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The exploration of the metabolites in the degradation pathways of vitamin D (VTD) has gained importance in recent years and simultaneous quantitation of twenty-five-hydroxy vitamin D (25(OH)D) mass concentration together with 24,25-dihydroxyvitamin D (24,25(OH)2D) has been proposed as a newer approach to define VTD deficiency. Yet, no data are available on 24,25(OH)2D biological variation (BV). In this study, we evaluated 24,25(OH)2D's BV on the European Biological Variation Study (EuBIVAS) cohort samples to determine if analytical performance specifications (APS) for 24,25(OH)2D could be generated. Six European laboratories recruited 91 healthy participants. 25(OH)D and 24,25(OH)2D concentrations in K3-EDTA plasma were examined weekly for up to 10 weeks in duplicate with a validated LC-MS/MS method. The Vitamin D Metabolite Ratio (24,25(OH)2D divided by 25(OH)D × 100) was also calculated at each time point. Linear regression of the mean 24,25(OH)2D concentrations at each blood collection showed participants were not in steady state. Variations of 24,25(OH)2D over time were significantly positively associated with the slopes of 25(OH)D concentrations over time and the concentration of 25(OH)D of the participant at inclusion, and negatively associated with body mass index (BMI), but not with age, gender, or location of the participant. The variation of the 24,25(OH)2D concentration in participants over a 10 weeks period was 34.6%. Methods that would detect a significant change linked to the natural production of 24,25(OH)2D over this period at p<0.05 would need a relative measurement uncertainty (u%)<14.9% while at p<0.01, relative measurement uncertainty should be <10.5%. We have defined for the first time APS for 24,25(OH)2D examinations. According to the growing interest in this metabolite, several laboratories and manufacturers might aim to develop specific methods for its determination. The results presented in this paper are thus necessary prerequisites for the validation of such methods. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) is an acute-phase protein which is synthesized by the liver in response to the secretion of several inflammatory cytokines including interleukin 6 (IL-6), IL-1 and tumor necrosis factor (TNF). CRP was the first acute-phase protein to be described and adopted in clinical laboratories as an exquisitely sensitive systemic marker of inflammation and tissue damage. The measurement of CRP is widely used for the diagnosis and monitoring of inflammatory conditions, including sepsis, trauma, and malignancies. In the last decades, impressive advances in analytical methods (from qualitative to high-sensitivity assays), automation and availability of results in a short time, not only translated in an increasing demand for the right management of systemic inflammatory diseases, but also in evaluating subclinical inflammatory processes underlying atherothrombotic events. CRP measurement is one of the most requested laboratory tests for both the wide range of clinical conditions in which it may assure a valuable information and some analytical advantages due to the evidence that it is a "robust biomarker". Even recently, the measurement of CRP received new interest, particularly as a biomarker of severity of Coronavirus disease 2019 (COVID-19), and it deserves further concern for improving demand appropriateness and result interpretation. [ABSTRACT FROM AUTHOR]

A circadian regulation of renal function it has been described in the last few years. An intradaily variation in glomerular filtration rate (eGFR) has also been discovered at the individual level. The aim of this study was to check if there exists a circadian pattern of eGFR at population data group level and to compare the population results with those described at individual level. We have studied a total of 446,441 samples analysed in the emergency laboratories of two Spanish hospitals between January 2015 and December 2019. We selected all the records of eGFR values between 60 and 140 mL/min/1.73 m2 using CKD-EPI formula from patients between 18 and 85 years. The intradaily intrinsic eGFR pattern was computed using the extraction time of day in four nested mixed linear and sinusoidal regression models. All models showed an intradaily eGFR pattern, but the estimated model coefficients differed depending on whether age was included. The inclusion of age improved the performance of the model. In this model, the acrophase occurred at 7:46 h. We describe the distribution of eGFR values depending on the time in two different populations. This distribution is adjusted to a circadian rhythm that behaves similarly to the individual rhythm. This pattern is similar in each of the years studied from each hospital as well as between both hospitals. The results found suggest the incorporation of the concept of "population circadian rhythm" into the scientific world. [ABSTRACT FROM AUTHOR]

Geometric morphometrics is widely used to quantify morphological variation between biological specimens, but the fundamental influence of operator bias on data reproducibility is rarely considered, particularly in studies using photographs of live animals taken under field conditions. We examined this using four independent operators that applied an identical landmarking scheme to replicate photographs of 291 live Atlantic salmon (Salmo salar L.) from two rivers. Using repeated measures tests, we found significant inter-operator differences in mean body shape, suggesting that the operators introduced a systematic error despite following the same landmarking scheme. No significant differences were detected when the landmarking process was repeated by the same operator on a random subset of photographs. Importantly, in spite of significant operator bias, small but statistically significant morphological differences between fish from the two rivers were found consistently by all operators. Pairwise tests of angles of vectors of shape change showed that these between-river differences in body shape were analogous across operator datasets, suggesting a general reproducibility of findings obtained by geometric morphometric studies. In contrast, merging landmark data when fish from each river are digitised by different operators had a significant impact on downstream analyses, highlighting an intrinsic risk of bias. Overall, we show that, even when significant inter-operator error is introduced during digitisation, following an identical landmarking scheme can identify morphological differences between populations. This study indicates that operators digitising at least a sub-set of all data groups of interest may be an effective way of mitigating inter-operator error and potentially enabling data sharing. [ABSTRACT FROM AUTHOR]

Cell state atlases constructed through single-cell RNA-seq and ATAC-seq analysis are powerful tools for analyzing the effects of genetic and drug treatment-induced perturbations on complex cell systems. Comparative analysis of such atlases can yield new insights into cell state and trajectory alterations. Perturbation experiments often require that single-cell assays be carried out in multiple batches, which can introduce technical distortions that confound the comparison of biological quantities between different batches. Here we propose CODAL, a variational autoencoder-based statistical model which uses a mutual information regularization technique to explicitly disentangle factors related to technical and biological effects. We demonstrate CODAL's capacity for batch-confounded cell type discovery when applied to simulated datasets and embryonic development atlases with gene knockouts. CODAL improves the representation of RNA-seq and ATAC-seq modalities, yields interpretable modules of biological variation, and enables the generalization of other count-based generative models to multi-batched data. Comparing single-cell RNA-seq and ATAC-seq data from multiple batches is challenging due to technical artifacts. Here, the authors propose a method that disentangles technical and biological effects, facilitating batch-confounded chromatin and gene expression state discovery and enhancing the analysis of perturbation effects on cell populations. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer has become one of the top health concerns for women, and triple-negative breast cancer (TNBC) leads to treatment resistance and poor prognosis due to its high degree of heterogeneity and malignancy. Reactive oxygen species (ROS) have been found to play a dual role in tumors, and modulating ROS levels may provide new insights into prognosis and tumor treatment. Methods: This study attempted to establish a robust and valid ROS signature (ROSig) to aid in assessing ROS levels. The driver ROS prognostic indicators were searched based on univariate Cox regression. A well-established pipeline integrating 9 machine learning algorithms was used to generate the ROSig. Subsequently, the heterogeneity of different ROSig levels was resolved in terms of cellular communication crosstalk, biological pathways, immune microenvironment, genomic variation, and response to chemotherapy and immunotherapy. In addition, the effect of the core ROS regulator HSF1 on TNBC cell proliferation was detected by cell counting kit-8 and transwell assays. Results: A total of 24 prognostic ROS indicators were detected. A combination of the Coxboost+ Survival Support Vector Machine (survival-SVM) algorithm was chosen to generate ROSig. ROSig proved to be the superior risk predictor for TNBC. Cellular assays show that knockdown of HSF1 can reduce the proliferation and invasion of TNBC cells. The individual risk stratification based on ROSig showed good predictive accuracy. High ROSig was identified to be associated with higher cell replication activity, stronger tumor heterogeneity, and an immunosuppressive microenvironment. In contrast, low ROSig indicated a more abundant cellular matrix and more active immune signaling. Low ROSig has a higher tumor mutation load and copy number load. Finally, we found that low ROSig patients were more sensitive to doxorubicin and immunotherapy. Conclusion: In this study, we developed a robust and effective ROSig model that can be used as a reliable indicator for prognosis and treatment decisions in TNBC patients. This ROSig also allows a simple assessment of TNBC heterogeneity in terms of biological function, immune microenvironment, and genomic variation. [ABSTRACT FROM AUTHOR]

A challenge in the development of dry powder formulations for inhalation is the poor reproducibility of their administration to small laboratory animals. The currently used devices for the pulmonary administration of dry powder formulations to small rodents often function sub-optimally as they use the same puff of air for both powder dispersion and aerosol delivery. As a result, either the air volume and flow rate are too low for complete powder deagglomeration or they are too high for effective aerosol delivery to the lungs of the animal. Therefore, novel and better devices are desired. We here present an aerosol generator designed to administer a pre-generated aerosol to the lungs of mice. By mapping the complex relationship between the airflow rate, delivery time and emitted dose, we were able to control the amount of powder being delivered from the aerosol generator. The emitted aerosol had a size range favorable for lung deposition and could be measured reproducibly. Nevertheless, in vivo fluorescent imaging still revealed considerable differences between the mice in terms of the dose deposited and the distribution of powder over the lungs, suggesting that a certain biological variation in lung deposition is inevitable. [ABSTRACT FROM AUTHOR]

With the advancement of science and technology the diagnostic modality has been gradually getting integrated with the health care, thereby evolving into a new discipline of lab medicine. Therefore, the role of lab is no more limited to analytical phase only but expanded to clinical decision making and management planning. This demanded better quality assurance in lab reporting. The advent of sophisticated technology in clinical biochemistry lab, the error in analytical phase is drastically reduced, However, the preanalytical including biological variations has emerged as the major source of variations in the lab report. Therefore, definite need has been felt to think beyond the total error paradigm of lab quality control, resulting into the concept of uncertainty which can accommodate all possible components of the lab medicine as a probable source of uncertainty in the lab result. The knowledge and implication of the measurement of uncertainty seems to be challenging for the lab professional as well as the clinicians due to apparent complexity of the statistical methods involved and also for the lack of accessibility and orientation regarding the requisite computer applications. The regulatory guidelines are endorsing uncertainty measurement. Hence, it might be imperative to embrace this system in near future. [ABSTRACT FROM AUTHOR]

Urine samples are frequently used in the clinical practice. In our study, we aimed to calculate the biological variations (BV) of analytes and analyte/creatinine ratios measured in spot urine. Second-morning spot urine samples were collected from 33 (16 female, 17 male) healthy volunteers once weekly for 10 weeks and analyzed in the Roche Cobas 6,000 instrument. Statistical analyzes were performed using BioVar, an online BV calculation software. The data were evaluated in terms of normality, outliers, steady state, homogeneity of the data, and BV values were obtained by analysis of variance (ANOVA). A strict protocol was established for within-subject (CVI) and between-subject (CVG) estimates for both genders. There was a significant difference between female/male CVI estimates of all analytes except potassium, calcium and magnesium. No difference was found in CVG estimates. When the analytes that had a significant difference in CVI estimates in spot urine analytes were compared to creatinine, it was observed that the significant difference between the genders disappeared. There was no significant difference between female/male CVI and CVG estimates in all spot urine analyte/creatinine ratios. Since the CVI estimates of analyte/creatinine ratios are lower, it would be more reasonable to use them in result reporting. Reference ranges should be used with caution, since II values of almost all parameters are between 0.6 and 1.4. The CVI detection power of our study is 1, which is the highest value. [ABSTRACT FROM AUTHOR]

The diagnosis and monitoring of bleeding and thrombotic disorders depend on correct haemostatic measurements. The availability of high-quality biological variation (BV) data is important in this context. Many studies have reported BV data for these measurands, but results are varied. The present study aims to deliver global within-subject (CVI) and between-subject (CVG) BV estimates for haemostasis measurands by meta-analyses of eligible studies, by assessment with the Biological Variation Data Critical Appraisal Checklist (BIVAC). Relevant BV studies were graded by the BIVAC. Weighted estimates for CVI and CVG were obtained via meta-analysis of the BV data derived from BIVAC-compliant studies (graded A–C; whereby A represents optimal study design) performed in healthy adults. In 26 studies BV data were reported for 35 haemostasis measurands. For 9 measurands, only one eligible publication was identified and meta-analysis could not be performed. 74% of the publications were graded as BIVAC C. The CVI and CVG varied extensively between the haemostasis measurands. The highest estimates were observed for PAI-1 antigen (CVI 48.6%; CVG 59.8%) and activity (CVI 34.9%; CVG 90.2%), while the lowest were observed for activated protein C resistance ratio (CVI 1.5%; CVG 4.5%). This study provides updated BV estimates of CVI and CVG with 95% confidence intervals for a wide range of haemostasis measurands. These estimates can be used to form the basis for analytical performance specifications for haemostasis tests used in the diagnostic work-up required in bleeding- and thrombosis events and for risk assessment. [ABSTRACT FROM AUTHOR]

Plasma uracil is a new biomarker to assess the activity of dihydropyrimidine dehydrogenase before cancer treatment with fluoropyrimidine drugs. Knowledge on the biological variation of plasma uracil is important to assess the applicability of plasma uracil as a biomarker of drug tolerance and efficacy. A total of 33 apparently healthy individuals were submitted to sequential blood draws for three days. On the second day, blood draws were performed every third hour for 12 h. Plasma uracil was quantified by LC-MS/MS. The within-subject (CVI) and between-subject (CVG) biological variation estimates were calculated using linear mixed-effects models. The overall median value of plasma uracil was 10.6 ng/mL (range 5.6–23.1 ng/mL). The CVI and CVG were 13.5 and 22.1%, respectively. Plasma uracil remained stable during the day, and there was no day-to-day variation observed. No differences in biological variation components were found between sex and no correlation to age was found. Four samples were calculated to be required to estimate the homeostatic set-point ±15% with 95% confidence. Plasma uracil is subject to tight homeostatic regulation without semidiurnal and day-to-day variation, however between-subject variation exists. This emphasizes plasma uracil as a well-suited biomarker for evaluation of dihydropyrimidine dehydrogenase activity, but four samples are required to establish the homeostatic set-point in a patient. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the results of five methods for the determination of total 25(OH)D. For that purpose, two mass spectrometry and three immunoassay methods were used. A total of 124 serum samples were analyzed on five different methods (i.e., a reference LC-MS/MS, Cascadion, Lumipulse, Roche Elecsys II and Roche Elecsys III). Analytical performance against LC-MS/MS was evaluated and compared to the Milan models 1 (analytical performance based on the clinical outcome using thresholds of 12, 20 and 30 ng/mL) and 2 (analytical performance based on biological variation). Additionally, imprecision studies and accuracy using NIST SRM972a samples were carried out. Compared to the reference LC-MS/MS method, the Lumipulse and the Roche Elecsys III assays reached the optimal criterion for bias, while the Cascadion met the desirable one. The Roche Elecsys II was not able to reach the minimal criteria. The proportion of correctly classified patients was higher using the Cascadion (95.2%) compared to the three immunoassays. In addition to its better precision, the Cascadion was not impacted by a high concentration of 3-epi-25(OH)D3 compared to the three immunoassays. Compared to the LC-MS/MS reference method, the Cascadion presented the highest level of concordance at medical decision cut-offs for total 25(OH)D and reached the desirable specification for bias. Moreover, the presence of 3-epi-25(OH)D3 in enriched samples was only problematic in immunoassay methods, and especially considering Roche Elecsys methods. The release of performant fully automated mass spectrometry assays with high throughput might therefore facilitate the wide scale adoption of LC-MS/MS, even in non-specialized clinical laboratories. [ABSTRACT FROM AUTHOR]

Background: In observational and experimental studies, allergic diseases (AD) have been reported to be associated with some types of cardiovascular diseases (CVD), as both share common pathophysiological processes involving inflammation and metabolic disorders. However, the direction of the causal association between them remains unclear. This Mendelian randomization (MR) study aims to examine the bidirectional causality between AD and CVD. Methods: We utilized publicly available genome-wide association study (GWAS) summary statistics data from European participants in the UK Biobank and the IEU Open GWAS database. Genetic variants associated with AD, asthma, and CVD were identified and used as instrumental variables to investigate the genetically causal association between them. MR analyses were performed using various analytical methods, including inverse variance weighted-fixed effects (IVW-FE), inverse variance weighted-multiplicative random effects (IVW-RE), MR-Egger, weighted median, weighted mode, and maximum likelihood. Sensitivity tests were conducted to assess the validity of the causality. Results: The MR analysis with the IVW method revealed a genetically predicted association between AD and essential hypertension [odds ratio (OR)=0.9987, 95% confidence interval (CI): 0.9976-0.9998, P=0.024], as well as between asthma and atrial fibrillation (OR=1.001, 95% CI: 1.0004-1.0017, P=6.43E-05). In the reverse MR analyses, heart failure was associated with allergic diseases (OR=0.0045, 95% CI: 1.1890E-04 - 0.1695, P=0.004), while atherosclerosis (OR=8.7371E-08, 95% CI: 1.8794E-14 - 4.0617E-01, P=0.038) and aortic aneurysm and dissection (OR=1.7367E-07, 95% CI: 3.8390E-14 – 7.8567E-01, P=0.046) might be protective factors of asthma. However, after a Bonferroni correction, only the association between asthma and atrial fibrillation remained robust. Conclusion: The MR study revealed that asthma is a predominant risk of atrial fibrillation in European individuals, consistent with most experimental and observational studies. Whether AD affects other CVD and the causality between them needs further investigation. [ABSTRACT FROM AUTHOR]

Background: Perfusion imaging has the potential to identify neurodegenerative disorders in a preclinical stage. However, to correctly interpret perfusion-derived parameters, the impact of perfusion modifiers should be evaluated. Objective: In this systematic review, the impact of acute and chronic intake of four acetylcholinesterase inhibitors (AChEIs) on cerebral perfusion in adults was investigated: physostigmine, donepezil, galantamine, and rivastigmine. Results: Chronic AChEI treatment results in an increase of cerebral perfusion in treatment-responsive patients with Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease dementia in the frontal, parietal, temporal, and occipital lobes, as well as the cingulate gyrus. These effects appear to be temporary, dose-related, and consistent across populations and different AChEI types. On the contrary, further perfusion decline was reported in patients not receiving AChEIs or not responding to the treatment. Conclusion: AChEIs appear to be a potential perfusion modifier in neurodegenerative patients. More research focused on quantitative perfusion in both patients with and without a cholinergic deficit is needed to draw conclusions on whether AChEI intake should be considered when analyzing perfusion data. [ABSTRACT FROM AUTHOR]

Motivation Transcriptional profiles of diverse tissues provide significant insights in both fundamental and translational researches, while transcriptome information is not always available for tissues that require invasive biopsies. Alternatively, predicting tissue expression profiles from more accessible "surrogate" samples, especially blood transcriptome, has become a promising strategy when invasive procedures are not practical. However, existing approaches ignore tissue-shared intrinsic relevance, inevitably limiting predictive performance. Results We propose a unified deep learning-based multi-task learning framework, multi-tissue transcriptome mapping (MTM), enabling the prediction of individualized expression profiles from any available tissue of an individual. By jointly leveraging individualized cross-tissue information from reference samples through multi-task learning, MTM achieves superior sample-level and gene-level performance on unseen individuals. With the high prediction accuracy and the ability to preserve individualized biological variations, MTM could facilitate both fundamental and clinical biomedical research. Availability and implementation MTM's code and documentation are available upon publication on GitHub (https://github.com/yangence/MTM). [ABSTRACT FROM AUTHOR]

Suboptimal conditions during development can shorten telomeres, the protective DNA caps on the end of chromosomes. Shorter early‐life telomere length (TL) can indicate reduced somatic maintenance, leading to lower survival and shorter lifespan. However, despite some clear evidence, not all studies show a relationship between early‐life TL and survival or lifespan, which may be due to differences in biology or study design (e.g., survival period measured). In superb fairy‐wrens (Malurus cyaneus), we assessed whether early‐life TL predicts mortality across different life‐history stages (fledgling, juvenile, adult). However, in contrast to a similar study on a congener, early‐life TL did not predict mortality across any life stage in this species. We then performed a meta‐analysis including 32 effect sizes from 23 studies (15 birds and three mammals) to quantify the effect of early‐life TL on mortality whilst taking into consideration potential sources of biological and methodological variation. Overall, the effect of early‐life TL on mortality was significant, corresponding to a 15% reduction in mortality risk with each standard deviation increase in TL. However, the effect became weaker when correcting for publication bias. Contrary to our predictions, there was no evidence that effects of early‐life TL on mortality varied with species lifespan or the period over which survival was measured. However, negative effects of early‐life TL on mortality risk were pervasive throughout life. These results imply that effects of early‐life TL on mortality are more likely to be context‐dependent than age‐dependent, although substantial power and publication bias issues highlight the need for more research. [ABSTRACT FROM AUTHOR]

Human tissue samples are often mixtures of heterogeneous cell types, which can confound the analyses of gene expression data derived from such tissues. The cell type composition of a tissue sample may itself be of interest and is needed for proper analysis of differential gene expression. A variety of computational methods have been developed to estimate cell type proportions using gene‐level expression data. However, RNA isoforms can also be differentially expressed across cell types, and isoform‐level expression could be equally or more informative for determining cell type origin than gene‐level expression. We propose a new computational method, IsoDeconvMM, which estimates cell type fractions using isoform‐level gene expression data. A novel and useful feature of IsoDeconvMM is that it can estimate cell type proportions using only a single gene, though in practice we recommend aggregating estimates of a few dozen genes to obtain more accurate results. We demonstrate the performance of IsoDeconvMM using a unique data set with cell type–specific RNA‐seq data across more than 135 individuals. This data set allows us to evaluate different methods given the biological variation of cell type–specific gene expression data across individuals. We further complement this analysis with additional simulations. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to perform a verification of the Dymind D7-CRP automated analyser and compare it with established analysers. Materials and methods: Analytical verification included estimation of repeatability, between run precision, within-laboratory precision, and bias in control samples with low, normal and high levels. The acceptance criteria for analytical verification were defined using the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) 2019 Biological Variation Database. Method comparison between the Dymind D7-CRP and the Sysmex XN1000 for haematological parameters and the Dymind D7-CRP and the Beckman Coulter AU680 for CRP values was performed on 40 patient samples. Results: Analytical verification criteria were adequately met with the exception of monocyte count for repeatability and within-laboratory precision (13.4% and 11.5%, respectively, acceptance criteria 10.1%) and measurement uncertainty (23.0, acceptance criteria 20.0%) at low level, eosinophil count for BIAS at the low level (37.7%, acceptance criteria 25.2%), basophil count (BAS) for BIAS at the high level (14.2%, acceptance criteria 10.9%), and mean platelet volume (MPV) for repeatability (4.2% and 6.8%), between run precision (2.2% and 4.7%), within-laboratory precision (4.0% and 7.3%) (acceptance criteria 1.7%), and measurement uncertainty (8.0 and 14.6%, acceptance criteria 3.4%) at both the low and high concentrations. Method comparison showed no clinically significant constant or proportional differences for all parameters except BAS and MPV. Conclusion: The analytical verification of the Dymind D7-CRP showed adequate analytical characteristics. The Dymind D7-CRP can be used inter- changeably with the Sysmex XN-1000 for all parameters tested, except BAS and MPV, and with the Beckman Coulter AU-680 for the determination of CRP. [ABSTRACT FROM AUTHOR]

Ecogeographic rules describe spatial patterns in biological trait variation and shed light on the drivers of such variation. In animals, a consensus is emerging that 'pioneering' traits may facilitate range shifts via a set of bold, aggressive and stress‐resilient traits. Many of these same traits are associated with more northern latitudes, and most range shifts in the northern hemisphere indicate northward movement. As a consequence, it is unclear whether pioneering traits are simply corollaries of existing latitudinal variation, or whether they override other well‐trodden latitudinal patterning as a unique ecogeographic rule of phenotypic variation.The tree swallow Tachycineta bicolor is a songbird undergoing a southward range shift in the eastern United States, in direct opposition of the poleward movement seen in most other native species' range shifts. Because this organic range shift countervails the typical direction of movement, this case study provides for unique ecological insights on organisms and their ability to thrive in our changing world.We sampled female birds across seven populations, quantifying behavioural, physiological and morphological traits. We also used GIS and field data to quantify a core set of ecological factors with strong ties to these traits as well as female performance.Females at more southern expansion sites displayed higher maternal aggression, higher baseline corticosterone and more pronounced elevation of corticosterone following a standardized stressor, contrary to otherwise largely conserved latitudinal patterning in these traits. Microhabitat variation explained some quantitative phenotypic variation, but the expansion and historic ranges did not differ in openness, distance to water or breeding density.This countervailing range shift therefore suggests that pioneering traits are not simply corollaries of existing latitudinal variation, but rather, they may override other well‐trodden latitudinal patterning as a unique ecogeographic rule of phenotypic variation. [ABSTRACT FROM AUTHOR]

• A ß-CTX decline of 40% is suggested for osteoporosis therapy success in populations. • We modelled ß-CTX decreases incorporating measurement uncertainty. • Measurement uncertainty was estimated from published assay and population data. • An observed drop in ß-CTX must be 56% for 95% confidence a 40% decrease occurred. • Application of a 40% decrease target may not be reliable for individual patients. Bone turnover markers (BTM) are measures for understanding the effect of anti-resorptives upon osteoclast activity. Post-hoc trial data suggests reduction in BTM of 40% may represent a target for defining appropriate response to therapy. We modeled clinical application of this target threshold in an individual patient setting where assay measurement uncertainty and biological variation are included. Using serum C-telo-peptide (ß-CTX), we constructed hypothetical scenarios of ß-CTX measurement pre and post bisphosphonate therapy. Using typical ß-CTX assay characteristics (analytical coefficient of variation, CV 5.0%) and published intra-individual ß-CTX data for post-menopausal women (CV 18.0%), we calculated the post-therapy ß-CTX that must be seen on single repeat measure for 95% confidence that the observed result was ≥40% below baseline. Sensitivity analyses considered greater and lesser variations in the combined sources of variation. The one-tailed 95% reference change value for any detectable therapeutic decrease in ß-CTX was 22%. However, to have 95% confidence of having achieved a reduction ≥40%, an observed ß-CTX decrease of ≥56% is required. Larger decreases are needed for scenarios of greater analytical or intra-individual variation. Although population data suggest a ß-CTX decrease of 40% is commensurate with adequate therapeutic response to anti-resorptives, application to an individual patient where measurement and natural variation are present is problematic. ß-CTX decreases much >40% are required to be confident of having achieved the optimal treatment response. It is uncertain whether this is a legitimate change to be expected in all individual patients and therefore clinical application of this threshold is uncertain. [ABSTRACT FROM AUTHOR]

In accordance with all the most recent international guidelines, the variation of circulating levels of cardiac troponins I and T, measured with high-sensitivity methods (hs-cTnI and hs-cTnT), should be used for the detection of acute myocardial injury. Recent experimental and clinical evidences have demonstrated that the evaluation of hs-cTnI and hs-cTnT variations is particularly relevant: a) for the differential diagnosis of Acute Coronary Syndromes (ACS) in patients admitted to the Emergency Department (ED); b) for the evaluation of cardiovascular risk in patients undergoing major cardiac or non-cardiac surgery, and in asymptomatic subjects of the general population aged >55 years and with co-morbidities; c) for the evaluation of cardiotoxicity caused by administration of some chemotherapy drugs in patients with malignant tumors. The aim of this document is to discuss the fundamental statistical and biological considerations on the intraindividual variability of hs-cTnI and hs-cTnT over time in the same individual. Firstly, it will be discussed in detail as the variations of circulating levels strictly depend not only on the analytical error of the method used but also on the intra-individual variability of the biomarker. Afterwards, the pathophysiological interpretation and the clinical relevance of the determination of the variability of the hs-cTnI and hs-cTnT values ​​ in patients with specific clinical conditions are discussed. Finally, the evaluation over time of the variation in circulating levels of hs-cTnI and hs-cTnT is proposed for a more accurate estimation of cardiovascular risk in asymptomatic subjects from the general population. [ABSTRACT FROM AUTHOR]

Tumor markers are well-known for being important tools in the support of diagnosis, monitoring of treatment efficacy and follow-up of cancers. CA 125, CA 15-3 and HE 4 have demonstrated potential efficacy in other clinical indications. The main objective was to evaluate the biological variation of these glycoproteins using two different immunoassays in an apparently healthy Caucasian population. Nineteen healthy volunteers including 11 women and 8 men were sampled weekly for 5 consecutive weeks. Samples were analyzed in duplicate on Lumipulse® G600II (Fujirebio) and on the Cobas e602 (Roche Diagnostics) analyzers. After assessment of normality, exclusion of outliers and analysis of homogeneity of variance, analytical variation (CVA), within-subject biological variation (CVI) and between-subject biological variation (CVG) were determined using a nested ANOVA. CVA, CVI and CVG were determined on both analyzers and both genders. For CA 125, the CVA ranges from 1.0 to 3.4%, the CVI from 5.7 to 13.8% and the CVG from 32.2 to 42.9%. For CA 15-3, the CVA is between 1.1 and 3.4%, the CVI between 3.9 and 6.5% and the CVG between 43.7 and 196.9%. Lastly, HE 4 has CVA values between 1.4 and 2.4%, CVI between 5.1 and 10.5% and CVG between 7.1 and 12.6%. Our study provided updated data on the biological variation of CA 125, HE 4 and CA 15-3. These data allow to improve the clinical interpretation and thus the management of the patient. [ABSTRACT FROM AUTHOR]

The genus Pinus represents more than a hundred different tree species, most of them forming stems that can be commercially utilised for both timber and wood pulp industry. Pines are native to most of the Northern Hemisphere, while introduced and often naturalized in the Southern Hemisphere. The sapwood of pines is considered 'not durable' but generally easy to impregnate. On the contrary, the coloured heartwood of pines is difficult to impregnate and considered 'less to moderately durable' against decay fungi, but due to varying content and composition of extractives, both moisture performance and inherent durability vary within and between species. This study reviewed the literature to quantify the extent of variability of pine wood and its potential causes. Literature data from durability tests performed under laboratory and field conditions made it possible to compile reference factors for 26 pine species. The inter-species variation of biological durability is more prominent in above-ground exposure (0.7–14.9 times higher compared to the non-durable pine sapwood) compared to soil contact scenarios (1.0–2.4). The latter might be explained by fungicidal and hydrophobic extractives of pines, which play a more dominant role in above-ground exposure compared to soil exposure with permanent wetting. [ABSTRACT FROM AUTHOR]

Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.

As social animals, many primates use acoustic communication to maintain relationships. Vocal individuality has been documented in a diverse range of primate species and call types, many of which have presumably different functions. Auditory recognition of ones neighbors may confer a selective advantage if identifying conspecifics decreases the need to participate in costly territorial behaviors. Alternatively, vocal individuality may be nonadaptive and the result of a unique combination of genetics and environment. Pair-bonded primates, in particular, often participate in coordinated vocal duets that can be heard over long distances by neighboring conspecifics. In contrast to adult calls, infant vocalizations are short-range and used for intragroup communication. Here, we provide two separate but complementary analyses of vocal individuality in distinct call types of coppery titi monkeys (Plecturocebus cupreus) to test whether individuality occurs in call types from animals of different age classes with presumably different functions. We analyzed 600 trill vocalizations from 30 infants and 169 pulse-chirp duet vocalizations from 30 adult titi monkeys. We predicted that duet contributions would exhibit a higher degree of individuality than infant trills, given their assumed function for long-distance, intergroup communication. We estimated 7 features from infant trills and 16 features from spectrograms of adult pulse-chirps, then used discriminant function analysis with leave-one-out cross-validation to classify individuals. We correctly classified infants with 48% accuracy and adults with 83% accuracy. To further investigate variance in call features, we used a multivariate variance components model to estimate variance partitioning in features across two levels: within- and between-individuals. Between-individual variance was the most important source of variance for all features in adults, and three of four features in infants. We show that pulse-chirps of adult titi monkey duets are individually distinct, and infant trills are less individually distinct, which may be due to the different functions of the vocalizations.

Clinical benefit of immune checkpoint blockade in glioblastoma (GBM) is rare, and we hypothesize that tumor clonal evolution and the immune microenvironment are key determinants of response. Here, we present a detailed molecular characterization of the intratumoral and immune heterogeneity in an IDH wild-type, MGMT-negative GBM patient who plausibly benefited from anti-PD-1 therapy with an unusually long 25-mo overall survival time. We leveraged multiplex immunohistochemistry, RNA-seq, and whole-exome data from the primary tumor and three resected regions of recurrent disease to survey regional tumor-immune interactions, genomic instability, mutation burden, and expression profiles. We found significant regional heterogeneity in the neoantigenic and immune landscape, with a differential T-cell signature among recurrent sectors, a uniform loss of focal amplifications in EGFR, and a novel subclonal EGFR mutation. Comparisons with recently reported correlates of checkpoint blockade in GBM and with TCGA-GBM revealed appreciable intratumoral heterogeneity that may have contributed to a differential PD-1 blockade response.

Changes in affect over time have been associated with health outcomes. However, previously utilized measurement methods focus on variability of affect (e.g., standard deviation, root mean squared successive difference) and ignore the more complex temporal patterns of affect over time. These patterns may be an important feature in understanding how the dynamics of affect relate to health. Recurrence quantification analysis (RQA) may help alleviate this problem by assessing temporal characteristics unassessed by past methods. RQA metrics, such as determinism and recurrence, can provide a measure of the predictability of affect over time, indexing how often patterns within affective experiences repeat. In Study 1, we first contrasted RQA metrics with commonly used measures of variability to demonstrate that RQA can further differentiate among patterns of affect. In Study 2, we analyzed the associations between these new metrics and health, namely, depressive and somatic symptoms. We found that RQA metrics predicted health above and beyond mean levels and variability of affect over time. The most desirable health outcomes were observed in people who had high mean positive affect, low mean negative affect, low affect variability, and high affect predictability. These studies are the first to demonstrate the utility of RQA for determining how temporal patterns in affective experiences are important for health outcomes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

BackgroundCleft lip and palate is one of the most common human birth defects, but the underlying etiology is poorly understood. The A/WySn mouse is a spontaneously occurring model of multigenic clefting in which 20% to 30% of individuals develop an orofacial cleft. Recent work has shown altered methylation at a specific retrotransposon insertion downstream of the Wnt9b locus in clefting animals, which results in decreased Wnt9b expression.ResultsUsing a newly developed protocol that allows us to measure morphology, gene expression, and DNA methylation in the same embryo, we relate gene expression in an individual embryo directly to its three-dimensional morphology for the first time. We find that methylation at the retrotransposon relates to Wnt9b expression and morphology. IAP methylation relates to shape of the nasal process in a manner consistent with clefting. Embryos with low IAP methylation exhibit increased among-individual variance in facial shape.ConclusionsMethylation and gene expression relate nonlinearly to nasal process morphology. Individuals at one end of a continuum of phenotypic states display a clinical phenotype and increased phenotypic variation. Variable penetrance and expressivity in this model is likely determined both by among-individual variation in methylation and changes in phenotypic robustness along the underlying liability distribution for orofacial clefting.

BackgroundCytokines, chemokines, adipocytokines, soluble cell receptors, and immune activation markers play an important role in immune responsiveness and can provide prognostic value since they reflect underlying conditions and disease states. This study was undertaken to investigate the components of biological variation for various laboratory tests of blood immunological biomarkers.ResultsEstimates of intra-individual coefficient of variation (CVI) and inter-individual coefficient of variation (CVG) were examined for blood immunological biomarkers. Biomarkers with CVI  40% were adiponectin, IL-1ra, leptin, MIP-1β, sCD163, and sIL-2Rα.ConclusionThe biological variations of biomarkers have important monitoring value for longitudinal investigation and are essential for quality specification of tests that are performed in the laboratory. The CVI was relatively small while CVG was comparatively large and mean values of each biomarker vary between subjects. The individuality of biomarkers significantly influences reference interval values. A majority of the biomarkers in this study had strong individuality and the result of each biomarker should be cautiously interpreted if using established reference interval values. Comparison of a patient's test result with previous ones may be more useful than the usage of conventional reference values.

This study intends to evaluate prenatal screening risk assessment performance based on biological variation to help clinical laboratories realize their own screening performance and set the appropriate performance specifications for prenatal screening risk assessment in China.

High levels of methylated DNA in urine represent an emerging biomarker for non-small cell lung cancer (NSCLC) detection and are the subject of ongoing research. This study aimed to investigate the circadian variation of urinary cell-free DNA (cfDNA) abundance and methylation levels of cancer-associated genes in NSCLC patients. In this prospective study of 23 metastatic NSCLC patients with active disease, patients were asked to collect six urine samples during the morning, afternoon, and evening of two subsequent days. Urinary cfDNA concentrations and methylation levels of CDO1, SOX17, and TAC1 were measured at each time point. Circadian variation and between- and within-subject variability were assessed using linear mixed models. Variability was estimated using the Intraclass Correlation Coefficient (ICC), representing reproducibility. No clear circadian patterns could be recognized for cfDNA concentrations or methylation levels across the different sampling time points. Significantly lower cfDNA concentrations were found in males (p=0.034). For cfDNA levels, the between- and within-subject variability were comparable, rendering an ICC of 0.49. For the methylation markers, ICCs varied considerably, ranging from 0.14 to 0.74. Test reproducibility could be improved by collecting multiple samples per patient. In conclusion, there is no preferred collection time for NSCLC detection in urine using methylation markers, but single measurements should be interpreted carefully, and serial sampling may increase test performance. This study contributes to the limited understanding of cfDNA dynamics in urine and the continued interest in urine-based liquid biopsies for cancer diagnostics.

Abstract Background Minor alterations in thyroid function are frequent, and interpretation of thyroid function tests in the individual patient can be challenging. Furthermore, the choice of thyroid function test is debatable. To inform the debate, we performed a comparative evaluation of the variation in thyrotropin (TSH) and thyroxine (T4) in two different cohorts to illustrate the precision of TSH and T4 in the diagnosis and monitoring of thyroid dysfunction. Methods A comparative analysis of two separate longitudinal studies previously surveyed with monthly blood sampling for one year among 35 subjects. Participants were included based on T4 within the reference range and TSH either within (euthyroid; n = 15) or above (subclinical hypothyroidism; n = 20) the laboratory reference range on two independent blood samplings before inclusion. Exclusion criteria were known thyroid disease or use of thyroid interfering medication. TSH and T4 in individual samples were measured in a single batch to prevent between-batch variation. The distributions TSH and T4 were compared among euthyroid and subclinical hypothyroid individuals, and bootstrap estimates were used to calculate area under the curve (AUC). Results Collection of twelve, monthly blood samples in the 35 participants provided 420 samples, and data completeness was 100%. The mean TSH was 1.27/7.19 mIU/L and the mean total T4 was 106/85 nmol/L in euthyroid/subclinical hypothyroid participants. The subclinical hypothyroidism state deviated from the euthyroid by 20% for total T4 and by 466% for TSH. The overlap between the euthyroid and subclinical hypothyroid groups was 92.6% (389/420) for total T4 and 9.0% (38/420) of test results for TSH. The estimated AUC was 0.999 (95%-CI: 0.995; 1.00) for TSH and 0.853 (0.736; 0.935) for total T4. There was no confidence interval overlap between participant groups for TSH while there was a considerable overlap for total T4 (p

Approximately 10%–30% of individuals with posttraumatic stress disorder (PTSD) exhibit a dissociative subtype of the condition defined by symptoms of depersonalization and derealization. This study examined the psychometric evidence for the dissociative subtype of PTSD in a sample of young, primarily male post-9/11-era Veterans (n = 374 at baseline and n = 163 at follow-up) and evaluated its biological correlates with respect to resting state functional connectivity (default mode network [DMN]; n = 275), brain morphology (hippocampal subfield volume and cortical thickness; n = 280), neurocognitive functioning (n = 337), and genetic variation (n = 193). Multivariate analyses of PTSD and dissociation items suggested a class structure was superior to dimensional and hybrid ones, with 7.5% of the sample comprising the dissociative class; this group showed stability over 1.5 years. Covarying for age, sex, and PTSD severity, linear regression models revealed that derealization/depersonalization severity was associated with: decreased DMN connectivity between bilateral posterior cingulate cortex and right isthmus (p =.015; adjusted-p [padj] =.097); increased bilateral whole hippocampal, hippocampal head, and molecular layer head volume (p =.010–.034; padj =.032–.053); worse self-monitoring (p =.018; padj =.079); and a candidate genetic variant (rs263232) in the adenylyl cyclase 8 gene (p =.026), previously associated with dissociation. Results converged on biological structures and systems implicated in sensory integration, the neural representation of spatial awareness, and stress-related spatial learning and memory, suggesting possible mechanisms underlying the dissociative subtype of PTSD. General Scientific Summary: This study evaluated biological correlates of the dissociative subtype of posttraumatic stress disorder (PTSD) among trauma-exposed Veterans. The study identified several neuroimaging and genetic biomarkers that were differentially associated with symptoms of derealization and depersonalization relative to PTSD. These biomarkers have relevance for sensory integration, spatial awareness, and memory, suggesting that alterations in these basic processes may underlie the clinical manifestations of the dissociative subtype of PTSD. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) accounts for about 13% of all pediatric cancer mortality and is the leading cause of pediatric cancer death for children aged 1 to 5 years. NB, a developmental malignancy of neural ganglia, originates from neural crest-derived cells, which undergo a defective sympathetic neuronal differentiation due to genomic and epigenetic aberrations. NB is a complex disease with remarkable biological and genetic variation and clinical heterogeneity, such as spontaneous regression, treatment resistance, and poor survival rates. Depending on its severity, NB is categorized as high-risk, intermediate-risk, and low-risk., whereas high-risk NB accounts for a high infant mortality rate. Several studies revealed that NB cells suppress immune cell activity through diverse signaling pathways, including exosome-based signaling pathways. Exosome signaling has been shown to modulate gene expression in the target immune cells and attenuate the signaling events through non-coding RNAs. Since high-risk NB is characterized by a low survival rate and high clinical heterogeneity with current intensive therapies, it is crucial to unravel the molecular events of pathogenesis and develop novel therapeutic targets in high-risk, relapsed, or recurrent tumors in NB to improve patient survival. This article discusses etiology, pathophysiology, risk assessment, molecular cytogenetics, and the contribution of extracellular vesicles, non-coding RNAs, and cancer stem cells in the tumorigenesis of NB. We also detail the latest developments in NB immunotherapy and nanoparticle-mediated drug delivery treatment options. [Display omitted] [ABSTRACT FROM AUTHOR]

Students explored variation in our donated mix of vegetable seeds and planted their individual mini-gardens so they could later look for variation in seedlings. Students suggested that they could plant only a few widely spaced seeds in the mini-gardens, or that they could plant in an outside garden where there is more space. Students asked to plant seeds from their lunches, started plants from cuttings, became excited about growing mini-gardens at home, and ended the year with lots of ideas of how to plan a fall garden on their return to school. Ms. Sky read aloud "From Seed to Plant" (Gibbons 1991), which follows plant life cycles from seed to adult and back again. [Extracted from the article]

Simple Summary: Calculating hematological reference intervals for bottlenose dolphins poses a challenge due to a limited number of reference individuals. However, individual reference intervals (iRIs) can be used to overcome this limitation. We evaluated the biological variations in hematological measurands and calculated the index of individuality (IoI) and the reference change value (RCV), which enable the production of iRIs, in healthy managed bottlenose dolphins. Analysis of IoI indicates that the use of iRIs is suitable for most hematological measurands. Furthermore, the calculated RCV can be applied to other dolphins that have undergone serial hematological exams. These tools provide valuable information for interpreting hematologic exams in managed bottlenose dolphins. Hematological analyses are particularly useful in assessing a dolphin's health status. However, the creation of appropriate reference intervals for this species is difficult due to the low number of reference individuals. The implementation of individual reference intervals (iRIs) allows researchers to overcome this limitation and, moreover, also consider the within-individual variability. The aims of this study were (1) to evaluate the biological variations in some hematological measurands, including erythrocytes (RBC), hematocrit (Hct), mean cellular volume and hemoglobin content (MCV and MCHC, respectively), RBC distribution width (RDW), leukocytes (WBC), and platelets (PLT); and (2) to calculate the index of individuality (IoI) and reference change value (RCV), which enable the production of iRIs, in healthy managed bottlenose dolphins. Seven dolphins were included, and the results of six hematological exams were analyzed for each animal. Analytical imprecision (CVa), within-dolphin variation (CVi), and between-dolphins variations (CVg) were calculated, and the IoI and RCV were derived for each measurand. All the hematological measurands had intermediate IoI except WBC, for which Iol was low. The calculated RCV ranged from 10.33% (MCV) to 186.51% (WBC). The results reveal that the majority of hematological measurands have an intermediate level of individuality in dolphins, and thus the application of iRIs is appropriate. The calculated RCV can also be applied to other managed dolphins and could be useful in interpreting serial CBC exams. [ABSTRACT FROM AUTHOR]

New millennium diagnostic criteria for acute myocardial infarction precipitated a revolutionary shift from an approach based primarily on electrocardiography and clinical symptoms to a strategy based on biomarkers, and preferably cardiac troponins (cTn) I and T. In the last 20 years, clinical recommendations have strengthened the role of cTn and led to the development of highly sensitive (hs-cTn) assays, which are now leading players in all current clinical practice guidelines. To optimize the clinical use of these hs-cTn assays, focus on their analytical aspects has become increasingly important, emphasizing the need for the establishment of suitable analytical performance by the definition and implementation of appropriate specifications. An accurate estimate of measurement uncertainty, together with the acquisition of the highest analytical quality when very low concentrations of hs-cTn are measured, are essential requirements and should represent a practical laboratory standard in assuring optimal clinical use. Additional goals for further improving the quality of laboratory information should be the establishment of robust data concerning biological variation of cTn and the resolution of practical challenges opposed to the harmonization of cTn I results obtained by differing commercial measuring systems. [ABSTRACT FROM AUTHOR]

Biological variation (BV) data have many applications in laboratory medicine. However, these depend on the availability of relevant and robust BV data fit for purpose. BV data can be obtained through different study designs, both by experimental studies and studies utilizing previously analysed routine results derived from laboratory databases. The different BV applications include using BV data for setting analytical performance specifications, to calculate reference change values, to define the index of individuality and to establish personalized reference intervals. In this review, major achievements in the area of BV from last decade will be presented and discussed. These range from new models and approaches to derive BV data, the delivery of high-quality BV data by the highly powered European Biological Variation Study (EuBIVAS), the Biological Variation Data Critical Appraisal Checklist (BIVAC) and other standards for deriving and reporting BV data, the EFLM Biological Variation Database and new applications of BV data including personalized reference intervals and measurement uncertainty. [ABSTRACT FROM AUTHOR]

To evolve, and remain adaptive, collective behaviours must have a positive impact on overall individual fitness. However, these adaptive benefits may not be immediately apparent owing to an array of interactions with other ecological traits, which can depend on a lineage's evolutionary past and the mechanisms controlling group behaviour. A coherent understanding of how these behaviours evolve, are exhibited, and are coordinated across individuals, therefore requires an integrative approach spanning traditional disciplines in behavioural biology. Here, we argue that lepidopteran larvae are well placed to serve as study systems for investigating the integrative biology of collective behaviour. Lepidopteran larvae display a striking diversity in social behaviour, which illustrates critical interactions between ecological, morphological and behavioural traits. While previous, often classic, work has provided an understanding of how and why collective behaviours evolve in Lepidoptera, much less is known about the developmental and mechanistic basis of these traits. Recent advances in the quantification of behaviour, and the availability of genomic resources and manipulative tools, allied with the exploitation of the behavioural diversity of tractable lepidopteran clades, will change this. In doing so, we will be able to address previously intractable questions that can reveal the interplay between levels of biological variation. [ABSTRACT FROM AUTHOR]

Many horses, just before and during their athletic career, show vertical movement asymmetries, to the same degree as clinically lame horses. It is unknown whether these asymmetries are caused by pain or have alternative explanations, such as inherent biological variation. In the latter case, movement asymmetries would be expected to be present at a very young age. This study aimed to investigate the prevalence of movement asymmetries in foals. Motion analysis, using an inertial measurement unit-based system (Equinosis), was performed on 54 foals (31 Swedish Warmbloods, 23 Standardbreds) during straight-line trot. The foals were between 4–13 weeks old and considered sound by their owners. Differences between the vertical minimum and maximum values recorded for the head (HDmin, HDmax) and pelvis (PDmin, PDmax) between left and right stance were calculated for each stride and an average was computed for each trial. Thresholds for asymmetry were defined as absolute trial mean >6 mm for HDmin and HDmax, and >3 mm for PDmin and PDmax. These thresholds were exceeded for one or several parameters by 83% of Standardbred foals and 45% of Swedish Warmblood foals, demonstrating surprisingly high prevalence of asymmetries in young foals, although the risk of repetitive strain injuries and cumulative risk of trauma injuries was expected to be low in this age group. Standardbred foals showed similar prevalence of asymmetries to that reported previously for yearling Standardbred trotters, so relatively higher prevalence of movement asymmetries may be expected among trotters as a breed. In general, vertical head and pelvic movement asymmetries can be anticipated among foals considered sound by their owners. A better understanding of the aetiology of asymmetries is needed for correct interpretation of objective symmetry measurements in different populations of horses. [ABSTRACT FROM AUTHOR]

When necessary, RNA-sequencing data or polymerase chain reaction (PCR) assays can be used to determine the presence of the chromosome Y (ChrY) in samples. This information allows for biological variation due to sexual dimorphism to be studied. A prime example is when researchers conduct RNA-sequencing of single embryos, or conceptuses, prior to the development of gonads. A recent publication of a complete sequence of the ChrY has removed limitations for the development of these procedures in cattle, otherwise imposed by the absence of a ChrY in the reference genome. Using the sequence of the cattle ChrY and transcriptome data, we conducted a systematic search for genes in the ChrY that are exclusively expressed in male tissues. The genes ENSBIXG00000029763, ENSBIXG00000029774, ENSBIXG00000029788, and ENSBIXG00000029892 were consistently expressed across male tissues and lowly expressed or absent in female samples. We observed that the cumulative values of counts permillion were 2688-fold greater in males than the equivalent values in female samples. Thus, we deemed these genes suitable for the sexing of samples using RNA-sequencing data. We successfully used this set of genes to infer the sex of 22 cattle blastocysts (8 females and 14males). Additionally, the completed sequence of the cattle ChrY has segments in the male-specific region that are not repeated. We designed a pair of oligonucleotides that targets one of these non-repeated regions in the malespecific sequence of the ChrY. Using this pair of oligonucleotides, in a multiplexed PCR assay with oligonucleotides that anneal to an autosome chromosome, we accurately identified the sex of cattle blastocysts. We developed efficient procedures for the sexing of samples in cattle using either transcriptome data or their DNA. The procedures using RNA-sequencing will greatly benefit researchers who work with samples limited in cell numbers which are only sufficient to produce transcriptome data. The oligonucleotides used for the accurate sexing of samples using PCR are transferable to other cattle tissue samples. [ABSTRACT FROM AUTHOR]

Introduction: Technological advancements enabled the analyses of limited sample volumes on 1H NMR. Manual spectral profiling of the data is, however, complex, and timely. Objective: To evaluate the performance of BAYESIL for automated identification and quantification of 1H NMR spectra of limited volume samples. Method: Aliquots of a pooled African elephant serum sample were analyzed using standard and reduced volumes. Performance was evaluated on confidence scores, non-detects and laboratory CV. Results: Of the 47 compounds detected, 28 had favorable performances. The approach could differentiate samples based on biological variation. Conclusions: BAYESIL is valuable for limited sample 1H NMR data analyses. [ABSTRACT FROM AUTHOR]

The concentration of biomolecules in living systems shows numerous systematic and random variations. Systematic variations can be classified based on the frequency of variations as ultradian (<24 h), circadian (approximately 24 h), and infradian (>24 h), which are partly predictable. Random biological variations are known as between-subject biological variations that are the variations among the set points of an analyte from different individuals and within-subject biological variation, which is the variation of the analyte around individuals' set points. The random biological variation cannot be predicted but can be estimated using appropriate measurement and statistical procedures. Physiological rhythms and random biological variation of the analytes could be considered the essential elements of predictive, preventive, and particularly personalized laboratory medicine. This systematic review aims to summarize research that have been done about the types of physiological rhythms, biological variations, and their effects on laboratory tests. We have searched the PubMed and Web of Science databases for biological variation and physiological rhythm articles in English without time restrictions with the terms "Biological variation, Within-subject biological variation, Between-subject biological variation, Physiological rhythms, Ultradian rhythms, Circadian rhythm, Infradian rhythms". It was concluded that, for effective management of predicting, preventing, and personalizing medicine, which is based on the safe and valid interpretation of patients' laboratory test results, both physiological rhythms and biological variation of the measurands should be considered simultaneously. [ABSTRACT FROM AUTHOR]

The experiment was carried out with the aim of studying the effect of biological stress on some morphological parameters of ten varieties of potatoes grown in vitro. Biological stress was applied by adding different concentrations of fusaric acid (0, 0.0125, 0.025, 0.05, 0.1, 0.2 mM), to the growth medium MS, and some growth parameters were measured, such as plant height (cm), number of leaves (leaf/plant¹), leaf area (mm²), number of roots (root.plant¹) and length it (cm), wet and dry weight of the plant (g). The results showed that the studied varieties were different in the response to biological stress according to the studied parameters. The addition of fusaric acid led to reduce all growth parameters compared with the control. The cluster analysis showed that based on the sum of the relative values of the studied growth parameters, the studied varieties were distributed in three different groups: The first group includes three tolerant varieties to biological stress, and these are Toronto, Barcelona, and Suria). The second group includes four Moderate varieties of bio-stress, and these are Fabulla, Nectare, Spunta, and Ardappel. The third group included the following sensitive varieties, 7-four-7, Farida, and Joly. The results indicate that the in vitro screening technology can be used as a fast and efficient method to investigate the genetic variation of biological stress tolerance in potatoes. [ABSTRACT FROM AUTHOR]

Biological variation is often considered in a scalable hierarchy, e.g. within the individual, within the populations, above the species level. Morphological integration, the concept of covariation among constituent parts of an organism, is also hierarchical; the degree to which these "modules" covary is a matter of the scale of the study as well as underlying processes driving the covariation. Multilevel analyses of trait covariation are a valuable tool to infer the origins and historical persistence of morphological diversity. Here, we investigate concordance in patterns of integration and modularity across three biological levels of variation: within a species, within two genera-level radiations, and among species at the family level. We demonstrate this approach using the skull of mammalian family Leporidae (rabbits and hares), which is morphologically diverse and has a rare-among-mammals functional signal of locomotion adaptation. We tested three alternative hypotheses of modularity; from the most supported we investigated disparity and integration of each module to infer which is most responsible for patterns of cranial variation across these levels, and whether variation is partitioned consistently across levels. We found a common pattern of modularity underlies leporid cranial diversity, though there is inconsistency across levels in each module's disparity and integration. The face module contributes the most to disparity at all levels, which we propose is facilitating evolutionary diversity in this clade. Therefore, the distinctive facial tilt of leporids is an adaptation to locomotory behavior facilitated by a modular system that allows lineages to respond differently to selection pressures. [ABSTRACT FROM AUTHOR]

Progress in precision medicine is being achieved through the design of clinical trials that use genetic biomarkers to guide stratification of patients and assignation to treatment or control groups. Genetic analysis of biomarkers is, therefore, essential to complete their objectives, and this involves the study of biological samples from donor patients that have been recruited according to criteria previously established in the design of the clinical trial. Nevertheless, it is becoming very common that, in the solicitation of biological samples, purposes that are beyond the objectives of the stated therapeutic trial research are introduced, like the development of ill-explained exploratory studies or the use in unspecified future research. In the digital era, the sequencing of patients' DNA needs to be considered as a serious security matter, not only for the patients, but also for their relatives. Genetic information may be easily stored, even forever, in digital files. This engenders a permanent risk of being stolen or misused in many ways. Furthermore, re-identification of sample donors is technically feasible through their genetic data. For these reasons, genetic analysis of samples collected in clinical trials should be restricted to the accomplishment of their main objectives or well justified goals. [ABSTRACT FROM AUTHOR]

The distinction between shallow coral reefs and mesophotic coral ecosystems (MCEs) has not been fully clarified yet. The original definition of MCEs, by depths of 30–150 m, fixes their bathymetrical limits and fails to accommodate environmental and biological variation. Recent studies have indicated that water transparency and light availability may explain why MCEs do not occur at fixed depths but vary among localities. This study aimed to evaluate the presence and distribution of MCEs, along the central coast of Oaxaca, through optical depths and the associated benthic community. Using MODIS-Aqua satellite data (Kd490), we estimated the mesophotic optical depths monthly (z10%, z1%, z0.1%), over the last four years. In addition, to characterize benthic community structure, we conducted underwater photo quadrat surveys at two locations on the southern Mexican Pacific coast from 10 to 55 m depth. Significant differences between depths and locations were found in benthic communities. Furthermore, the lower distribution of photosynthetic taxa was different between the two locations but indicative to the z10% and z1% in both cases. Those differences were associated with the upwelling season, which reduces, drastically and differentially, the light availability for benthic communities between the two locations and limits the development of MCEs on the central coast of Oaxaca. [ABSTRACT FROM AUTHOR]