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1.
Harmful Algae ; 91: 101632, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32057342

RESUMO

There is increasing concern that accelerating environmental change attributed to human-induced warming of the planet may substantially alter the patterns, distribution and intensity of Harmful Algal Blooms (HABs). Changes in temperature, ocean acidification, precipitation, nutrient stress or availability, and the physical structure of the water column all influence the productivity, composition, and global range of phytoplankton assemblages, but large uncertainty remains about how integration of these climate drivers might shape future HABs. Presented here are the collective deliberations from a symposium on HABs and climate change where the research challenges to understanding potential linkages between HABs and climate were considered, along with new research directions to better define these linkages. In addition to the likely effects of physical (temperature, salinity, stratification, light, changing storm intensity), chemical (nutrients, ocean acidification), and biological (grazer) drivers on microalgae (senso lato), symposium participants explored more broadly the subjects of cyanobacterial HABs, benthic HABs, HAB effects on fisheries, HAB modelling challenges, and the contributions that molecular approaches can bring to HAB studies. There was consensus that alongside traditional research, HAB scientists must set new courses of research and practices to deliver the conceptual and quantitative advances required to forecast future HAB trends. These different practices encompass laboratory and field studies, long-term observational programs, retrospectives, as well as the study of socioeconomic drivers and linkages with aquaculture and fisheries. In anticipation of growing HAB problems, research on potential mitigation strategies should be a priority. It is recommended that a substantial portion of HAB research among laboratories be directed collectively at a small sub-set of HAB species and questions in order to fast-track advances in our understanding. Climate-driven changes in coastal oceanographic and ecological systems are becoming substantial, in some cases exacerbated by localized human activities. That, combined with the slow pace of decreasing global carbon emissions, signals the urgency for HAB scientists to accelerate efforts across disciplines to provide society with the necessary insights regarding future HAB trends.

2.
PLoS One ; 15(1): e0227714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917814

RESUMO

Vitamin B1 (thiamin) deficiency is an issue periodically affecting a wide range of taxa worldwide. In aquatic pelagic systems, thiamin is mainly produced by bacteria and phytoplankton and is transferred to fish and birds via zooplankton, but there is no general consensus on when or why this transfer is disrupted. We focus on the occurrence in salmon (Salmo salar) of a thiamin deficiency syndrome (M74), the incidence of which is highly correlated among populations derived from different spawning rivers. Here, we show that M74 in salmon is associated with certain large-scale abiotic changes in the main common feeding area of salmon in the southern Baltic Sea. Years with high M74 incidence were characterized by stagnant periods with relatively low salinity and phosphate and silicate concentrations but high total nitrogen. Consequently, there were major changes in phytoplankton and zooplankton, with, e.g., increased abundances of Cryptophyceae, Dinophyceae, Diatomophyceae and Euglenophyceae and Acartia spp. during high M74 incidence years. The prey fish communities also had increased stocks of both herring and sprat in these years. Overall, this suggests important changes in the entire food web structure and nutritional pathways in the common feeding period during high M74 incidence years. Previous research has emphasized the importance of the abundance of planktivorous fish for the occurrence of M74. By using this 27-year time series, we expand this analysis to the entire ecosystem and discuss potential mechanisms inducing thiamin deficiency in salmon.

3.
Toxins (Basel) ; 11(12)2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31805656

RESUMO

The fresh-water cyanobacterium Microcystis is known to form blooms world-wide, and is often responsible for the production of microcystins found in lake water. Microcystins are non-ribosomal peptides with toxic effects, e.g. on vertebrates, but their function remains largely unresolved. Moreover, not all strains produce microcystins, and many different microcystin variants have been described. Here we explored the diversity of microcystin variants within Microcystis botrys, a common bloom-former in Sweden. We isolated a total of 130 strains through the duration of a bloom in eutrophic Lake Vomb, and analyzed their microcystin profiles with tandem mass spectrometry (LC-MS/MS). We found that microcystin producing (28.5%) and non-producing (71.5%) M. botrys strains, co-existed throughout the bloom. However, microcystin producing strains were more prevalent towards the end of the sampling period. Overall, 26 unique M. botrys chemotypes were identified, and while some chemotypes re-occurred, others were found only once. The M. botrys chemotypes showed considerable variation both in terms of number of microcystin variants, as well as in what combinations the variants occurred. To our knowledge, this is the first report on microcystin chemotype variation and dynamics in M. botrys. In addition, our study verifies the co-existence of microcystin and non-microcystin producing strains, and we propose that environmental conditions may be implicated in determining their composition.

4.
PLoS One ; 14(10): e0224286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31671116

RESUMO

The methodological challenges to effectiveness evaluation of complex interventions has been widely discussed. Bottom-up case management for frail older person was implemented in Belgium, and indeed, it was evaluated as a complex intervention. This paper presents the methodological approach we developed to respond to four main methodological challenges regarding the evaluation of case management: (1) the standardization of the interventions, (2) stratification of the frail older population that was used to test various modalities of case management with different risks groups, (3) the building of a control group, and (4) the use of multiple outcomes in evaluating case management. To address these challenges, we developed a mixed-methods approach that (1) used multiple embedded case studies to classify case management types according to their characteristics and implementation conditions; and (2) compared subgroups of beneficiaries with specific needs (defined by Principal Component Analysis prior to cluster analysis) and a control group receiving 'usual care', to evaluate the effectiveness of case management. The beneficiaries' subgroups were matched using propensity scores and compared using generalized pairwise comparison and the hurdle model with the control group. Our results suggest that the impact of case management on patient health and the services used varies according to specific needs and categories of case management. However, these equivocal results question our methodological approach. We suggest to reconsider the evaluation approach by moving away from a viewing case management as an intervention. Rather, it should be considered as a process of interconnected actions taking place within a complex system.

5.
Stat Methods Med Res ; : 962280219853599, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31213153

RESUMO

Medical time-to-event studies frequently include two groups of patients: those who will not experience the event of interest and are said to be "cured" and those who will develop the event and are said to be "susceptible". However, the cure status is unobserved in (right-)censored patients. While most of the work on cure models focuses on the time-to-event for the uncured patients (latency) or on the baseline probability of being cured or not (incidence), we focus in this research on the conditional probability of being cured after a medical intervention given survival until a certain time. Assuming the availability of longitudinal measurements collected over time and being informative on the risk to develop the event, we consider joint models for longitudinal and survival data given a cure fraction. These models include a linear mixed model to fit the trajectory of longitudinal measurements and a mixture cure model. In simulation studies, different shared latent structures linking both submodels are compared in order to assess their predictive performance. Finally, an illustration on HIV patient data completes the comparison.

6.
Cancer Med ; 8(6): 3036-3046, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31025552

RESUMO

BACKGROUND: In uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra-tumor immune population, compare it to other established biomarkers and to patients' outcome. METHODS: Primary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT-qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation-dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array-CGH (n = 17), and survival statistics (n = 86). RESULTS: Gene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1-IRF1 pathway activation. Tumors with IFNγ-signature had poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three-tier stratification) than two (two-tier stratification). CNA-based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease-free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk-groups according to the number of DNA alterations. Immune cell infiltration was increased in the high-risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk-group. CONCLUSIONS: High degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon-gamma-related, and associated with poor survival. It allows for two-tier stratification, which is prognostically less efficient than a three-tier one. The best prognostic stratification is by CNA model with three risk-groups where immune cell infiltration impacts only some subgroups.

7.
Eur J Anaesthesiol ; 36(6): 390-399, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30950900

RESUMO

BACKGROUND: Better understanding of risk factors for adverse events during monitored anaesthesia care (MAC) for paediatric gastrointestinal endoscopy may improve outcome in children. OBJECTIVES: To identify the prevalence and predictors of adverse events during MAC for paediatric endoscopy. DESIGN: An observational study. SETTING: Tertiary university hospital, single-centre cohort, from January 2010 to August 2016. PATIENTS: The prospectively collected electronic anaesthetic records of 3435 children aged up to 16 years who underwent diagnostic gastrointestinal endoscopy under MAC were analysed retrospectively. Children with an American Society of Anesthesiologists' physical status at least 4, and those requiring mechanical ventilation and therapeutic or urgent endoscopy were excluded. MAIN OUTCOME MEASURES: The prevalence and predictors of adverse events during MAC for paediatric gastrointestinal endoscopy, with particular reference to the use of different anaesthetic or sedative agents. RESULTS: Mean ±â€ŠSD age of the children was 8.5 ±â€Š4.4 years. The incidences of adverse events and adverse respiratory events were 3.4 and 3.3%, respectively. Multivariate analysis identified 12 independent predictors: age [odds ratio (OR) 0.92, P = 0.002], children's size for example underweight (OR 1.78, P = 0.039), overweight (OR 2.20, P = 0.039), (morbid) obesity (OR 4.25, P = 0.006), presence of respiratory comorbidities (OR 8.18, P < 0.001), recent respiratory infection (OR 23.55, P < 0.001) or both (OR 17.46, P < 0.001), neurological comorbidities (OR 2.18, P = 0.007), upper gastrointestinal endoscopy (OR 5.66, P < 0.001), propofol co-administration with ketamine (OR 10.34, P < 0. 001) or after sevoflurane induction (OR 44.95, P < 0.001), and propofol induction dose (OR 18.97, P < 0.001). Posthoc secondary analyses revealed a significantly higher risk of adverse events (OR 3.9, P < 0.0001) and also significantly more respiratory comorbidities and respiratory infections (P < 0.0001) in children aged less than 2 years when compared with children aged at least 2 years. No cardiovascular events were observed and outcome was uneventful. CONCLUSION: The present cohort demonstrated the feasibility and safety of MAC for paediatric gastrointestinal endoscopy by an experienced team. Although adverse events occurred rarely, their predictive factors were clinically identifiable. Applying this information in risk assessment and modifying anaesthetic management accordingly could improve outcome. TRIAL REGISTRATION: ISRCTN70362666.


Assuntos
Anestesia Geral/efeitos adversos , Sedação Profunda/efeitos adversos , Endoscopia Gastrointestinal/efeitos adversos , Complicações Intraoperatórias/epidemiologia , Monitorização Neurofisiológica Intraoperatória , Adolescente , Anestesia Geral/métodos , Criança , Pré-Escolar , Sedação Profunda/métodos , Estudos de Viabilidade , Feminino , Humanos , Incidência , Lactente , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/etiologia , Masculino , Prevalência , Estudos Prospectivos , Medição de Risco , Fatores de Risco
8.
Vaccine ; 37(14): 2004-2015, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30850240

RESUMO

BACKGROUND: Adjuvants like AS01B increase the immunogenicity of vaccines and generally cause increased transient reactogenicity compared with Alum. A phase II randomized trial was conducted to characterize the response to AS01B and Alum adjuvanted vaccines. A post-hoc analysis was performed to examine the associations between reactogenicity and innate immune parameters. METHODS: The trial involved 60 hepatitis B-naïve adults aged 18-45 years randomized 1:1 to receive either two doses of HBsAg-AS01B on Day (D)0 and D30, or three doses of HBsAg-Alum on D0, D30, D180. Prior to vaccination, all subjects received placebo injection in order to differentiate the impact of injection process and the vaccination. Main outcomes included reactogenicity symptoms, vital signs, blood cytokines, biochemical and hematological parameters after vaccination. Associations were explored using linear regression. FINDINGS: The vaccine with AS01B induced higher HBsAg-specific antibody levels than Alum. Local and systemic symptoms were more frequent in individuals who received HBsAg AS01B/Alum vaccine or placebo, but were mild and short-lived. Blood levels of C-reactive protein (CRP), bilirubin, leukocyte, monocyte and neutrophil counts increased rapidly and transiently after AS01B but not after Alum or placebo. Lymphocyte counts decreased in the AS01B group and lactate dehydrogenase levels decreased after Alum. Modelling revealed associations between systemic symptoms and increased levels of CRP and IL-6 after the first HBsAg-AS01B or HBsAg-Alum immunization. Following the second vaccine dose, CRP, IL-6, IP-10, IFN-γ, MIP-1ß and MCP-2 were identified as key parameters associated with systemic symptoms. These observations were confirmed using an independent data set extracted from a previous study of the immune response to HBsAg-adjuvanted vaccines (NCT00805389). CONCLUSIONS: IL-6 and IFN-γ signals were associated with systemic reactogenicity following administration of AS01B-adjuvanted vaccine. These signals were similar to those previously associated with antibody and T-cell responses induced by HBsAg-adjuvanted vaccines, suggesting that similar innate immune signals may underlie adjuvant reactogenicity and immunogenicity. TRIAL REGISTRATION: www.clinicaltrials.gov NCT01777295.

9.
Environ Microbiol Rep ; 11(3): 425-433, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30672139

RESUMO

Phytoplankton and bacteria interactions have a significant role in aquatic ecosystem functioning. Associations can range from mutualistic to parasitic, shaping biogeochemical cycles and having a direct influence on phytoplankton growth. How variations in phenotype and sampling location, affect the phytoplankton microbiome is largely unknown. A high-resolution characterization of the bacterial community in cultures of the dinoflagellate Alexandrium was performed on strains isolated from different geographical locations and at varying anthropogenic impact levels. Microbiomes of Baltic Sea Alexandrium ostenfeldii isolates were dominated by Betaproteobacteria and were consistent over phenotypic and genotypic Alexandrium strain variation, resulting in identification of an A. ostenfeldii core microbiome. Comparisons with in situ bacterial communities showed that taxa found in this A. ostenfeldii core were specifically associated to dinoflagellate dynamics in the Baltic Sea. Microbiomes of Alexandrium tamarense and minutum, isolated from the Mediterranean Sea, differed from those of A. ostenfeldii in bacterial diversity and composition but displayed high consistency, and a core set of bacterial taxa was identified. This indicates that Alexandrium isolates with diverse phenotypes host predictable, species-specific, core microbiomes reflecting the abiotic conditions from which they were isolated. These findings enable in-depth studies of potential interactions occurring between Alexandrium and specific bacterial taxa.

10.
Lifetime Data Anal ; 25(1): 1-25, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29388073

RESUMO

In this paper, we extend the vertical modeling approach for the analysis of survival data with competing risks to incorporate a cure fraction in the population, that is, a proportion of the population for which none of the competing events can occur. The proposed method has three components: the proportion of cure, the risk of failure, irrespective of the cause, and the relative risk of a certain cause of failure, given a failure occurred. Covariates may affect each of these components. An appealing aspect of the method is that it is a natural extension to competing risks of the semi-parametric mixture cure model in ordinary survival analysis; thus, causes of failure are assigned only if a failure occurs. This contrasts with the existing mixture cure model for competing risks of Larson and Dinse, which conditions at the onset on the future status presumably attained. Regression parameter estimates are obtained using an EM-algorithm. The performance of the estimators is evaluated in a simulation study. The method is illustrated using a melanoma cancer data set.


Assuntos
Simulação por Computador , Modelos Estatísticos , Análise de Sobrevida , Algoritmos , Confiabilidade dos Dados , Análise de Dados , Humanos , Estimativa de Kaplan-Meier , Funções Verossimilhança , Medição de Risco
11.
Biometrics ; 75(2): 452-462, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30430553

RESUMO

In survival analysis, it often happens that a certain fraction of the subjects under study never experience the event of interest, that is, they are considered "cured." In the presence of covariates, a common model for this type of data is the mixture cure model, which assumes that the population consists of two subpopulations, namely the cured and the non-cured ones, and it writes the survival function of the whole population given a set of covariates as a mixture of the survival function of the cured subjects (which equals one), and the survival function of the non-cured ones. In the literature, one usually assumes that the mixing probabilities follow a logistic model. This is, however, a strong modeling assumption, which might not be met in practice. Therefore, in order to have a flexible model which at the same time does not suffer from curse-of-dimensionality problems, we propose in this paper a single-index model for the mixing probabilities. For the survival function of the non-cured subjects we assume a Cox proportional hazards model. We estimate this model using a maximum likelihood approach. We also carry out a simulation study, in which we compare the estimators under the single-index model and under the logistic model for various model settings, and we apply the new model and estimation method on a breast cancer data set.


Assuntos
Modelos Estatísticos , Modelos de Riscos Proporcionais , Análise de Sobrevida , Neoplasias da Mama/mortalidade , Simulação por Computador , Feminino , Humanos , Funções Verossimilhança , Modelos Logísticos
12.
Microb Ecol ; 77(2): 288-303, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30019110

RESUMO

Two annual Baltic Sea phytoplankton blooms occur in spring and summer. The bloom intensity is determined by nutrient concentrations in the water, while the period depends on weather conditions. During the course of the bloom, dead cells sink to the sediment where their degradation consumes oxygen to create hypoxic zones (< 2 mg/L dissolved oxygen). These zones prevent the establishment of benthic communities and may result in fish mortality. The aim of the study was to determine how the spring and autumn sediment chemistry and microbial community composition changed due to degradation of diatom or cyanobacterial biomass, respectively. Results from incubation of sediment cores showed some typical anaerobic microbial processes after biomass addition such as a decrease in NO2- + NO3- in the sediment surface (0-1 cm) and iron in the underlying layer (1-2 cm). In addition, an increase in NO2- + NO3- was observed in the overlying benthic water in all amended and control incubations. The combination of NO2- + NO3- diffusion plus nitrification could not account for this increase. Based on 16S rRNA gene sequences, the addition of cyanobacterial biomass during autumn caused a large increase in ferrous iron-oxidizing archaea while diatom biomass amendment during spring caused minor changes in the microbial community. Considering that OTUs sharing lineages with acidophilic microorganisms had a high relative abundance during autumn, it was suggested that specific niches developed in sediment microenvironments. These findings highlight the importance of nitrogen cycling and early microbial community changes in the sediment due to sinking phytoplankton before potential hypoxia occurs.


Assuntos
Bactérias/isolamento & purificação , Cianobactérias/crescimento & desenvolvimento , Diatomáceas/crescimento & desenvolvimento , Sedimentos Geológicos/microbiologia , Fitoplâncton/crescimento & desenvolvimento , Bactérias/classificação , Bactérias/genética , Biomassa , Cianobactérias/classificação , Cianobactérias/genética , Cianobactérias/isolamento & purificação , Diatomáceas/classificação , Diatomáceas/genética , Diatomáceas/isolamento & purificação , Eutrofização , Sedimentos Geológicos/química , Nitratos/análise , Nitratos/metabolismo , Nitritos/análise , Nitritos/metabolismo , Filogenia , Fitoplâncton/classificação , Fitoplâncton/genética , Fitoplâncton/isolamento & purificação , Estações do Ano , Água do Mar/química , Água do Mar/microbiologia
13.
Biometrics ; 75(1): 297-307, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30076713

RESUMO

Measurement error in the continuous covariates of a model generally yields bias in the estimators. It is a frequent problem in practice, and many correction procedures have been developed for different classes of models. However, in most cases, some information about the measurement error distribution is required. When neither validation nor auxiliary data (e.g., replicated measurements) are available, this specification turns out to be tricky. In this article, we develop a flexible likelihood-based procedure to estimate the variance of classical additive error of Gaussian distribution, without additional information, when the covariate has compact support. The performance of this estimator is investigated both in an asymptotic way and through finite sample simulations. The usefulness of the obtained estimator when using the simulation extrapolation (SIMEX) algorithm, a widely used correction method, is then analyzed in the Cox proportional hazards model through other simulations. Finally, the whole procedure is illustrated on real data.


Assuntos
Viés , Modelos Estatísticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Creatinina/análise , Feminino , Hemoglobinas/análise , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/mortalidade , Modelos de Riscos Proporcionais , Análise de Sobrevida
14.
Biom J ; 61(1): 162-165, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30417414

RESUMO

A well-known problem in classical two-tailed hypothesis testing is that P-values go to zero when the sample size goes to infinity, irrespectively of the effect size. This pitfall can make the testing of data consisting of large sample sizes potentially unreliable. In this note, we propose to test for relevant differences to overcome this issue. We illustrate the proposed test a on real data set of about 40 million privately insured patients.


Assuntos
Biometria/métodos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Humanos , Tamanho da Amostra , Viroses/epidemiologia
15.
Front Microbiol ; 9: 1562, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30090087

RESUMO

Frequencies and biomass of Baltic Sea cyanobacterial blooms are expected to be higher in future climate conditions, but also of longer duration as a result of increased sea surface temperature. Concurrently, climate predictions indicate a reduced salinity in the Baltic Sea. These climate-driven changes are expected to alter not solely the phytoplankton community but also the role of microbial communities for nutrient remineralization. Here, we present the response of summer plankton communities (filamentous cyanobacteria, picocyanobacteria, and heterotrophic bacteria) to the interplay of increasing temperature (from 16 to 18°C and 20°C) and reduced salinity (from salinity 6.9 to 5.9) in the Baltic Proper (NW Gotland Sea) using a microcosm approach. Warmer temperatures led to an earlier peak of cyanobacterial biomass, while yields were reduced. These conditions caused a decrease of nitrogen-fixers (Dolichospermum sp.) biomass, while non nitrogen-fixers (Pseudanabaena sp.) increased. Salinity reduction did not affect cyanobacterial growth nor community composition. Among heterotrophic bacteria, Actinobacteria showed preference for high temperature, while Gammaproteobacteria thrived at in situ temperature. Heterotrophic bacteria community changed drastically at lower salinity and resembled communities at high temperature. Picocyanobacteria and heterotrophic bacterial biomass had a pronounced increase associated with the decay of filamentous cyanobacteria. This suggests that shifts in community composition of heterotrophic bacteria are influenced both directly by abiotic factors (temperature and salinity) and potentially indirectly by cyanobacteria. Our findings suggest that at warmer temperature, lower yield of photosynthetic cyanobacteria combined with lower proportion of nitrogen-fixers in the community could result in lower carbon export to the marine food web with consequences for the decomposer community of heterotrophic bacteria.

16.
Arthritis Res Ther ; 20(1): 131, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29929535

RESUMO

BACKGROUND: Changes of serum concentrations of glycated, oxidized, and nitrated amino acids and hydroxyproline and anticyclic citrullinated peptide antibody status combined by machine learning techniques in algorithms have recently been found to provide improved diagnosis and typing of early-stage arthritis of the knee, including osteoarthritis (OA), in patients. The association of glycated, oxidized, and nitrated amino acids released from the joint with development and progression of knee OA is unknown. We studied this in an OA animal model as well as interleukin-1ß-activated human chondrocytes in vitro and translated key findings to patients with OA. METHODS: Sixty male 3-week-old Dunkin-Hartley guinea pigs were studied. Separate groups of 12 animals were killed at age 4, 12, 20, 28 and 36 weeks, and histological severity of knee OA was evaluated, and cartilage rheological properties were assessed. Human chondrocytes cultured in multilayers were treated for 10 days with interleukin-1ß. Human patients with early and advanced OA and healthy controls were recruited, blood samples were collected, and serum or plasma was prepared. Serum, plasma, and culture medium were analyzed for glycated, oxidized, and nitrated amino acids. RESULTS: Severity of OA increased progressively in guinea pigs with age. Glycated, oxidized, and nitrated amino acids were increased markedly at week 36, with glucosepane and dityrosine increasing progressively from weeks 20 and 28, respectively. Glucosepane correlated positively with OA histological severity (r = 0.58, p < 0.0001) and instantaneous modulus (r = 0.52-0.56; p < 0.0001), oxidation free adducts correlated positively with OA severity (p < 0.0009-0.0062), and hydroxyproline correlated positively with cartilage thickness (p < 0.0003-0.003). Interleukin-1ß increased the release of glycated and nitrated amino acids from chondrocytes in vitro. In clinical translation, plasma glucosepane was increased 38% in early-stage OA (p < 0.05) and sixfold in patients with advanced OA (p < 0.001) compared with healthy controls. CONCLUSIONS: These studies further advance the prospective role of glycated, oxidized, and nitrated amino acids as serum biomarkers in diagnostic algorithms for early-stage detection of OA and other arthritic disease. Plasma glucosepane, reported here for the first time to our knowledge, may improve early-stage diagnosis and progression of clinical OA.


Assuntos
Biomarcadores/sangue , Cartilagem Articular/metabolismo , Produtos Finais de Glicação Avançada/sangue , Osteoartrite do Joelho/sangue , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/metabolismo , Animais , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Progressão da Doença , Feminino , Glicosilação , Cobaias , Humanos , Interleucina-1beta/farmacologia , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico
17.
Stat Methods Med Res ; 27(7): 2114-2131, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-27815495

RESUMO

Models for interval-censored survival data presenting a fraction of "cure" or "immune" patients have recently been proposed in the literature, particularly extending the mixture cure model to interval-censored data. However, little is known about the goodness-of-fit of such models. In a mixture cure model, the survival distribution of the entire population is improper and expressed in terms of the survival distribution of uncured individuals, i.e. the latency part of the model, and the probability to experience the event of interest, i.e. the incidence part. To validate a mixture cure model, assumptions made on both parts need to be checked, i.e. the survival distribution of uncured individuals, the link function used in the latency and the linearity of the covariates used in the both parts of the model. In this work, we investigate the Cox-Snell and deviance residuals and show how they can be adapted and used to perform diagnostics checks when all subjects are right- or interval-censored and some subjects are cured with unknown cure status. A large simulation study investigates the ability of these residuals to detect a departure from the assumptions of the mixture model. Developed techniques are applied to a real data set about Alzheimer's disease.


Assuntos
Modelos Estatísticos , Análise de Sobrevida , Algoritmos , Doença de Alzheimer , Bases de Dados Factuais , Humanos
18.
Front Microbiol ; 9: 3296, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30705671

RESUMO

Marine bacterioplankton are essential in global nutrient cycling and organic matter turnover. Time-series analyses, often at monthly sampling frequencies, have established the paramount role of abiotic and biotic variables in structuring bacterioplankton communities and productivities. However, fine-scale seasonal microbial activities, and underlying biological principles, are not fully understood. We report results from four consecutive years of high-frequency time-series sampling in the Baltic Proper. Pronounced temporal dynamics in most investigated microbial variables were observed, including bacterial heterotrophic production, plankton biomass, extracellular enzyme activities, substrate uptake rate constants of glucose, pyruvate, acetate, amino acids, and leucine, as well as nutrient limitation bioassays. Spring blooms consisting of diatoms and dinoflagellates were followed by elevated bacterial heterotrophic production and abundances. During summer, bacterial productivity estimates increased even further, coinciding with an initial cyanobacterial bloom in early July. However, bacterial abundances only increased following a second cyanobacterial bloom, peaking in August. Uptake rate constants for the different measured carbon compounds varied seasonally and inter-annually and were highly correlated to bacterial productivity estimates, temperature, and cyanobacterial abundances. Further, we detected nutrient limitation in response to environmental conditions in a multitude of microbial variables, such as elevated productivities in nutrient bioassays, changes in enzymatic activities, or substrate preferences. Variations among biotic variables often occurred on time scales of days to a few weeks, yet often spanning several sampling occasions. Such dynamics might not have been captured by sampling at monthly intervals, as compared to more predictable transitions in abiotic variables such as temperature or nutrient concentrations. Our study indicates that high resolution analyses of microbial biomass and productivity parameters can help out in the development of biogeochemical and food web models disentangling the microbial black box.

19.
Polit Anal ; 104(1): 31-50, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29151774

RESUMO

In many situations in survival analysis, it may happen that a fraction of individuals will never experience the event of interest: they are considered to be cured. The promotion time cure model takes this into account. We consider the case where one or more explanatory variables in the model are subject to measurement error, which should be taken into account to avoid biased estimators. A general approach is the simulation-extrapolation algorithm, a method based on simulations which allows one to estimate the effect of measurement error on the bias of the estimators and to reduce this bias. We extend this approach to the promotion time cure model. We explain how the algorithm works, and we show that the proposed estimator is approximately consistent and asymptotically normally distributed, and that it performs well in finite samples. Finally, we analyse a database in cardiology: among the explanatory variables of interest is the ejection fraction, which is known to be measured with error.

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