients by controlling for confounding effects. The TC/HDL-C ratio ≥4 significantly predicts ≥50 % stenosis in all vessels individually with the odds ratio (OR) ranging from 1.22 to 1.92. The OR increased with increasing number of ≥50 % stenotic vessels (1.39 for 2 vessels and 1.64 for 3-4 vessels), as did risk due to diabetes, CAD family history, gender, and age. The younger than average age of onset subgroup shows a pronounced increase in risk for occlusion of the left main coronary artery due to TC/HDL-C ≥4 (OR 3.26). In conclusion, low levels of HDL-cholesterol and high levels TC/HDL-C ratio are strong biological markers of disease occurrence and severity in the Lebanese population.
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HDL-Colesterol/sangue , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: With the continuous spread and emergence of transmissible diseases, focusing on preventive measures is essential to decrease their incidence and spread. In addition to behavioral measures, vaccination is an optimal way to protect the population and eradicate infectious diseases. The majority are aware of children's vaccinations, while many might not know that adult vaccinations are also essential. OBJECTIVES: This study aims to understand the perception of Lebanese adults towards vaccination and their knowledge and awareness of its importance. This is a national cross-sectional study, conducted between January 2020 and January 2021. RESULTS: the data were collected from 1023 subjects, the majority being Lebanese, previously healthy, and with a graduate or post-graduate level of education. Out of these participants, 44.9% were advised to take vaccines, half of them by healthcare workers. The most common vaccine received during adult life is the Flu vaccine. Overall, 25.6% of the participants were unaware that they needed vaccines and 27.9% thought it is not indicated. Participants' knowledge about vaccination is variable. In total, 39.4% agree or are uncertain whether vaccines contain harmful chemicals and 48.4% believe that vaccines will trigger diseases. The level of education and occupation significantly enhances knowledge about vaccination. Some participants 27.3% are concerned about the vaccine's side effects. The group of young participants, graduates, and nonsmokers think that the vaccine is a necessity and had a positive attitude towards vaccination. CONCLUSIONS: Many Lebanese lack knowledge about adult vaccination protection and its benefits in the community. It is essential that the country's health ministry department collaborate with the healthcare system to launch awareness campaigns about adult vaccination in the country to overcome the barriers and ensure better coverage.
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Data comparing the occurrence of gastroesophageal cancer after gastric bypass procedures are lacking and are only available in the form of case reports. We perform in this study a systematic review and a meta-analysis of all the reported cases of gastroesophageal cancer following Roux-en-Y gastric bypass (RYGB) and loop gastric bypass-one anastomosis gastric bypass/mini gastric bypass (LGB-OAGB/MGB). We conducted a systematic review of all the reported cases in articles referenced in PubMed/Medline, Cochrane, and Scholar Google. Only cases of gastro-esophageal adenocarcinoma following RYGB or LGB-OAGB/MGB are included. Statistical analysis was done accordingly. Fifty cases were identified, along with 2 reported in this paper. Sixty-one percent (27/44) of the cancers after RYGB were in the gastric tube compared to 37.5% (3/8) after LGB-OAGB/MGB. This resulted in an odds ratio of 0.38 (p-value = 0.26), which failed to prove an increase in cancer occurrence in the gastric tube after LGB-MGB/OAGB compared to RYGB. The most common symptoms were dysphagia for cancers occurring in the gastric tube (15/30) and abdominal pain for those occurring in the excluded stomach (10/22). Twenty-nine/thirty of the cancers in the gastric tube were diagnosed by gastroscopy and 13/22 of the cancers in the excluded stomach were diagnosed by CT scan. Gastroesophageal cancers after gastric bypass procedures occur commonly in the excluded stomach where many are not identified by conventional means. Physician awareness and patient education as well as lifelong follow-up are essential for maintaining bypass surgeries on the beneficial side.
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Neoplasias Esofágicas , Derivação Gástrica , Obesidade Mórbida , Neoplasias Gástricas , Neoplasias Esofágicas/cirurgia , Derivação Gástrica/efeitos adversos , Derivação Gástrica/métodos , Humanos , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Neoplasias Gástricas/cirurgiaRESUMO
OBJECTIVE: Diabetes self-management education (DSME) is an essential component of lifestyle management needed for diabetes care. This pilot-study tested the effect of culturally-tailored education targeting diabetes selfcare on glycemia and cardiovascular risk factors of Lebanese with type 2 diabetes mellitus (T2DM) (n = 27; Age: 61 ± 10 yrs, 59% males, HbA1c: 8.98 ± 1.38%). RESULTS: Diabetes self-care (Diet, Self-Monitoring Blood Glucose and foot care) improved after 6 months, which was reflected in a significant drop in glycemic levels (HbA1c:-0.5%; FPG: - 38 mg/dl), and cholesterol/HDL ratio (4.45 ± 1.39 vs. 4.06 ± 1.29). Waist circumference decreased at 6 months compared to 3 months (p < 0.05). This is the first effective culturally-tailored intervention that improved self-care, glycemic control, body adiposity and lipid profile of Lebanese with T2DM. Larger scale implementation with representative sample is warranted.
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Diabetes Mellitus Tipo 2 , Adulto , Idoso , Glicemia , Diabetes Mellitus Tipo 2/terapia , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , AutocuidadoRESUMO
Objectives: The World Health Organization has promoted the use of serological testing as a rapid and accurate technique for the detection of immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In Lebanon, a better understanding of the immune response against SARS-CoV-2 is needed to develop effective measures for prevention and to plan an appropriate national vaccination program. This study aimed to measure the immunity status in Lebanon. Methods: In this cross-sectional study, the population comprised male and female Lebanese and non-Lebanese residents of Lebanon between the ages 15 and 75. The exclusion criteria included: same household, symptomatic individuals, and extremes of age (< 15 and > 75). Representative testing for SARS-CoV-2 antibodies (anti-SARS-CoV-2 electrochemiluminescence immunoassay/ECLIA) was used to assess the prevalence of SARS-CoV-2 infection in Lebanon. Results: In total, 13 755 participants were recruited over a 6-month period. Of these, 3168 (23.03%) individuals tested positive for anti-SARS-CoV-2, with levels of positivity varying among districts. A higher level of seropositivity was detected in the female participants. Conclusion: Seroprevalence against SARS-CoV-2 varied within Lebanon, but was comparable to the levels reported in the MENA region at the time of the study. The seroprevalence documented in this study represents a level of immunity that is not protective at the national level. Funding: This study was funded by the Lebanese American University School of Medicine.
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Because of their considerable number and diversity, membrane proteins and their macromolecular complexes represent the functional units of cells. Their quaternary structure may be stabilized by interactions between the α-helices of different proteins in the hydrophobic region of the cell membrane. Membrane proteins equally represent potential pharmacological targets par excellence for various diseases. Unfortunately, their experimental 3D structure and that of their complexes with other intramembrane protein partners are scarce due to technical difficulties. To overcome this key problem, we devised PPIMem, a computational approach for the specific prediction of higher-order structures of α-helical transmembrane proteins. The novel approach involves proper identification of the amino acid residues at the interface of molecular complexes with a 3D structure. The identified residues compose then nonlinear interaction motifs that are conveniently expressed as mathematical regular expressions. These are efficiently implemented for motif search in amino acid sequence databases, and for the accurate prediction of intramembrane protein-protein complexes. Our template interface-based approach predicted 21,544 binary complexes between 1,504 eukaryotic plasma membrane proteins across 39 species. We compare our predictions to experimental datasets of protein-protein interactions as a first validation method. The online database that results from the PPIMem algorithm with the annotated predicted interactions are implemented as a web server and can be accessed directly at https://transint.univ-evry.fr.
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BACKGROUND: Coronary Artery Disease (CAD) is the narrowing or blockage of the coronary arteries. It is closely associated with numerous genetics and environmental factors that have been extensively evaluated in various populations. In recent studies, severe phenotypes have been strongly linked to genetic risk factors. METHODS: This study investigated the association of clinical, demographic, and genetic factors with severe coronary artery stenosis phenotypes in our population composed of 1734 individuals with severe coronary stenosis (≥ 50% in coronary vessels) and comparing them to 757 controls with no evidence of stenosis on angiography. We performed generalized linear model (GLM) genome-wide association studies to evaluate three stratification models and their associations to characteristics of the clinical disease. In model 1, patients were not stratified. In model 2, patients were stratified based on presence or absence of CAD family history (FxCAD). In model 3, patients were stratified by young age of CAD onset. RESULTS: Eight SNPs (single nucleotide polymorphism) were significantly associated with severe CAD phenotypes in the various models [Formula: see text], four of these SNPs were associated with severe CAD and the four others were specifically significant for young CAD patients. While these SNPs were not previously reported for association with CAD, six of them are present in genes that have already been linked to coronary disease. CONCLUSION: In conclusion, this study presents new genetic factors associated with severe stenosis and highlights different risk factors associated with a young age at diagnosis of CAD.
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Alelos , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Adulto , Doença da Artéria Coronariana , Estenose Coronária , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: CYP3A5 and ABCB1 are highly implicated in the pharmacokinetics and pharmacodynamics of immunosuppressive agents, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. The polymorphisms of their coding genes play important roles in the interindividual and intraindividual differences of bioavailability of these drugs. In this study, our objective was to investigate, in a Lebanese population,the frequency of ABCB1C3435T (rs1045642) and CYP3A5*3 (rs776746) polymorphisms and to compare the results to preexisting data from other populations. MATERIALS AND METHODS: We determined the frequencies of the allelic variants of interest for 1824 Lebanese participants, and we compared these results with those from other major ethnic groups. RESULTS: The allelic frequencies were 91.4% (C) and 8.6% (T) for CYP3A5*3 and 50.8% (T) and 49.2% (C) for ABCB1 C3435T. Our results were significantly different from most other world populations, except the European population. CONCLUSIONS: The frequencies of gene variants of interest in our Lebanese population were similar to those found in European populations. Most of our study population were CYP3A5*3 carriers, and more than half may have a lower P-glycoprotein efflux pump. These characteristics might render Lebanese transplant recipients more prone to the development of drug toxicity and in need of lower drug doses.
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Subfamília B de Transportador de Cassetes de Ligação de ATP , Citocromo P-450 CYP3A , Polimorfismo Genético , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Citocromo P-450 CYP3A/genética , Genética Populacional , Humanos , Líbano , TransplantadosRESUMO
BACKGROUND: Candida bloodstream infection (BSI) remains one of the leading causes of BSI in critically ill and immunosuppressed cancer patients. In light of the changing epidemiology and rising resistant species, duration of treatment and appropriate timing of stepdown therapy from intravenous (IV) to oral antifungal agents are crucial for utmost disease control and overall survival. METHOD: We performed a multicenter retrospective study, with 119 non-neutropenic patients enrolled from four different medical institutions in Brazil, Lebanon, Spain and the United States, to assess the duration of IV therapy and appropriate time to step-down to oral therapy in adult patients, 14 years of age and older, with documented candidemia. The analysis was done using the statistical program R and SAS v9.4. Descriptive statistics are presented as frequencies and tables and the Fisher exact test was used to test the association between the categorical variables: organism, cancer, country, antifungal drug and duration of therapy, and time of step-down. RESULTS: Candida albicans contributed to 45% of bloodstream infection versus 55% of infection caused by Candida non-albicans. The three most common Candida non-albicans are: Candida glabrata 24%, Candida parapsilosis 13% and Candida tropicalis 8%. Most (57%) of the patients were admitted to ICU, whereas 52% had underlying malignancy. Multivariate analysis showed that a stay at ICU or an underlying cancer requiring chemotherapy were independently associated with failure and death (p <0.001). The average total duration of therapy was 14 days in all patients and 16 days in those who responded and survived. Forty-five patients were stepped down to either fluconazole and/or voriconazole in association with clinical and microbiologic resolution of the candidemia. The average (and median) day of step-down was 5 days. Patients who had a stepdown had more favorable outcomes (78% survival) as compared to those with no stepdown (56% survival) (P = 0.022). However, the 20 patients who received 1-4 days of first IV treatment before a stepdown to oral azoles had a comparable outcome (20% mortality) to the 25 patients who received >5 days of treatment (24% mortality - p = 0.75). CONCLUSION: Our data support the IDSA guidelines in that the total duration of treatment for candidemia should be at least 14 days after a negative blood culture. However, in non-neutropenic cancer patients with candidemia, a step-down to oral azole therapy can safely take place early (within 4 days of initiating IV therapy) as long as the patient had clinical and microbiologic resolution of the bloodstream infections.
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Aortic valve stenosis (AVS) is a prevalent condition among the elderly population that eventually requires aortic valve replacement. The lack of reliable biomarkers for AVS poses a challenge for its early diagnosis and the application of preventive measures. Untargeted gas chromatography mass spectrometry (GC-MS) metabolomics was applied in 46 AVS cases and 46 controls to identify plasma and urine metabolites underlying AVS risk. Multivariate data analyses were performed on pre-processed data (e.g. spectral peak alignment), in order to detect changes in metabolite levels in AVS patients and to evaluate their performance in group separation and sensitivity of AVS prediction, followed by regression analyses to test for their association with AVS. Through untargeted analysis of 190 urine and 130 plasma features that could be detected and quantified in the GC-MS spectra, we identified contrasting levels of 22 urine and 21 plasma features between AVS patients and control subjects. Following metabolite assignment, we observed significant changes in the concentration of known metabolites in urine (n = 14) and plasma (n = 15) that distinguish the metabolomic profiles of AVS patients from healthy controls. Associations with AVS were replicated in both plasma and urine for about half of these metabolites. Among these, 2-Oxovaleric acid, elaidic acid, myristic acid, palmitic acid, estrone, myo-inositol showed contrasting trends of regulation in the two biofluids. Only trans-Aconitic acid and 2,4-Di-tert-butylphenol showed consistent patterns of regulation in both plasma and urine. These results illustrate the power of metabolomics in identifying potential disease-associated biomarkers and provide a foundation for further studies towards early diagnostic applications in severe heart conditions that may prevent surgery in the elderly.
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Estenose da Valva Aórtica/metabolismo , Valva Aórtica/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Plasma/metabolismo , Urina/química , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/urina , Estudos de Casos e Controles , Ecocardiografia/métodos , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Próteses Valvulares Cardíacas , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Urinálise/métodosRESUMO
BACKGROUND: Medication overuse headache (MOH) is a chronic pain syndrome that arises from the frequent use of acute antimigraine drugs. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique with a possible therapeutic effect in this particular context. METHODS: This was a randomized, sham-controlled, cross-over study. Eighteen patients with MOH (17 women, age range: 20-38 years) received three sets of three consecutive daily sessions of tDCS: anodal tDCS over the prefrontal cortex, cathodal tDCS over the occipital cortex ipsilateral to the dominant side of migraine pain, and sham. The order in which the tDCS blocks were delivered was randomly defined based on a 1:1:1 ratio. Patients filled in a migraine diary that allowed recording of the pain intensity (visual analogue scale) and the daily consumption of analgesic pills from one week before to two weeks after each condition. RESULTS: Both prefrontal and occipital tDCS lowered the total number of migraine days and the number of severe migraine days per week at week 1, but only the effects of occipital tDCS on these two outcomes lasted until week 2. Only occipital tDCS decreased the daily analgesic pills consumption, at weeks 1 and 2. CONCLUSION: Three consecutive days of cathodal occipital tDCS appear to improve the clinical outcomes in patients with MOH.
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[This corrects the article DOI: 10.1371/journal.pone.0218443.].