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Omics-based methods are increasingly used in current ecotoxicology. Therefore, a large number of observations for various toxic substances and organisms are available and may be used for identifying modes of action, adverse outcome pathways, or novel biomarkers. For these purposes, good statistical analysis of toxicogenomic data is vital. In contrast to established ecotoxicological techniques, concentration-response modeling is rarely used for large datasets. Instead, statistical hypothesis testing is prevalent, which provides only a limited scope for inference. The present study therefore applied automated concentration-response modeling for 3 different ecotoxicotranscriptomic and ecotoxicometabolomic datasets. The modeling process was performed by simultaneously applying 9 different regression models, representing distinct mechanistic, toxicological, and statistical ideas that result in different curve shapes. The best-fitting models were selected by using Akaike's information criterion. The linear and exponential models represented the best data description for more than 50% of responses. Models generating U-shaped curves were frequently selected for transcriptomic signals (30%), and sigmoid models were identified as best fit for many metabolomic signals (21%). Thus, selecting the models from an array of different types seems appropriate, because concentration-response functions may vary because of the observed response type, and they also depend on the compound, the organism, and the investigated concentration and exposure duration range. The application of concentration-response models can help to further tap the potential of omics data and is a necessary step for quantitative mixture effect assessment at the molecular response level.
- Klíčová slova
- Biostatistics, Dose-response modeling, Ecotoxicogenomics, Mixture toxicity, Myriophyllum, Zebrafish embryo,
- MeSH
- dánio pruhované růst a vývoj metabolismus MeSH
- ekosystém * MeSH
- embryo nesavčí účinky léků metabolismus MeSH
- genomika * MeSH
- látky znečišťující životní prostředí toxicita MeSH
- lineární modely MeSH
- metabolomika * MeSH
- rychlé screeningové testy MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- tetrachlorethylen toxicita MeSH
- transkriptom účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- látky znečišťující životní prostředí MeSH
- tetrachlorethylen MeSH
OBJECTIVE: The Cooper-Norcross Inventory of Preferences (C-NIP) is a brief, multidimensional measure of clients' therapy preferences. This study aimed to examine the factor structure and measurement invariance of the C-NIP. METHOD: Fifteen datasets (N = 10,088 observations) representing the C-NIP in nine language versions were obtained from authors of psychometric studies. Confirmatory factor analysis and exploratory structural equation modeling were used to analyze the data. RESULTS: None of the proposed models adequately fit the data. Therefore, a new model was developed that sufficiently fit most of the C-NIP version 1.1 datasets. The new model was invariant up to the strict and means levels across genders, ages, and psychotherapy experience but only up to the metric level across translations. CONCLUSIONS: The C-NIP can be used to compare men and women, people of diverse ages, and people with some vs. no experience with psychotherapy. Lower reliabilities of the C-NIP scales are a limitation.
- Klíčová slova
- C-NIP, Cooper-Norcross Inventory of Preferences, measurement invariance, preferences, psychotherapy,
- MeSH
- dospělí MeSH
- faktorová analýza statistická MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- pacientova volba MeSH
- psychometrie * přístrojové vybavení normy MeSH
- psychoterapie * normy MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Spinal muscular atrophy (SMA) is a genetic disorder that causes progressive degeneration of lower motor neurons and the subsequent loss of muscle function throughout the body. It is the second most common recessive disorder in individuals of European descent and is present in all populations. Accurate tools exist for diagnosing SMA from genome sequencing data. However, there are no publicly available tools for GRCh38-aligned data from panel or exome sequencing assays which continue to be used as first line tests for neuromuscular disorders. This deficiency creates a critical gap in our ability to diagnose SMA in large existing rare disease cohorts, as well as newly sequenced exome and panel datasets. We therefore developed and extensively validated a new tool - SMA Finder - that can diagnose SMA not only in genome, but also exome and panel sequencing samples aligned to GRCh37, GRCh38, or T2T-CHM13. It works by evaluating aligned reads that overlap the c.840 position of SMN1 and SMN2 in order to detect the most common molecular causes of SMA. We applied SMA Finder to 16,626 exomes and 3,911 genomes from heterogeneous rare disease cohorts sequenced at the Broad Institute Center for Mendelian Genomics as well as 1,157 exomes and 8,762 panel sequencing samples from Tartu University Hospital. SMA Finder correctly identified all 16 known SMA cases and reported nine novel diagnoses which have since been confirmed by clinical testing, with another four novel diagnoses undergoing validation. Notably, out of the 29 total SMA positive cases, 23 had an initial clinical diagnosis of muscular dystrophy, congenital myasthenic syndrome, or myopathy. This underscored the frequency with which SMA can be misdiagnosed as other neuromuscular disorders and confirmed the utility of using SMA Finder to reanalyze phenotypically diverse neuromuscular disease cohorts. Finally, we evaluated SMA Finder on 198,868 individuals that had both exome and genome sequencing data within the UK Biobank (UKBB) and found that SMA Finder's overall false positive rate was less than 1 / 200,000 exome samples, and its positive predictive value (PPV) was 97%. We also observed 100% concordance between UKBB exome and genome calls. This analysis showed that, even though it is located within a segmental duplication, the most common causal variant for SMA can be detected with comparable accuracy to monogenic disease variants in non-repetitive regions. Additionally, the high PPV demonstrated by SMA Finder, the existence of treatment options for SMA in which early diagnosis is imperative for therapeutic benefit, as well as widespread availability of clinical confirmatory testing for SMA, warrants the addition of SMN1 to the ACMG list of genes with reportable secondary findings after genome and exome sequencing.
- Publikační typ
- časopisecké články MeSH
- preprinty MeSH
Patient-specific approach is gaining a wide popularity in computational simulations of biomechanical systems. Simulations (most often based on the finite element method) are to date routinely created using data from imaging devices such as computed tomography which makes the models seemingly very complex and sophisticated. However, using a computed tomography in finite element calculations does not necessarily enhance the quality or even credibility of the models as these depend on the quality of the input images. Low-resolution (medical-)CT datasets do not always offer detailed representation of trabecular bone in FE models and thus might lead to incorrect calculation of mechanical response to external loading. The effect of image resolution on mechanical simulations of bone-implant interaction has not been thoroughly studied yet. In this study, the effect of image resolution on the modeling procedure and resulting mechanical strains in bone was analyzed on the example of cranial implant. For this purpose, several finite element models of bone interacting with fixation-screws were generated using seven computed tomography datasets of a bone specimen but with different image resolutions (ranging from micro-CT resolution of 25 μm to medical-CT resolution of 1250 μm). The comparative analysis revealed that FE models created from images of low resolution (obtained from medical computed tomography) can produce biased results. There are two main reasons: 1. Medical computed tomography images do not allow generating models with complex trabecular architecture which leads to substituting of the intertrabecular pores with a fictitious mass; 2. Image gray value distribution can be distorted resulting in incorrect mechanical properties of the bone and thus in unrealistic or even completely fictitious mechanical strains. The biased results of calculated mechanical strains can lead to incorrect conclusion, especially when bone-implant interaction is investigated. The image resolution was observed not to significantly affect stresses in the fixation screw itself; however, selection of bone material representation might result in significantly different stresses in the screw.
- Klíčová slova
- Bone tissue, Computational modeling, Computed tomography, Finite element method, Image resolution, Mechanical strain,
- MeSH
- analýza metodou konečných prvků MeSH
- biomechanika MeSH
- kosti a kostní tkáň * MeSH
- kostní šrouby * MeSH
- lidé MeSH
- mechanický stres MeSH
- rentgenová mikrotomografie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Genetic differentiation and phenotypic plasticity jointly shape intraspecific trait variation, but their roles differ among traits. In short-lived plants, reproductive traits may be more genetically determined due to their impact on fitness, whereas vegetative traits may show higher plasticity to buffer short-term perturbations. Combining a multi-treatment greenhouse experiment with observational field data throughout the range of a widespread short-lived herb, Plantago lanceolata, we (1) disentangled genetic and plastic responses of functional traits to a set of environmental drivers and (2) assessed how genetic differentiation and plasticity shape observational trait-environment relationships. Reproductive traits showed distinct genetic differentiation that largely determined observational patterns, but only when correcting traits for differences in biomass. Vegetative traits showed higher plasticity and opposite genetic and plastic responses, masking the genetic component underlying field-observed trait variation. Our study suggests that genetic differentiation may be inferred from observational data only for the traits most closely related to fitness.
- Klíčová slova
- biomass, common garden experiment, countergradient variation, fecundity, genotype by environment interaction, intraspecific trait variation, observational datasets, root:shoot ratio, specific leaf area, widespread species,
- MeSH
- biomasa MeSH
- fenotyp MeSH
- fyziologická adaptace MeSH
- masky * MeSH
- Plantago * MeSH
- Publikační typ
- dopisy MeSH
AIMS: To evaluate our proposed multivariate approach to identify patients who will develop sight-threatening diabetic retinopathy (STDR) within a 1-year screen interval, and explore the impact of simple stratification rules on prediction. MATERIALS AND METHODS: A 7-year dataset (2009-2016) from people with diabetes (PWD) was analysed using a novel multivariate longitudinal discriminant approach. Level of diabetic retinopathy, assessed from routine digital screening photographs of both eyes, was jointly modelled using clinical data collected over time. Simple stratification rules based on retinopathy level were also applied and compared with the multivariate discriminant approach. RESULTS: Data from 13 103 PWD (49 520 screening episodes) were analysed. The multivariate approach accurately predicted whether patients developed STDR or not within 1 year from the time of prediction in 84.0% of patients (95% confidence interval [CI] 80.4-89.7), compared with 56.7% (95% CI 55.5-58.0) and 79.7% (95% CI 78.8-80.6) achieved by the two stratification rules. While the stratification rules detected up to 95.2% (95% CI 92.2-97.6) of the STDR cases (sensitivity) only 55.6% (95% CI 54.5-56.7) of patients who did not develop STDR were correctly identified (specificity), compared with 85.4% (95% CI 80.4-89.7%) and 84.0% (95% CI 80.7-87.6%), respectively, achieved by the multivariate risk model. CONCLUSIONS: Accurate prediction of progression to STDR in PWD can be achieved using a multivariate risk model whilst also maintaining desirable specificity. While simple stratification rules can achieve good levels of sensitivity, the present study indicates that their lower specificity (high false-positive rate) would therefore necessitate a greater frequency of eye examinations.
- Klíčová slova
- cohort study, diabetic retinopathy, observational study, primary care,
- MeSH
- časná diagnóza MeSH
- datové soubory jako téma MeSH
- diabetes mellitus 2. typu komplikace diagnóza epidemiologie patologie MeSH
- diabetická retinopatie diagnóza epidemiologie MeSH
- dospělí MeSH
- individualita MeSH
- individualizovaná medicína metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- plošný screening metody MeSH
- progrese nemoci MeSH
- rizikové faktory MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- hodnotící studie MeSH
- práce podpořená grantem MeSH
BACKGROUND: Treatment options for Waldenström's macroglobulinaemia are heterogeneous, and no well established treatment standards exist. Although guidelines from the Eighth International Workshop on Waldenstrom's Macroglobulinemia were published in 2016, inconsistent awareness and budget constraints have prevented their widespread implementation, and real-life treatment patterns might differ across health-care systems. We aimed to generate information about treatment and outcome patterns for patients with Waldenström's macroglobulinaemia outside of clinical trials. METHODS: In this large, observational, retrospective chart review, academic and community physicians in ten European countries were invited to retrospectively complete electronic records for patients with symptomatic Waldenström's macroglobulinaemia who had begun treatment after Jan 1, 2000, and before Jan 1, 2014, and had available clinical and biological data. The primary endpoints were reasons for treatment initiation, treatment choices, progression-free survival, and overall survival. We assessed the variables that affected choice of front-line therapy, progression-free survival, and overall survival in multivariate analyses. FINDINGS: Electronic records were reviewed for 454 eligible patients. The most frequent reasons for starting front-line treatment were anaemia (in 328 [72%] patients) and constitutional symptoms (in 264 [58%] patients). Choice of therapy varied between front-line, second-line, and third-line approaches; age; and type of institution. In the front-line setting, 193 (43%) of 454 patients received monotherapy, 164 (36%) received chemoimmunotherapy, and 95 (21%) received other combination regimens (data on front-line treatment were missing for one patient, and another patient received only steroids). After front-line treatment, median progression-free survival was 29 months (95% CI 25-31), median overall survival was not reached (not reached-not reached), and 10-year overall survival was 69% (62-74). In multivariate analyses, patients who were high risk according to the International Prognostic Scoring System for Waldenström Macroglobulinemia had significantly worse progression-free survival and overall survival than did those who were low risk. Additionally, progression-free survival was shortened in patients treated with monotherapy compared with those treated with chemoimmunotherapy or other combination therapies and in those treated at an academic institution compared with those treated in the community. Constitutional symptoms (excluding fatigue) were associated with worsened overall survival. INTERPRETATION: This large observational dataset should inform and help set guidelines, and improve understanding of treatment practices and outcomes, for European patients with Waldenström's macroglobulinaemia. FUNDING: Pharmacyclics LLC (an AbbVie company).
- MeSH
- biologické markery MeSH
- Kaplanův-Meierův odhad MeSH
- kombinovaná terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- management nemoci MeSH
- multivariační analýza MeSH
- přežití bez známek nemoci MeSH
- retrospektivní studie MeSH
- senioři MeSH
- určení symptomu MeSH
- věkové faktory MeSH
- výsledek terapie MeSH
- Waldenströmova makroglobulinemie diagnóza epidemiologie terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
- Názvy látek
- biologické markery MeSH
OBJECTIVE: To investigate the clinical outcomes of patients who underwent cardioversion compared with those who did not have cardioverson in a large dataset of patients with recent onset non-valvular atrial fibrillation. DESIGN: Observational study using prospectively collected registry data (Global Anticoagulant Registry in the FIELD-AF-GARFIELD-AF). SETTING: 1317 participating sites in 35 countries. PARTICIPANTS: 52 057 patients aged 18 years and older with newly diagnosed atrial fibrillation (up to six weeks' duration) and at least one investigator determined stroke risk factor. MAIN OUTCOME MEASURES: Comparisons were made between patients who received cardioversion and those who had no cardioversion at baseline, and between patients who received direct current cardioversion and those who had pharmacological cardioversion. Overlap propensity weighting with Cox proportional hazards models was used to evaluate the effect of cardioversion on clinical endpoints (all cause mortality, non-haemorrhagic stroke or systemic embolism, and major bleeding), adjusting for baseline risk and patient selection. RESULTS: 44 201 patients were included in the analysis comparing cardioversion and no cardioversion, and of these, 6595 (14.9%) underwent cardioversion at baseline. The propensity score weighted hazard ratio for all cause mortality in the cardioversion group was 0.74 (95% confidence interval 0.63 to 0.86) from baseline to one year follow-up and 0.77 (0.64 to 0.93) from one year to two year follow-up. Of the 6595 patients who had cardioversion at baseline, 299 had a follow-up cardioversion more than 48 days after enrolment. 7175 patients were assessed in the analysis comparing type of cardioversion: 2427 (33.8%) received pharmacological cardioversion and 4748 (66.2%) had direct current cardioversion. During one year follow-up, event rates (per 100 patient years) for all cause mortality in patients who received direct current and pharmacological cardioversion were 1.36 (1.13 to 1.64) and 1.70 (1.35 to 2.14), respectively. CONCLUSION: In this large dataset of patients with recent onset non-valvular atrial fibrillation, a small proportion were treated with cardioversion. Direct current cardioversion was performed twice as often as pharmacological cardioversion, and there appeared to be no major difference in outcome events for these two cardioversion modalities. For the overall cardioversion group, after adjustments for confounders, a significantly lower risk of mortality was found in patients who received early cardioversion compared with those who did not receive early cardioversion. STUDY REGISTRATION: ClinicalTrials.gov NCT01090362.
- MeSH
- elektrická defibrilace metody mortalita MeSH
- fibrilace síní mortalita patologie terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- příčina smrti MeSH
- proporcionální rizikové modely MeSH
- prospektivní studie MeSH
- registrace MeSH
- senioři MeSH
- tendenční skóre MeSH
- terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
Tropical forests store 40-50 per cent of terrestrial vegetation carbon1. However, spatial variations in aboveground live tree biomass carbon (AGC) stocks remain poorly understood, in particular in tropical montane forests2. Owing to climatic and soil changes with increasing elevation3, AGC stocks are lower in tropical montane forests compared with lowland forests2. Here we assemble and analyse a dataset of structurally intact old-growth forests (AfriMont) spanning 44 montane sites in 12 African countries. We find that montane sites in the AfriMont plot network have a mean AGC stock of 149.4 megagrams of carbon per hectare (95% confidence interval 137.1-164.2), which is comparable to lowland forests in the African Tropical Rainforest Observation Network4 and about 70 per cent and 32 per cent higher than averages from plot networks in montane2,5,6 and lowland7 forests in the Neotropics, respectively. Notably, our results are two-thirds higher than the Intergovernmental Panel on Climate Change default values for these forests in Africa8. We find that the low stem density and high abundance of large trees of African lowland forests4 is mirrored in the montane forests sampled. This carbon store is endangered: we estimate that 0.8 million hectares of old-growth African montane forest have been lost since 2000. We provide country-specific montane forest AGC stock estimates modelled from our plot network to help to guide forest conservation and reforestation interventions. Our findings highlight the need for conserving these biodiverse9,10 and carbon-rich ecosystems.
- MeSH
- biomasa MeSH
- datové soubory jako téma MeSH
- deštný prales * MeSH
- geografická kartografie MeSH
- klimatické změny MeSH
- postoj * MeSH
- sekvestrace uhlíku * MeSH
- stromy metabolismus MeSH
- tropické klima * MeSH
- uhlík analýza MeSH
- zachování přírodních zdrojů MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Afrika MeSH
- Názvy látek
- uhlík MeSH
BACKGROUND: Severe sepsis/septic shock is associated with high mortality. In Central Europe, there is a dearth of information on the prevalence and treatment of severe sepsis. The EPOSS (Data-based Evaluation and Prediction of Outcome in Severe Sepsis) project launched in 2011 was aimed at collecting data on patients with severe sepsis/septic shock. METHODS: The EPOSS study processes data from the EPOSS project database, and is a retrospective, multicentre, observational study. This included all consecutive patients aged 18 and over who were admitted to participating ICUs from 1 January 2011 to 5 November 2013 and met the inclusion criteria of severe sepsis/septic shock. The primary endpoint was to analyse the relationship between in-hospital mortality (either in ICU or after discharge from ICU) and the type and number of fulfilled diagnostic and treatment interventions during the first 6 h after the diagnosis of severe sepsis/septic shock. RESULTS: The collected dataset involved 1082 patients meeting the criteria of severe sepsis/septic shock. Following data validation, a final dataset of 897 patients was obtained. The average age of the patient group was 64.7 years; mortality at discharge from EPOSS ICUs was 35.5% and from hospital 40.7%. Of the 10 evaluated diagnostic and treatment interventions within the initial 6 hours of identifying severe sepsis/septic shock (i.e. fulfilment of SSC bundles), four or five diagnostic and treatment interventions were administered to 58.4% patients. Combined diagnostic and treatment interventions associated with the lowest in-hospital mortality were: CVP of ≥8-12 mm Hg & MAP of ≥65 mm Hg & Urine output at ≥0.5 mL/kg/h & Lactate of ≤4.0 mmol/L & Initial lactate measured & Antibiotics in the first hour. Lactate at <4 mmol/L and MAP of ≥65 mm Hg remained statistically significant even after adjustment for patient age and APACHE II score. Statistically significantly increased in-hospital mortality was found in patients admitted from general departments (45.7%) or from other ICUs (41.6%), compared to a lower in-hospital mortality of patients transferred from outpatient clinics (26.5%) or Emergency (38.0%). Severe sepsis/septic shock patients transferred from the department of internal medicine were associated with a higher in-hospital mortality (45.1%) than surgical patients (35.5%). CONCLUSIONS: The most effective measures associated with the lowest in-hospital mortality in septic shock patients were CVP of ≥8-12 mm Hg, MAP of ≥65 mm Hg, urine output at ≥0.5 mL/kg/h, initial lactate level of ≤4.0 mmol/L and administration of antibiotics within the first hour.
- Klíčová slova
- assessment, lactate, mortality, septic shoc, severe sepsis,
- MeSH
- dospělí MeSH
- jednotky intenzivní péče statistika a číselné údaje MeSH
- lidé středního věku MeSH
- lidé MeSH
- mortalita v nemocnicích MeSH
- péče o pacienty v kritickém stavu statistika a číselné údaje MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sepse mortalita MeSH
- septický šok mortalita MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- Geografické názvy
- Česká republika epidemiologie MeSH