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OBJECTIVE: This study aimed to explore whether phenotypic characteristics of patients with chronic widespread pain (CWP) and fibromyalgia (FM) can be aggregated into definable clusters that may help to tailor treatments. METHOD: Baseline variables (sex, age, education, marital/employment status, pain duration, prior CWP/FM diagnosis, concomitant rheumatic disease, analgesics, tender point count, and disease variables derived from standardized questionnaires) collected from 1099 patients (93.4% females, mean age 44.6 years) with a confirmed CWP or FM diagnosis were evaluated by hierarchical cluster analysis. The number of clusters was based on coefficients in the agglomeration schedule, supported by dendrograms and silhouette plots. Simple and multiple regression analyses using all variables as independent predictors were used to assess the likelihood of cluster assignment, reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Only one cluster emerged (Cluster 1: 455 patients). Participants in this cluster were characterized as working (OR 66.67, 95% CI 7.14 to 500.00), with a medium-term/higher education (OR 16.80, 95% CI 1.94 to 145.41), married/cohabiting (OR 14.29, 95% CI 1.26 to 166.67), and using mild analgesics (OR 25.64, 95% CI 0.58 to > 999.99). The odds of being an individual in Cluster 1 were lower when having a worse score on the PDQ (score ≥ 18) (OR < 0.001, 95% CI < 0.001 to 0.02). CONCLUSION: We identified one cluster, where participants were characterized by a potentially favourable clinical profile. More studies are needed to evaluate whether these characteristics could be used to guide the management of patients with CWP and FM.
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OBJECTIVE: The Brief Illness Perception Questionnaire (B-IPQ) is a frequently used measure of illness perception (IP). The aim of this study was to explore the psychometric properties of the questionnaire when used in elderly people with knee pain. METHOD: Based on data from the Frederiksberg Cohort on elderly people reporting knee pain (N = 836), the psychometric properties of the eight B-IPQ items (1 'Consequences', 2 'Timeline', 3 'Personal control', 4 'Treatment control', 5 'Identity', 6 'Concern', 7 'Coherence', and 8 'Emotions') were analysed using Rasch analysis to establish whether the questionnaire provides reliable and valid measures of IP. RESULTS: Threshold disordering was found on the 1-10 rating scale in all items. When rescaling to a 0-2 rating scale, disordering was resolved in six items. Item goodness-of-fit analyses revealed that two items displayed underfit misfit and four items overfit misfit; hence, the B-IPQ does not present unidimensionality. The person separation index indicated that items separate respondents into only two IP levels. Finally, floor and ceiling effects were found, indicating that the B-IPQ may not fully describe the extent of IP in this population. CONCLUSION: The 1-10 rating scale used in the Danish B-IPQ targeting knee pain is suboptimal, while a 0-2 scale improves the psychometric properties of the scale. The B-IPQ does not present unidimensionality and the use of a sum score is therefore not recommended when assessing IP. The B-IPQ may not cover the extent of IP in elderly people with knee pain.
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Articulação do Joelho , Percepção , Humanos , Idoso , Inquéritos e Questionários , Psicometria , Reprodutibilidade dos TestesRESUMO
PURPOSE: Small bowel obstruction (SBO) is a common surgical emergency. Previous studies have shown the value computed tomography (CT) scanning in both confirming this diagnosis and identifying indications for urgent surgical intervention, such as strangulated bowel or closed loop obstructions. However, most of the literature is based on retrospective expert review of previous imaging and little data regarding the real-time accuracy of CT reporting is available. Here, we investigated the real-world accuracy of CT reporting in patients admitted with SBO. METHODS: This was a multicentre prospective study including consecutive patients admitted with SBO. The primary outcomes were the sensitivity and specificity of CT scanning for bowel obstruction with ischaemia and closed loop obstruction. Data were retrieved from the original CT reports written by on-call radiologists and compared with operative findings. RESULTS: One hundred seventy-six patients were included, all of whom underwent CT scanning with intravenous contrast followed by operative management of SBO. Bowel obstruction with ischaemia was noted in 20 patients, with a sensitivity and specificity of CT scanning of 40.0% and 85.5%, respectively. Closed loop obstructions were noted in 26 patients, with a sensitivity and specificity of CT scanning of 23.1% and 98.0%, respectively. CONCLUSIONS: The real-world accuracy of CT scanning appears to be lower than previously reported in the literature. Strategies to address this could include the development of standardised reporting schemas and to increase the surgeon's own familiarity with relevant CT features in patients admitted with SBO.
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Obstrução Intestinal , Tomografia Computadorizada por Raios X , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , HospitalizaçãoRESUMO
AIMS: The optimal management of small bowel obstruction (SBO) remains a matter of debate and treatment varies internationally. In Denmark, a more surgically aggressive strategy has traditionally been used, but to what extent patient outcomes differ from international reports is unknown. This study aimed to describe the current management and outcomes of patients admitted with SBO in Denmark. METHODS: This was a prospective cohort study conducted at six acute hospitals in Denmark over a 4-month period. Patients aged ≥ 18 years with a clinical or radiological diagnosis of SBO were eligible. Primary outcomes were 30 day morbidity and mortality rates. RESULTS: 316 patients were included during the study period. The median age was 72 years and 56% were female. Diagnosis was made by computed tomography (CT) in 313 patients (99.1%), with the remaining three diagnosed clinically. Non-operative management was the initial strategy in 152 patients (48.1%) and successful in 119 (78.3%). Urgent surgery was performed in the remaining 164 (51.9%), with a laparoscopic approach used in 84 patients (51.2%). The entire cohort had a 30 day mortality rate of 7.3% and a 30 day morbidity rate of 17.1%. CONCLUSIONS: The management of SBO in Denmark differs markedly to previous international reports, with an almost ubiquitous use of CT for diagnosis and a high proportion of patients undergoing urgent surgery. Despite higher rates of surgery, patient outcomes are broadly similar to reports of more conservative strategies, perhaps due to a reduction in delayed operations. TRIAL REGISTRATION: Trial registration number: NCT04750811. Trial registration date: 11/02/2021.
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Obstrução Intestinal , Humanos , Feminino , Idoso , Masculino , Estudos Prospectivos , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Morbidade , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/cirurgia , Dinamarca/epidemiologiaRESUMO
BACKGROUND: Cornelia de Lange syndrsome (CdLS) is a rare genetic syndrome with notable impaired expressive communication characterised by reduced spoken language. We examined gesture use to refine the description of expressive communication impairments in CdLS. METHODS: During conversations, we compared gesture use in people with CdLS to peers with Down syndrome (DS) matched for receptive language and adaptive ability, and typically developing (TD) individuals of similar chronological age. RESULTS: As anticipated the DS and CdLS groups used fewer words during conversation than TD peers (P < .001). However, the CdLS group used twice the number of gestures per 100 words compared with the DS and TD groups (P = .003). CONCLUSIONS: Individuals with CdLS have a significantly higher gesture rate than expected given their level of intellectual disability and chronological age. This result indicates the cause of reduced use of spoken language does not extend to all forms of expressive communication.
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Síndrome de Cornélia de Lange , Síndrome de Down , Deficiência Intelectual , Síndrome de Cornélia de Lange/genética , Gestos , Humanos , FalaRESUMO
Rapid advances in the development of sequencing technologies, numbers of commercial providers and diminishing costs have made DNA-based identification and diagnostics increasingly accessible to doctors and laboratories, eliminating the need for local investments in expensive technology and training or hiring of skilled technicians. However, reliable and comparable molecular analyses of bacteria in stool samples are dependent on storage and workflow conditions that do not introduce post-sampling bias, the most important factor being the need to keep the DNA at a stable detectable level. For that reason, there may remain other prohibitively costly requirements for cooling or freezing equipment or special chemical additives. This study investigates the diagnostic detectability of Salmonella and Campylobacter DNA in human, pig and chicken stool samples, stored at different temperatures and with different preservation methods. Stool samples were spiked with 106 CFU/mL of both Salmonella and Campylobacter strains stored at -20 °C, 5 °C and 20 °C (Room temperature, RT) and treated with either RNAlater, EDTA or Silica/ethanol. DNA was extracted at 9 different time points within 30 days and quantified by Qubit (total DNA) and qPCR (Salmonella and Campylobacter DNA). We found no statistically significant differences among the different preservation methods, and DNA from both species was easily detected at all time points and at all temperatures, both with and without preservation. This suggests that infections by these bacteria can be diagnosed and possibly also analysed in further detail simply by taking a stool sample in any suitable sealed container that can be transported to laboratory analysis without special storage or preservation requirements. We briefly discuss how this finding can benefit infection control in both developed and developing countries.
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Levodopa-entacapone-carbidopa intestinal gel (LECIG) provides continuous drug delivery through intrajejunal infusion. The aim of this study was to characterize the population pharmacokinetics of levodopa following LECIG and levodopa-carbidopa intestinal gel (LCIG) infusion to investigate suitable translation of dose from LCIG to LECIG treatment, and the impact of common variations in the dopa-decarboxylase (DDC) and catechol-O-methyltransferase (COMT) genes on levodopa pharmacokinetics. A non-linear mixed-effects model of levodopa pharmacokinetics was developed using plasma concentration data from a double-blind, cross-over study of LCIG compared with LECIG in patients with advanced Parkinson's disease (n = 11). All patients were genotyped for rs4680 (polymorphism of the COMT gene), rs921451 and rs3837091 (polymorphisms of the DDC gene). The final model was a one compartment model with a high fixed absorption rate constant, and a first order elimination, with estimated apparent clearances (CL/F), of 27.9 L/h/70 kg for LCIG versus 17.5 L/h/70 kg for LECIG, and apparent volume of distribution of 74.4 L/70 kg. Our results thus suggest that the continuous maintenance dose of LECIG, on a population level, should be decreased by approximately 35%, to achieve similar drug exposure as with LCIG. An effect from entacapone was identified on all individuals, regardless of COMT rs4680 genotype. The individuals with higher DDC and COMT enzyme activity showed tendencies towards higher levodopa CL/F. The simultaneous administration of entacapone to LCIG administration results in a 36.5% lower apparent levodopa clearance, and there is a need for lower continuous maintenance doses, regardless of patients' COMT genotype.
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Carbidopa/administração & dosagem , Carbidopa/farmacocinética , Catecóis , Sistemas de Liberação de Medicamentos , Levodopa/administração & dosagem , Levodopa/farmacocinética , Nitrilas , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Polimorfismo Genético , Catecol O-Metiltransferase/genética , Estudos Cross-Over , Dopa Descarboxilase/genética , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Géis , Genótipo , Humanos , Masculino , Modelos BiológicosRESUMO
Aquatic macrophytes grow abundantly in many lowland streams and play a key role in ecosystem functioning, such as nutrient retention. In this study, we performed a microcosm experiment to quantify and compare the contribution of two freshwater macrophyte growth forms to nutrient cycling. We measured and compared inorganic nitrogen (NH4-N and NO3-N) and phosphorus (PO4-P) uptake kinetic parameters (Vmax and Cmin) in 12 submerged and seven amphibious plant species. We tested whether relative growth rate (RGR) was related to high Vmax and low Cmin, and quantified changes in nutrient uptake kinetic in a subset of six out of 19 plants species during the growth season. Uptake rates of NH4-N were higher in submerged compared to amphibious plants, whereas uptake rates of NO3-N were significantly higher in amphibious species; PO4-P uptake kinetics were not significantly different between the two growth forms. There were also significant seasonal differences in Vmax NH4-N rate among both submerged and amphibious species and in Vmax NO3-N among amphibious species. Highest uptake rates were observed in summer for both submerged and amphibious species. Overall, we found that nutrient uptake kinetics differed between the two growth forms within and between seasons. Consequently, the presence of both growth forms should extend the period of nutrient uptake across the year and enhance nutrient uptake within seasons. We conclude that higher functional diversity enhances annual nutrient uptake in streams and that stream restoration efforts should consider increasing the niche space available for both submerged and amphibious species.
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Ecossistema , Fósforo , Nitrogênio , Nutrientes , RiosRESUMO
OBJECTIVES: This study aimed to explore the interactions of polymyxin B in combination with 13 other antibiotics against carbapenemase-producing Klebsiella pneumoniae. METHODS: Five clinical isolates of multidrug-resistant K. pneumoniae producing KPC-2, KPC-3, NDM-1, OXA-48 and VIM-1 carbapenemases were used. Polymyxin B was tested alone and in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampicin, temocillin, thiamphenicol and trimethoprim. Inhibition of growth during antibiotic exposure was evaluated in 24-hr automated time-lapse microscopy experiments. Combinations that showed positive interactions were subsequently evaluated in static time-kill experiments. RESULTS: All strains carried multiple (≥9) resistance genes as determined by whole-genome sequencing. In the initial screening the combination of polymyxin B and minocycline was most active with enhanced activity compared with the single antibiotics detected against all strains. Positive interactions were also observed with polymyxin B in combination with rifampicin and fosfomycin against four of five strains and less frequently with other antibiotics. Time-kill experiments demonstrated an additive or synergistic activity (1-2 log10 or ≥2 log10 CFU/mL reduction, respectively, compared with the most potent single antibiotic) with 21 of 23 tested combinations. However, because of regrowth, only 13 combinations were synergistic at 24 hr. Combinations with minocycline or rifampicin were most active, each showing synergy and bacteriostatic or bactericidal effects resulting in 1.93-3.97 and 2.55-5.91 log10 CFU/mL reductions, respectively, after 24 hr against four strains. DISCUSSION: Polymyxin B in combination with minocycline, rifampicin or fosfomycin could be of potential clinical interest. Time-lapse microscopy showed some discrepancy in results compared with the time-kill data but was useful for screening purposes.
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Proteínas de Bactérias/metabolismo , Klebsiella pneumoniae/efeitos dos fármacos , Microscopia/métodos , Polimixina B/administração & dosagem , Polimixina B/uso terapêutico , Imagem com Lapso de Tempo/métodos , beta-Lactamases/metabolismo , Técnicas Bacteriológicas , Quimioterapia Combinada , Humanos , Klebsiella pneumoniae/enzimologia , Fatores de TempoRESUMO
BACKGROUND: Sepsis is a dysregulated host response to infection. The aim of this study was to investigate the effects of complement- and CD14 inhibition on phagocytosis of live and dead Gram-negative and Gram-positive bacteria in human whole blood. METHODS: Lepirudin-anticoagulated blood was incubated with live or dead E. coli or S. aureus at 37 °C for 120 min with or without the C5aR1 antagonist PMX53 and/or anti-CD14. Granulocyte and monocyte phagocytosis were measured by flow cytometry, and five plasma cytokines by multiplex, yielding a total of 28 mediators of inflammation tested for. RESULTS: 16/28 conditions were reduced by PMX53, 7/28 by anti-CD14, and 24/28 by combined PMX53 and CD14 inhibition. The effect of complement inhibition was quantitatively more pronounced, in particular for the responses to S. aureus. The effect of anti-CD14 was modest, except for a marked reduction in INF-ß. The responses to live and dead S. aureus were equally inhibited, whereas the responses to live E. coli were inhibited less than those to dead E. coli. CONCLUSION: C5aR1 inhibited phagocytosis-induced inflammation by live and dead E. coli and S. aureus. CD14 blockade potentiated the effect of C5aR1 blockade, thus attenuating inflammation.
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Escherichia coli/imunologia , Receptores de Lipopolissacarídeos/antagonistas & inibidores , Fagocitose/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Citocinas/imunologia , Infecções por Escherichia coli/imunologia , Granulócitos/imunologia , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Interferon beta/imunologia , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Monócitos/microbiologia , Peptídeos Cíclicos/imunologia , Receptor da Anafilatoxina C5a/imunologia , Sepse/imunologia , Sepse/microbiologiaRESUMO
Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC0-24), clearance (CL), and central volume of distribution (V1) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC0-24 (r = 0.03; P = 0.84), CL (r = -0.07; P = 0.68), or V1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = -0.46; P = 0.004). Hypoalbuminemia correlated with low AUC0-24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = -0.31; P = 0.062) and somewhat higher V1 (r = -0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = -0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of ≥0.064 µg/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.
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Bilirrubina/metabolismo , Caspofungina/farmacologia , Hipoalbuminemia/metabolismo , Albumina Sérica/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Coronary artery disease and heart failure are both highly prevalent diseases with a global prevalence of 93 million and 40 million. These patients are at increased risk of morbidity and mortality. The management of these patients involves medical therapy, and both diseases can be treated using the heart rate-lowering drug ivabradine. However, the evidence regarding the use of ivabradine in the treatment of coronary artery disease and/or heart failure is unclear. Our objective is to assess the beneficial and harmful effects of ivabradine in the treatment of coronary artery disease and/or heart failure. METHODS: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P), and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ivabradine in the treatment of coronary artery disease and/or heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS in order to identify relevant trials. We will begin the searches in February 2019. All included trials will be assessed and classified at low risk of bias or at high risk of bias. Our primary conclusions will be based on the results from the primary outcomes at low risk of bias. Extracted data will be analysed using Review Manager 5.3 and Trial Sequential Analysis 0.9.5.10. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). DISCUSSION: The systematic review will have the potential to aid clinicians in decision-making regarding ivabradine and to benefit patients with coronary artery disease and/or heart failure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018112082.
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Doença da Artéria Coronariana/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Metanálise como Assunto , Revisões Sistemáticas como Assunto , Humanos , Ivabradina , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de PesquisaAssuntos
Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Adulto , Anticorpos Bloqueadores/metabolismo , Teorema de Bayes , Cálculos da Dosagem de Medicamento , Fator VIII/imunologia , Humanos , Isoanticorpos/metabolismo , Adesão à Medicação , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Medicina de PrecisãoRESUMO
The development of Genotyping-By-Sequencing (GBS) technologies enables cost-effective analysis of large numbers of Single Nucleotide Polymorphisms (SNPs), especially in "non-model" species. Nevertheless, as such technologies enter a mature phase, biases and errors inherent to GBS are becoming evident. Here, we evaluated the performance of double digest Restriction enzyme Associated DNA (ddRAD) sequencing in SNP genotyping studies including high number of samples. Datasets of sequence data were generated from three marine teleost species (>5500 samples, >2.5â¯×â¯1012 bases in total), using a standardized protocol. A common bioinformatics pipeline based on STACKS was established, with and without the use of a reference genome. We performed analyses throughout the production and analysis of ddRAD data in order to explore (i) the loss of information due to heterogeneous raw read number across samples; (ii) the discrepancy between expected and observed tag length and coverage; (iii) the performances of reference based vs. de novo approaches; (iv) the sources of potential genotyping errors of the library preparation/bioinformatics protocol, by comparing technical replicates. Our results showed use of a reference genome and a posteriori genotype correction improved genotyping precision. Individual read coverage was a key variable for reproducibility; variance in sequencing depth between loci in the same individual was also identified as an important factor and found to correlate to tag length. A comparison of downstream analysis carried out with ddRAD vs single SNP allele specific assay genotypes provided information about the levels of genotyping imprecision that can have a significant impact on allele frequency estimations and population assignment. The results and insights presented here will help to select and improve approaches to the analysis of large datasets based on RAD-like methodologies.
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Biologia Computacional/métodos , Peixes/genética , Genoma , Técnicas de Genotipagem/métodos , Análise de Sequência de DNA/métodos , Animais , Bass/genética , Linguados/genética , Reprodutibilidade dos Testes , Dourada/genéticaRESUMO
PURPOSE: Traditional teaching for fixation of paediatric femur fractures recommends 80% nail diameter/medullary canal diameter ratio (ND/MCD) for successful maintenance of reduction. Prior studies have investigated this with stainless steel Enders nails. Our aim was to assess the impact of ND/MCD on maintenance of reduction and malunion rates in paediatric femur fractures treated with flexible intramedullary nails (FINs). METHODS: Retrospective data was collected on all paediatric patients treated with FINs for diaphyseal femur fractures at a single tertiary care institution over a ten-year period. Patients with co-morbidities affecting bone quality were excluded. Patients were subdivided into groups based on ND/MCD. RESULTS: A total of 66 patients met inclusion criteria. Mean ND/MCD was 76.3% (32.9% to 98.8%, SD 14.3). In all, 50% (n = 33/66) of patients had > 80% ND/MCD, and only 13.6% (n = 9/66) of patients had less than 60% ND/MCD. When controlling for fracture stability, ND/MCD had no correlation with mean shortening (p = 0.07) There was no correlation between ND/MCD and angulation in the sagittal (p = 0.96) or coronal plane (p = 0.20). Three patients fit malunion criteria. ND/MCD for these patients were 40%, 67% and 79%. CONCLUSION: There was no correlation between ND/MCD and shortening or malangulation. The majority of patients in this series with less than 80% fill with FIN healed within acceptable parameters. LEVEL OF EVIDENCE: III.
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Essentials Complement, Toll-like receptors and coagulation cross-talk in the process of thromboinflammation. This is explored in a unique human whole-blood model of S. aureus bacteremia. Coagulation is here shown as a downstream event of C5a-induced tissue factor (TF) production. Combined inhibition of C5 and CD14 efficiently attenuated TF and coagulation. SUMMARY: Background There is extensive cross-talk between the complement system, the Toll-like receptors (TLRs), and hemostasis. Consumptive coagulopathy is a hallmark of sepsis, and is often mediated through increased tissue factor (TF) expression. Objectives To study the relative roles of complement, TLRs and TF in Staphylococcus aureus-induced coagulation. Methods Lepirudin-anticoagulated human whole blood was incubated with the three S. aureus strains Cowan, Wood, and Newman. C3 was inhibited with compstatin, C5 with eculizumab, C5a receptor 1 (C5aR1) and activated factor XII with peptide inhibitors, CD14, TLR2 and TF with neutralizing antibodies, and TLR4 with eritoran. Complement activation was measured by ELISA. Coagulation was measured according to prothrombin fragment 1 + 2 (PTF1 + 2 ) determined with ELISA, and TF mRNA, monocyte surface expression and functional activity were measured with quantitative PCR, flow cytometry, and ELISA, respectively. Results All three strains generated substantial and statistically significant amounts of C5a, terminal complement complex, PTF1 + 2 , and TF mRNA, and showed substantial TF surface expression on monocytes and TF functional activity. Inhibition of C5 cleavage most efficiently and significantly inhibited all six markers in strains Cowan and Wood, and five markers in Newman. The effect of complement inhibition was shown to be completely dependent on C5aR1. The C5 blocking effect was equally potentiated when combined with blocking of CD14 or TLR2, but not TLR4. TF blocking significantly reduced PTF1 + 2 levels to baseline levels. Conclusions S. aureus-induced coagulation in human whole blood was mainly attributable to C5a-induced mRNA upregulation, monocyte TF expression, and plasma TF activity, thus underscoring complement as a key player in S. aureus-induced coagulation.
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Bacteriemia/microbiologia , Coagulação Sanguínea , Ativação do Complemento , Complemento C5a/metabolismo , Monócitos/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Tromboplastina/metabolismo , Anticorpos Neutralizantes/farmacologia , Bacteriemia/sangue , Bacteriemia/genética , Bacteriemia/imunologia , Carga Bacteriana , Coagulação Sanguínea/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Complemento C5a/antagonistas & inibidores , Complemento C5a/genética , Complemento C5a/imunologia , Inativadores do Complemento/farmacologia , Interações Hospedeiro-Patógeno , Humanos , Receptores de Lipopolissacarídeos/antagonistas & inibidores , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Viabilidade Microbiana , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/sangue , Receptor da Anafilatoxina C5a/imunologia , Transdução de Sinais , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Tromboplastina/genética , Fatores de Tempo , Receptor 2 Toll-Like/antagonistas & inibidores , Receptor 2 Toll-Like/sangue , Receptor 2 Toll-Like/imunologiaRESUMO
OBJECTIVES: Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) may be misdiagnosed as multiple sclerosis. The aim of this study was to (i) to measure AQP4-IgG in patients who fulfilled the clinical and radiological criteria of NMOSD in the Central Denmark Region and (ii) to estimate the incidence of NMOSD in the region, according to both the 2006 Wingerchuk criteria and the 2015 International Panel for NMO Diagnosis criteria. MATERIALS AND METHODS: Medical records of all patients diagnosed with a demyelinating disorder in the region from 1 January 2012 to 31 December 2013 were reviewed. Patients were classified as having (i) "NMO" if the 2006 criteria were met, (ii) "NMOSD with AQP4-IgG" or (iii) "NMOSD without/unknown AQP-IgG" if the new 2015 NMOSD criteria were met. Patients with core symptoms were invited to provide a blood sample for AQP4-IgG analysis with an enzyme-linked immunosorbent assay and a cell-based indirect immunofluorescence assay. RESULTS: In 191 patients with core symptoms, one met the 2015 NMOSD with AQP4-IgG criteria. Two patients met the 2006 NMO and 2015 NMOSD without/unknown AQP4-IgG criteria. Among 108 patients providing a blood sample, all were seronegative. The estimated incidence of NMO (2006 criteria) and NMOSD (2015 criteria) was 0.08 and 0.12 per 100 000 person-years, respectively. CONCLUSION: NMO/NMOSD is a rare disease in the Central Denmark Region, with a considerably lower incidence rate than previously estimated in a neighbouring region.
Assuntos
Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/epidemiologia , Adulto , Aquaporina 4/sangue , Autoanticorpos/sangue , Dinamarca/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/epidemiologia , Neuromielite Óptica/sangueRESUMO
BACKGROUND: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. AIMS: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. SOURCES: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. CONTENT: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens. IMPLICATIONS: Semi-mechanistic PKPD models allow for integration of knowledge on the interaction between antibiotics for various PK and PD profiles, and can account for associated variability within the population as well as parameter uncertainty. Decisions on suitable combination regimens can thereby be facilitated. We find the application of semi-mechanistic PKPD models to be essential for efficient development of antibiotic combination regimens that optimize bacterial killing and/or suppress resistance development.