RESUMO
Objectives: Many studies have attempted to determine the disease severity and patterns of COVID-19. However, at the beginning of the pandemic, the complex patients' trajectories were only descriptively reported, and many analyses were worryingly prone to time-dependent-, selection-, and competing risk biases. Multi-state models avoid these biases by jointly analysing multiple clinical outcomes while taking into account their time dependency, including current cases, and modelling competing events. This paper uses a publicly available data set from the first wave in Israel as an example to demonstrate the benefits of analysing hospital data via multi-state methodology. Methods: We compared the outcome of the data analysis using multi-state models with the outcome obtained when various forms of bias are ignored. Furthermore, we used Cox regression to model the transitions among the states in a multi-state model. This allowed for the comparison of the covariates' influence on transition rates between the two states. Lastly, we calculated expected lengths of stay and state probabilities based on the multi-state model and visualised it using stacked probability plots. Results: Compared to standard methods, multi-state models avoid many biases in the analysis of real-time disease developments. The utility of multi-state models is further highlighted through the use of stacked probability plots, which visualise the results. In addition, by stratification of disease patterns by subgroups and visualisation of the distribution of possible outcomes, these models bring the data into an interpretable form. Conclusion: To accurately guide the provision of medical resources, this paper recommends the real-time collection of hospital data and its analysis using multi-state models, as this method eliminates many potential biases. By applying multi-state models to real-time data, the gained knowledge allows rapid detection of altered disease courses when new variants arise, which is essential when informing medical and political decision-makers as well as the general population.
RESUMO
BACKGROUND: Biomarkers simplifying the diagnostic workup by discriminating between non-ST-segment-elevation myocardial infarction (NSTEMI) and infarct-like myocarditis are an unmet clinical need. METHODS AND RESULTS: A total of 105 subjects were categorized into groups as follows: ST-segment-elevation myocardial infarction (n=36), NSTEMI (n=22), infarct-like myocarditis (n=19), cardiomyopathy-like myocarditis (n=18), and healthy control (n=10). All subjects underwent cardiac magnetic resonance imaging, and serum concentrations of matrix metalloproteinase-1 (MMP-1) and procollagen type I carboxy terminal propeptide (PICP) were measured. Biomarker concentrations in subjects presenting with acute coronary syndrome and non-ST-segment-elevation, for example NSTEMI or infarct-like myocarditis, categorized as the non-ST-segment-elevation acute coronary syndrome-like cohort, were of particular interest for this study. Compared with healthy controls, subjects with myocarditis had higher serum concentrations of MMP-1 and PICP, while no difference was observed in individuals with myocardial infarction. In the non-ST-segment-elevation acute coronary syndrome-like cohort, MMP-1 concentrations discriminated infarct-like myocarditis and NSTEMI with an area under the receiver operating characteristic curve (AUC) of 0.95 (95% CI, 0.89-1.00), whereas high-sensitivity cardiac troponin T performed inferiorly (AUC, 0.74 [95% CI, 0.58-0.90]; P=0.012). Application of an optimal MMP-1 cutoff had 94.4% sensitivity (95% CI, 72.7%-99.9%) and 90.9% specificity (95% CI, 70.8%-98.9%) for the diagnosis of infarct-like myocarditis in this cohort. The AUC of PICP in this context was 0.82 (95% CI, 0.68-0.97). As assessed by likelihood ratio tests, incorporating MMP-1 or PICP with age and C-reactive protein into composite prediction models enhanced their diagnostic performance. CONCLUSIONS: MMP-1 and PICP could potentially be useful biomarkers for differentiating between NSTEMI and infarct-like myocarditis in individuals with non-ST-segment-elevation acute coronary syndrome-like presentation, though further research is needed to validate their clinical applicability.
Assuntos
Biomarcadores , Metaloproteinase 1 da Matriz , Miocardite , Infarto do Miocárdio sem Supradesnível do Segmento ST , Fragmentos de Peptídeos , Pró-Colágeno , Humanos , Masculino , Feminino , Biomarcadores/sangue , Pessoa de Meia-Idade , Metaloproteinase 1 da Matriz/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/sangue , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Pró-Colágeno/sangue , Fragmentos de Peptídeos/sangue , Miocardite/sangue , Miocardite/diagnóstico , Diagnóstico Diferencial , Idoso , Estudos de Casos e Controles , Adulto , Valor Preditivo dos Testes , Imagem Cinética por Ressonância Magnética/métodos , Curva ROCRESUMO
Introduction: The fight against SARS-CoV-2 has been a major task worldwide since it was first identified in December 2019. An imperative preventive measure is the availability of efficacious vaccines while there is also a significant interest in the protective effect of a previous SARS-CoV-2 infection on a subsequent infection (natural protection rate). Methods: In order to compare protection rates after infection and vaccination, researchers consider different effect measures such as 1 minus hazard ratio, 1 minus odds ratio, or 1 minus risk ratio. These measures differ in a setting with competing risks. Nevertheless, as there is no unique definition, these metrics are frequently used in studies examining protection rate. Comparison of protection rates via vaccination and natural infection poses several challenges. For instance many publications consider the epidemiological definition, that a reinfection after a SARS-CoV-2 infection is only possible after 90 days, whereas there is no such constraint after vaccination. Furthermore, death is more prominent as a competing event during the first 90 days after infection compared to vaccination. In this work we discuss the statistical issues that arise when investigating protection rates comparing vaccination with infection. We explore different aspects of effect measures and provide insights drawn from different analyses, distinguishing between the first and the second 90 days post-infection or vaccination. Results: In this study, we have access to real-world data of almost two million people from Stockholm County, Sweden. For the main analysis, data of over 52.000 people is considered. The infected group is younger, includes more men, and is less morbid compared to the vaccinated group. After the first 90 days, these differences increased. Analysis of the second 90 days shows differences between analysis approaches and between age groups. There are age-related differences in mortality. Considering the outcome SARS-CoV-2 infection, the effect of vaccination versus infection varies by age, showing a disadvantage for the vaccinated in the younger population, while no significant difference was found in the elderly. Discussion: To compare the effects of immunization through infection or vaccination, we emphasize consideration of several investigations. It is crucial to examine two observation periods: The first and second 90-day intervals following infection or vaccination. Additionally, methods to address imbalances are essential and need to be used. This approach supports fair comparisons, allows for more comprehensive conclusions and helps prevent biased interpretations.
RESUMO
BACKGROUND: Extended illness-death models (a specific class of multistate models) are a useful tool to analyse situations like hospital-acquired infections, ventilation-associated pneumonia, and transfers between hospitals. The main components of these models are hazard rates and transition probabilities. Calculation of different measures and their interpretation can be challenging due to their complexity. METHODS: By assuming time-constant hazards, the complexity of these models becomes manageable and closed mathematical forms for transition probabilities can be derived. Using these forms, we created a tool in R to visualize transition probabilities via stacked probability plots. RESULTS: In this article, we present this tool and give some insights into its theoretical background. Using published examples, we give guidelines on how this tool can be used. Our goal is to provide an instrument that helps obtain a deeper understanding of a complex multistate setting. CONCLUSION: While multistate models (in particular extended illness-death models), can be highly complex, this tool can be used in studies to both understand assumptions, which have been made during planning and as a first step in analysing complex data structures. An online version of this tool can be found at https://eidm.imbi.uni-freiburg.de/ .
Assuntos
Probabilidade , Humanos , Infecção Hospitalar/prevenção & controle , Infecção Hospitalar/epidemiologia , Modelos Estatísticos , Modelos de Riscos Proporcionais , Pneumonia Associada à Ventilação Mecânica/mortalidade , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Aplicativos Móveis/estatística & dados numéricos , AlgoritmosRESUMO
BACKGROUND: Gallstone disease (GD) is common but remains asymptomatic in most cases. However, gallstones can lead to complications like choledocholithiasis or gallbladder cancer. In this study, we analyse the common genetic risk factor for GD, the p.D19H variant in the sterol transporter ABCG8, in Polish patients with gallstones and gallbladder cancer. METHODS: Three adult cohorts were prospectively recruited: 65 patients with gallbladder cancer, 170 obese individuals scheduled for bariatric surgery and 72 patients who underwent endoscopic retrograde cholangiopancreatography due to recurrent choledocholithiasis. The control cohort consisted of 172 gallstone-free adults. The ABCG8 p.D19H (rs11887534) polymorphism was genotyped using TaqMan assays. RESULTS: The minor allele frequency (MAF) of the ABCG8 p.D19H polymorphism was significantly (p = .02) higher among cases with either gallstones or gallbladder cancer (MAF = 8.4%) as compared to controls (MAF = 4.0%). The highest frequency of the risk allele was detected in patients with gallbladder cancer (18.5%) and obese patients with GD (17.5%), followed by individuals with choledocholithiasis (13.9%). Notably, the p.19H variant was associated with an increased risk of developing gallbladder cancer (OR 2.76, 95% CI 1.16-6.54, p = .01) and an increased risk of GD in obese individuals scheduled for bariatric surgery (OR = 2.70, 95% CI 1.05-6.49, p = .03), but did not significantly affect the risk of choledocholithiasis. CONCLUSIONS: The ABCG8 p.D19H common risk variant increases the risk of developing gallbladder cancer in Central Europeans and enhances the risk of gallstones in the obese. Carriers of the p.D19H variant might benefit from personalized preventive strategies, particularly regarding gallbladder cancer.
Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Neoplasias da Vesícula Biliar , Cálculos Biliares , Obesidade , Humanos , Masculino , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Feminino , Pessoa de Meia-Idade , Cálculos Biliares/genética , Obesidade/genética , Obesidade/complicações , Polônia/epidemiologia , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/epidemiologia , Adulto , Estudos de Casos e Controles , Idoso , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Frequência do Gene , Fatores de Risco , Polimorfismo GenéticoRESUMO
INTRODUCTION: The production of advanced glycation end-products (AGEs) is a key pathomechanism related to the complications of diabetes mellitus. The measurement of HbA1c as one of the AGEs is widely used in the clinic, but also other proteins undergo glycation in the course of diabetes. Here, we measure skin AGEs (SAGEs) in patients with diabetes type 1 (DM1) and type 2 (DM2) and correlate them with metabolic markers as well as non-invasively measured liver fibrosis and steatosis. PATIENTS AND METHODS: In this cross-sectional study, a total of 64 patients with either DM1 or DM2 and 28 healthy controls were recruited. SAGEs were measured using autofluorescence (AGE Reader). Liver fibrosis and steatosis were quantified using transient elastography, which determines liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). FGF19, FGF21 and GDF-15 were measured in blood samples using ELISA. RESULTS: SAGEs were elevated in both groups of patients with diabetes as compared to healthy controls (both p < 0.001) and were higher in patients with DM2 in comparison to DM1 (p = 0.006). SAGEs correlated positively with HbA1c (r = 0.404, p < 0.001), CAP (r = 0.260, p = 0.016) and LSM (r = 0.356, p < 0.001), and negatively with insulin growth factor binding protein 3 (p < 0.001). We also detected a positive correlation between GDF15 and SAGEs (r = 0.469, p < 0.001). CONCLUSIONS: SAGEs are significantly elevated in patients with both DM types 1 and 2 and correlate with metabolic markers, including HbA1c and GDF15. They might also help to detect patients with advanced liver injury in the setting of diabetes.
Assuntos
Diabetes Mellitus Tipo 1 , Fígado Gorduroso , Humanos , Controle Glicêmico , Estudos Transversais , Hemoglobinas Glicadas , Reação de Maillard , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etiologia , Metaboloma , BiomarcadoresRESUMO
Therapeutic drug monitoring (TDM) is an important tool in precision medicine as it allows estimating pharmacodynamic and pharmacokinetic effects of drugs in clinical settings. An accurate, fast and real-time determination of the drug concentrations in patients ensures fast decision-making processes at the bedside to optimize the clinical treatment. Surface-enhanced Raman spectroscopy (SERS), which is based on the application of metallic nanostructured substrates to amplify the inherent weak Raman signal, is a promising technique in medical research due to its molecular specificity and trace sensitivity accompanied with short detection times. Therefore, we developed a SERS-based detection scheme using silicon nanowires decorated with silver nanoparticles, fabricated by means of top-down etching combined with chemical deposition, to detect the antibiotic ceftriaxone (CRO) in spiked fresh plasma and microdialysis samples. We successfully detected CRO in both matrices with an LOD of 94 µM in protein-depleted fresh plasma and 1.4 µM in microdialysate.
Assuntos
Nanopartículas Metálicas , Nanofios , Humanos , Antibacterianos/farmacologia , Prata/química , Ceftriaxona , Silício/química , Nanopartículas Metálicas/química , Nanofios/química , Análise Espectral Raman/métodosRESUMO
BACKGROUND: Current assays for the detection of (allo)antibodies to platelet antigens are often laborious and widely based on the presence of well-characterized donor platelets. OBJECTIVES: To develop an easy-to-perform, sensitive, and specific test for the detection of antibodies against platelet antigens, in particular, glycoprotein (GP) antigens, called "Recombinantly Expressed Tagged SUrface Protein" (RETSUP) assay, which does not require donor platelets. METHODS: Twin-Strep-tagged GP complexes were recombinantly expressed in human embryonic kidney 293 cells after stable transfection. These cell lines were used as antigen sources in the RETSUP assay, combining cell-based and enzyme-linked immunosorbent assay-based assay procedures. The assay performance was tested with recombinant antibodies, anti-human platelet antigen (HPA) reference plasmas, and anti-HPA patient sera. RESULTS: Human embryonic kidney 293 cell lines stably expressing either Twin-Strep-labeled GPIa/IIa, GPIIb/IIIa, GPIb/IX, or GPIb/IX/V complexes or GPV as well as the distinct HPA-1, HPA-3, and HPA-5 epitopes were successfully generated. Applying the generated GP-expressing cell lines, the developed RETSUP assay proved very sensitive and specific with recombinant antibodies targeting different GPs and human plasma/serum samples. The results of the test were not affected by the GP carrying the Twin-Strep-tag or by using freshly harvested or cryopreserved cells. CONCLUSION: The RETSUP assay is an easy-to-perform, sensitive, and specific assay for the detection of plasma/serum antibodies to platelet GP, with performance comparable to or better than those of current state-of-the-art assays in antiplatelet antibody diagnostics. Owing to the recombinant nature of the target antigens, it can be easily adapted to detect antibodies in other antibody-mediated diseases.
Assuntos
Antígenos de Plaquetas Humanas , Proteínas de Membrana , Humanos , Isoanticorpos , Plaquetas , Ensaio de Imunoadsorção Enzimática/métodos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Antígenos de Plaquetas Humanas/genéticaRESUMO
Importance: Staphylococcus aureus surgical site infections (SSIs) and bloodstream infections (BSIs) are important complications of surgical procedures for which prevention remains suboptimal. Contemporary data on the incidence of and etiologic factors for these infections are needed to support the development of improved preventive strategies. Objectives: To assess the occurrence of postoperative S aureus SSIs and BSIs and quantify its association with patient-related and contextual factors. Design, Setting, and Participants: This multicenter cohort study assessed surgical patients at 33 hospitals in 10 European countries who were recruited between December 16, 2016, and September 30, 2019 (follow-up through December 30, 2019). Enrolled patients were actively followed up for up to 90 days after surgery to assess the occurrence of S aureus SSIs and BSIs. Data analysis was performed between November 20, 2020, and April 21, 2022. All patients were 18 years or older and had undergone 11 different types of surgical procedures. They were screened for S aureus colonization in the nose, throat, and perineum within 30 days before surgery (source population). Both S aureus carriers and noncarriers were subsequently enrolled in a 2:1 ratio. Exposure: Preoperative S aureus colonization. Main Outcomes and Measures: The main outcome was cumulative incidence of S aureus SSIs and BSIs estimated for the source population, using weighted incidence calculation. The independent association of candidate variables was estimated using multivariable Cox proportional hazards regression models. Results: In total, 5004 patients (median [IQR] age, 66 [56-72] years; 2510 [50.2%] female) were enrolled in the study cohort; 3369 (67.3%) were S aureus carriers. One hundred patients developed S aureus SSIs or BSIs within 90 days after surgery. The weighted cumulative incidence of S aureus SSIs or BSIs was 2.55% (95% CI, 2.05%-3.12%) for carriers and 0.52% (95% CI, 0.22%-0.91%) for noncarriers. Preoperative S aureus colonization (adjusted hazard ratio [AHR], 4.38; 95% CI, 2.19-8.76), having nonremovable implants (AHR, 2.00; 95% CI, 1.15-3.49), undergoing mastectomy (AHR, 5.13; 95% CI, 1.87-14.08) or neurosurgery (AHR, 2.47; 95% CI, 1.09-5.61) (compared with orthopedic surgery), and body mass index (AHR, 1.05; 95% CI, 1.01-1.08 per unit increase) were independently associated with S aureus SSIs and BSIs. Conclusions and Relevance: In this cohort study of surgical patients, S aureus carriage was associated with an increased risk of developing S aureus SSIs and BSIs. Both modifiable and nonmodifiable etiologic factors were associated with this risk and should be addressed in those at increased S aureus SSI and BSI risk.
Assuntos
Neoplasias da Mama , Infecções Estafilocócicas , Idoso , Feminino , Humanos , Masculino , Neoplasias da Mama/complicações , Estudos de Coortes , Mastectomia , Infecções Estafilocócicas/prevenção & controle , Staphylococcus aureus , Infecção da Ferida Cirúrgica/prevenção & controle , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Nucleotide-binding oligomerization domain containing 2 (NOD2) risk variants lead to impaired mucosal barrier function, increased bacterial translocation (BT), and systemic inflammation. AIM: To evaluate the association between the presence of NOD2 risk variants, BT, inflammation, and hepatic encephalopathy (HE). PATIENTS AND METHODS: This prospective multicenter study included patients with cirrhosis and testing for NOD2 risk variants (p.R702W, p.G908R, c.3020insC, N289S, and c.-958T>C). Patients were evaluated for covert (C) and overt (O) HE. Markers of systemic inflammation (leukocytes, CRP, IL-6, LBP) and immune activation (soluble CD14) as well as bacterial endotoxin (hTRL4 activation) were determined in serum. RESULTS: Overall, 172 patients (70% men; median age 60 [IQR 54-66] years; MELD 12 [IQR 9-16]; 72% ascites) were included, of whom 53 (31%) carried a NOD2 risk variant. In this cohort, 11% presented with OHE and 27% and CHE. Presence and severity of HE and surrogates of inflammation, BT, and immune activation did not differ between patients with and without a NOD2 risk variant, also not after adjustment for MELD. HE was associated with increased ammonia and systemic inflammation, as indicated by elevated CRP (w/o HE: 7.2 [2.7-16.7]; with HE 12.6 [4.5-29.7] mg/dL; p < 0.001) and elevated soluble CD14 (w/o HE 2592 [2275-3033]; with HE 2755 [2410-3456] ng/mL; p = 0.025). CONCLUSIONS: The presence of NOD2 risk variants in patients with cirrhosis is not associated with HE and has no marked impact on inflammation, BT, or immune activation. In contrast, the presence of HE was linked to ammonia, the acute phase response, and myeloid cell activation.
Assuntos
Encefalopatia Hepática , Proteína Adaptadora de Sinalização NOD2 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Amônia , Translocação Bacteriana , Encefalopatia Hepática/complicações , Inflamação , Receptores de Lipopolissacarídeos , Cirrose Hepática/complicações , Proteína Adaptadora de Sinalização NOD2/genética , Estudos ProspectivosRESUMO
The soil-dwelling plant symbiont Sinorhizobium meliloti is a major model organism of Alphaproteobacteria. Despite numerous detailed OMICS studies, information about small open reading frame (sORF)-encoded proteins (SEPs) is largely missing, because sORFs are poorly annotated and SEPs are hard to detect experimentally. However, given that SEPs can fulfill important functions, identification of translated sORFs is critical for analyzing their roles in bacterial physiology. Ribosome profiling (Ribo-seq) can detect translated sORFs with high sensitivity, but is not yet routinely applied to bacteria because it must be adapted for each species. Here, we established a Ribo-seq procedure for S. meliloti 2011 based on RNase I digestion and detected translation for 60% of the annotated coding sequences during growth in minimal medium. Using ORF prediction tools based on Ribo-seq data, subsequent filtering, and manual curation, the translation of 37 non-annotated sORFs with ≤ 70 amino acids was predicted with confidence. The Ribo-seq data were supplemented by mass spectrometry (MS) analyses from three sample preparation approaches and two integrated proteogenomic search database (iPtgxDB) types. Searches against standard and 20-fold smaller Ribo-seq data-informed custom iPtgxDBs confirmed 47 annotated SEPs and identified 11 additional novel SEPs. Epitope tagging and Western blot analysis confirmed the translation of 15 out of 20 SEPs selected from the translatome map. Overall, by combining MS and Ribo-seq approaches, the small proteome of S. meliloti was substantially expanded by 48 novel SEPs. Several of them are part of predicted operons and/or are conserved from Rhizobiaceae to Bacteria, suggesting important physiological functions.
RESUMO
BACKGROUND: MBOAT7 rs641738 variant is a risk factor for nonalcoholic fatty liver disease (NAFLD) and liver fibrosis, but the relationship between this polymorphism and early liver dysfunction remains uncertain. METHODS: Eighty outpatients underwent blood analyses, liver imaging by ultrasound and acoustic radiation force impulse shear wave elastography and were genotyped for MBOAT7 (wild-type [WT], rs641738 heterozygous or homozygous) polymorphism using TaqMan assays. RESULTS: NAFLD was confirmed in 53 patients. Portal uptake and hepatocyte microsomal metabolization of (13 C)-methacetin were explored by measuring 13 CO2 appearance in exhaled air. The distribution of the MBOAT7 genotypes was comparable in subjects with or without NAFLD. The majority of subjects with or without NAFLD had fibrosis ≤ F1 but decreased portal extraction of (13 C)-methacetin, i.e. 78.6% in homozygous, 45.0% in heterozygous and 46.2% in WT for the MBOAT7 variant. Both substrate extraction and microsomal metabolization were mostly defective in the homozygous carriers. The extraction efficiency from portal blood flow was minimal in subjects with both homozygous rs641738 polymorphism and NAFLD, as compared to those with WT/heterozygous polymorphism, with or without NAFLD. CONCLUSIONS: The homozygous MBOAT7 rs641738 polymorphism per se is associated with a reduced extraction efficiency of (13 C)-methacetin from the portal flow pointing to subclinical liver dysfunction independently from liver fibrosis. Liver steatosis worsens (13 C)-methacetin extraction efficiency. We urge to better explore the mechanisms of interaction between external factors and multiple gene polymorphisms (including MBOAT7), paving the road to primary prevention and novel therapeutic strategies.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Polimorfismo de Nucleotídeo Único , Aciltransferases/genética , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/complicações , Proteínas de Membrana/genéticaRESUMO
Antimicrobial peptides (AMP) are essential components of innate immunity with a broad range of antimicrobial activities against bacteria, viruses, and fungi. The aim of this study was to investigate AMP expression in the upper gastrointestinal tract in normal and pathological metabolic states in humans. Furthermore, we examined the correlation between vitamin D levels and AMP expression in the same cohort. Serum concentrations of 25-hydroxyvitamin D3 were measured, and mRNA expression of ß-defensins HBD-1, -2, -3, -4, α-defensins HD-5 and -6 and cathelicidin in the upper gastrointestinal tract epithelia were determined by quantitative RT-PCR in 31 individuals (10 with type 2 diabetes, 10 with insulin resistance, and 11 healthy controls). The majority of the cohort showed low vitamin D concentrations, which were negatively correlated with mRNA expression levels of HBD-3 in corpus mucosa. HBD-1 and HBD-3 mRNA were expressed in corpus mucosa, with the former significantly decreased in patients with diabetes. Hence, we conclude that type 2 diabetes is associated with reduced AMP expression in the upper gastrointestinal tract, which might contribute towards epithelial barrier dysfunction and increased bacterial translocation in these patients.
Assuntos
Defensinas , Diabetes Mellitus Tipo 2 , Humanos , Defensinas/metabolismo , Diabetes Mellitus Tipo 2/complicações , Catelicidinas , Vitamina D , RNA Mensageiro/genética , RNA Mensageiro/análiseRESUMO
OBJECTIVES: The therapeutic antibody infliximab (IFX) has improved the life quality of numerous autoinflammatory disease patients. However, IFX can trigger the generation of anti-drug antibodies (ADA), whose optimal evaluation and management are currently subject of controversial discussions. We present two novel surface plasmon resonance (SPR) biosensor assays for therapeutic drug monitoring of IFX and characterization of ADA and investigated the diagnostic value of ADA binding properties. METHODS: IFX and ADA were quantified via developed SPR biosensor assays (IFXmon and ADAmon, respectively) and diagnostics-approved ELISA in sera from inflammatory bowel disease patients. Pre-analytic ADA enrichment with magnetic beads enabled analytical drug tolerance of the ADAmon assay. The dissociation ratio (DissR) as an index for ADA:IFX binding stability was calculated from the SPR sensorgrams of ADA quantification runs. RESULTS: IFX levels determined by IFXmon assay and ELISA showed high agreement, whereas ADA quantification concordance between ADAmon assay and ELISA was poor. In patients, DissR was predominantly constant over time and differed significantly between therapy outcomes. A DissR cut-off of 1.524 indicated undetectable IFX levels with 71.4% sensitivity and 88.9% specificity. Additionally, the SPR reference surface was exploited as serum-individual negative control to check result plausibility within multi-sample run sequences. CONCLUSIONS: Overall, both SPR biosensor assays exhibited reliable quantitative performance with accuracies superior to their ELISA counterparts and precision inferior to ELISA only for ADAmon. DissR presented itself as promising ADA binding parameter and could contribute to both earlier and more tailored therapeutic decisions.
Assuntos
Monitoramento de Medicamentos , Ressonância de Plasmônio de Superfície , Humanos , Infliximab , Relevância Clínica , Anticorpos , Ensaio de Imunoadsorção EnzimáticaRESUMO
BACKGROUND & AIMS: Fatty liver disease (FLD) is common in women with polycystic ovary syndrome (PCOS). Here, we use non-invasive tests to quantify liver injury in women with PCOS and analyse whether FLD-associated genetic variants contribute to liver phenotypes in PCOS. METHODS: Prospectively, we recruited women with PCOS and controls at two university centres in Germany and Poland. Alcohol abuse was regarded as an exclusion criterion. Genotyping of variants associated with FLD was performed using TaqMan assays. Liver stiffness measurements (LSM), controlled attenuation parameters (CAP) and non-invasive HSI, FLI, FIB-4 scores were determined to assess hepatic steatosis and fibrosis. RESULTS: A total of 42 German (age range 18-53 years) and 143 Polish (age range 18-40 years) women with PCOS, as well as 245 German and 289 Polish controls were recruited. In contrast to Polish patients, Germans were older, presented with more severe metabolic profiles and had significantly higher LSM (median 5.9 kPa vs. 3.8 kPa). In the German cohort, carriers of the PNPLA3 p.I148M risk variant had an increased LSM (p = .01). In the Polish cohort, the minor MTARC1 allele was linked with significantly lower serum aminotransferases activities, whereas the HSD17B13 polymorphism was associated with lower concentrations of 17-OH progesterone, total testosterone, and androstenedione (all p < .05). CONCLUSIONS: FLD is common in women with PCOS. Its extent is modulated by both genetic and metabolic risk factors. Genotyping of variants associated with FLD might help to stratify the risk of liver disease progression in women suffering from PCOS.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Síndrome do Ovário Policístico , Humanos , Feminino , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/complicações , Fatores de Risco , Hepatopatia Gordurosa não Alcoólica/complicações , FenótipoRESUMO
The severity of hepatic steatosis is modulated by genetic variants, such as patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738. Recently, mitochondrial amidoxime reducing component 1 (MTARC1) rs2642438 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567 polymorphisms were shown to have protective effects on liver diseases. Here, we evaluate these variants in patients undergoing bariatric surgery. A total of 165 patients who underwent laparoscopic sleeve gastrectomy and intraoperative liver biopsies and 314 controls were prospectively recruited. Genotyping was performed using TaqMan assays. Overall, 70.3% of operated patients presented with hepatic steatosis. NASH (non-alcoholic steatohepatitis) was detected in 28.5% of patients; none had cirrhosis. The increment of liver fibrosis stage was associated with decreasing frequency of the MTARC1 minor allele (p = 0.03). In multivariate analysis MTARC1 was an independent protective factor against fibrosis ≥ 1b (OR = 0.52, p = 0.03) and ≥ 1c (OR = 0.51, p = 0.04). The PNPLA3 risk allele was associated with increased hepatic steatosis, fibrosis, and NASH (OR = 2.22, p = 0.04). The HSD17B13 polymorphism was protective against liver injury as reflected by lower AST (p = 0.04) and ALT (p = 0.03) activities. The TM6SF2 polymorphism was associated with increased ALT (p = 0.04). In conclusion, hepatic steatosis is common among patients scheduled for bariatric surgery, but the MTARC1 and HSD17B13 polymorphisms lower liver injury in these individuals.
Assuntos
17-Hidroxiesteroide Desidrogenases , Cirurgia Bariátrica , Proteínas Mitocondriais , Hepatopatia Gordurosa não Alcoólica , Oxirredutases , Humanos , Fibrose , Predisposição Genética para Doença , Fígado/patologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Proteínas Mitocondriais/genética , Oxirredutases/genética , 17-Hidroxiesteroide Desidrogenases/genéticaRESUMO
Purpose This guideline aims to summarize the current state of knowledge about vaginal birth at term. The guideline focuses on definitions of the physiological stages of labor as well as differentiating between various pathological developments and conditions. It also assesses the need for intervention and the options to avoid interventions. The second part of this guideline presents recommendations and statements on care during the dilation and expulsion stages as well as during the placental/postnatal stage. Methods The German recommendations largely reproduce the recommendations of the National Institute for Health and Care Excellence (NICE) CG190 guideline "Intrapartum care for healthy women and babies". Other international guidelines were also consulted in individual cases when compiling this guideline. In addition, a systematic search and analysis of the literature was carried out using PICO questions where necessary, and other systematic reviews and individual studies were taken into account. For easier comprehension, the assessment tools of the Scottish Intercollegiate Guidelines Network (SIGN) were used to evaluate the quality of additionally consulted studies. Otherwise, the GRADE system was used for the NICE guideline, and the evidence reports of the IQWiG were used to evaluate the quality of the evidence. Recommendations Recommendations and statements were formulated based on identified evidence and/or a structured consensus.
RESUMO
Purpose This guideline aims to summarize the current state of knowledge about vaginal birth at term. The guideline focuses on definitions of the physiological stages of labor as well as differentiating between various pathological developments and conditions. It also assesses the need for intervention and the options to avoid interventions. This first part presents recommendations and statements about patient information and counselling, general patient care, monitoring of patients, pain management and quality control measures for vaginal birth. Methods The German recommendations largely reproduce the recommendations of the National Institute for Health and Care Excellence (NICE) CG 190 guideline "Intrapartum care for healthy women and babies". Other international guidelines were also consulted in specific cases when compiling this guideline. In addition, a systematic search and analysis of the literature was carried out using PICO questions, if this was considered necessary, and other systematic reviews and individual studies were taken into account. For easier comprehension, the assessment tools of the Scottish Intercollegiate Guidelines Network (SIGN) were used to evaluate the quality of the additionally consulted studies. Otherwise, the GRADE system was used for the NICE guideline and the evidence reports of the IQWiG were used to evaluate the quality of the evidence. Recommendations Recommendations and statements were formulated based on identified evidence and/or a structured consensus.
RESUMO
Gallstones are increasingly frequent in children. In this candidate gene study, we genotyped 5 gene variants ( ANO1 , SPTLC3 , TMEM147 , TNRC6B , rs12532734) from a recent gallstone genome-wide association study (GWAS) in a cohort of 214 children with gallstones and 172 gallstone-free adult controls. In total, 138 genotyped children presented with symptomatic gallstone disease, 47 underwent cholecystectomy, and 126 received ursodeoxycholic acid (UDCA) as therapy for stones. Among 5 tested variants, the rs12532734 polymorphism modulated the gallstone risk in the studied cohort. Its genotype distribution significantly ( P = 0.025) departed from the Hardy-Weinberg equilibrium among cases, and the common allele was associated with increased odds of developing gallstones at young age (OR = 1.69, P = 0.014). SLC26A3 is the nearest gene to rs12532734 and is involved in the transepithelial bicarbonate and chloride transport. The association of rs12532734 with pediatric gallstones is a novel finding warranting further investigations also with regard to biliary bicarbonate flux and bile composition.