Intensity Variations Research Articles

Evaluation of Subseasonal Forecast Skill for Northern Hemisphere Winter Snow Cover

Abstract Accurate subseasonal forecasts for snow cover have significant socioeconomic value. This paper evaluates subseasonal forecasts for winter snow cover in the Northern Hemisphere as predicted by three numerical models: the Model for Prediction Across Scales–Atmosphere (MPAS-A), the China Meteorological Administration (CMA) model, and the European Centre for Medium-Range Weather Forecasts (ECMWF) model. While these models can generally simulate the spatial distribution of winter snow cover climatology and subseasonal variability, they tend to underestimate both the climatology and the intensity of subseasonal variability. Compared to persistence forecasts, these models demonstrate skill in subseasonal snow cover forecasting. Notably, the ECMWF model outperforms the MPAS and CMA models. The sensitivity of the surface air temperature subseasonal forecast skill to the predicted snow cover was also investigated using the MPAS. The results show that for forecasts with lead times of 1–2 weeks, the predicted snow cover contributes to the temperature forecasting skill. However, for forecasts with lead times of 3–4 weeks, the predicted snow cover does not enhance the temperature forecasting skill. Furthermore, part of the errors in temperature forecasts can be attributed to inaccuracies in snow cover forecasts with lead times of 2 weeks or more. These findings suggest that refining snow cover parameterization schemes and effectively exploiting predictability from snow cover can enhance the skill of subseasonal atmospheric forecasts. Significance Statement Snow cover is a crucial variable in hydrometeorology. Subseasonal forecasting, which involves predicting snow cover anomalies 1–4 weeks in advance, has socioeconomic value. We conducted an evaluation of the subseasonal forecasts for Northern Hemisphere winter snow cover produced by three numerical models. This evaluation provides insights into the accuracy and reliability of these models, which could contribute to their enhancement. Furthermore, we examined the impact of the predicted snow cover on the skill of surface air temperature subseasonal forecasts. The results suggest that improvements in snow cover modeling and forecasting can lead to more accurate subseasonal atmospheric forecasts. Therefore, future efforts to refine snow cover parameterization schemes suitable for subseasonal forecasting are promising and worthwhile.

Coupling Soil Erosion and Sediment Transport Processes With the Variable Infiltration Capacity Model (VIC‐SED) for Applications Suitable With Coarse Spatial and Temporal Resolutions

AbstractUnderstanding soil erosion and sediment transport from the hillslope scale to the regional scale is crucial for studies on water quality, soil‐water conservation, the lateral carbon cycle, environmental zoning and vulnerability. However, most existing erosion and sediment transport models are only applicable at the hillslope scale or for small watersheds with fine spatial resolutions (typically much less than 1 km). This study presents a process‐based soil erosion and sediment transport model for model applications designed for applications with coarse spatial (e.g., ≥10 km) and temporal (e.g., from hourly to daily) resolutions. This new model, referred to as VIC‐SED, effectively accounts for interactions between erosion and hydrological processes. This is achieved by tightly coupling the erosion processes with a hydrologically based Three‐layer Variable Infiltration Capacity (VIC‐3L) land surface model (LSM) and to a multi‐scale routing (MSR) model. VIC‐SED considers the impacts of (a) the spatio‐temporal variability of rainfall intensity on erosion processes and (b) soil moisture on the soil detachment process. VIC‐SED is evaluated in two watersheds. Results demonstrate that VIC‐SED is capable of reproducing water and suspended sediment discharges at coarse spatial resolutions and varying temporal scales varying from 15‐min to daily intervals. Our study indicates that the VIC‐SED model is a promising tool for studying and assessing the impacts of climate and land cover changes on suspended sediment yields over large regions using coarse spatial and temporal resolutions.

Geospatial Mapping and Seasonal Profiling of Urinary Schistosomiasis in Ase-Niger River Settlements: A Data-Driven Population-Base Study in Delta State, Nigeria.

This study is aimed to determine the geospatial, seasonal, age and gender prevalence and intensity of UgS; and to establish disease maps in the Ase-Niger River communities for effective drug administration. This study employed a 24 months longitudinal study design for parasitological investigations in 11 riparian communities of the Ase-Niger River basin, taking into cognizance their GPS locations imported into QGIS software for schistosomiasis mapping. A total of 7,219 urine samples with WHO structured questionnaires were retrieved and subjected to parasitological evaluation using swinnex urine filtration techniques. An overall prevalence of 48.10% was established. Geospatially, prevalence ranges from 34.27% (Ivrogbo) to 52.29% (Ase) with seasonal significant difference (p < 0.05) accounting for 76.19% of the total variance. Ashaka had the highest prevalence for both males (55.73%) and females (53.32%) with significant difference in the study sites (p < 0.05) accounting for 96.47% of the total variance. Age-group 11-20 years consistently maintain a high prevalence at all sites. The peak geometric mean intensity of 105.69 was obtained in the dry season at Lagos Iyede. Ashaka, Igbuku, Iyede-Ame, and Onogboko had heavy-intensity levels in both seasons. Overall, the intensity was lower during the wet season than the dry season, with significant variations (p < 0.05) at Awah and Itobi-Ige. Geospatial prevalence and intensity have a robust and strong positive correlation (r = 0.7178; p = 0.0129), with 51.53% of intensity variability being influenced by prevalence (R2 = 0.5153). UgS is a significant public health issue in the Ase-Niger River basin, with prevalences surpassing the national average of 29.0% which calls for MDA in these settlements.

Navigating the shadows: medical professionals' values and perspectives on end-of-life care within pediatric intensive care units in Croatia.

This study explores healthcare professionals' perspectives on end-of-life care in pediatric intensive care units (ICUs) in Croatia, aiming to illuminate their experiences with such practices, underlying attitudes, and major decision-making considerations. Amid the high variability, complexity, and emotional intensity of pediatric end-of-life decisions and practices, understanding these perspectives is crucial for improving care and policies. The study utilized a cross-sectional survey intended for physicians and nurses across all pediatric ICUs in Croatia. It included healthcare professionals from six neonatal and four pediatric ICUs in total. As the data from neonatal and pediatric ICUs were examined jointly, the term pediatric ICU was used to denominate both types of ICUs. A statistical analysis was performed using Python and JASP, focusing on professional roles, professional experience, and regional differences. The study included a total of 103 participants (with an overall response rate-in relation to the whole target population-of 48% for physicians and 29% for nurses). The survey revealed diverse attitudes toward and experiences with various aspects of end-of-life care, with a significant portion of healthcare professionals indicating infrequent involvement in life-sustaining treatment (LST) limitation discussions and decisions, as well as somewhat ambiguous attitudes regarding such practices. Notably, discrepancies emerged between different professional roles and, in particular, regions, underscoring the high variability of LST limitation-related procedures. The findings highlight a pressing need for more straightforward guidelines, legal frameworks, support mechanisms, and communication strategies to navigate the complex terrain of rather burdensome end-of-life pediatric care, which is intrinsically loaded with profound ethical quandaries.

Seasonal and Interannual Variability in Sea Surface Temperature Fronts in the Levantine Basin, Mediterranean Sea

Sea surface temperature (SST) fronts were analyzed in the Levantine Basin of the Mediterranean Sea over a 20-year period (2003–2022) using a high-resolution (~1 km) satellite dataset. Frontal gradients were strongest in regions of freshwater influence and around the Ierapetra eddies and Rhodes Gyre. Seasonally, maximum frontal activity was observed in fall and summer. Empirical orthogonal function (EOF) analysis revealed both monthly-to-seasonal variability and interannual variability in frontal gradients. Seasonal frontal variability is partially explained by atmospheric forcing; that is, wind stress curl (WSC) and net air–sea heat flux. The maximum frontal activity was observed in 2006, coinciding with the strongest WSC magnitude. The minimum frontal activity was observed in 2017, which saw the largest winter heat loss to the atmosphere. The highest frontal activity was typically observed in years with mild winters followed by strong Etesian winds. Over the study period (2003–2022), frontal gradients declined in the Levantine Basin. Our results suggest that years with a strong frontal boundary current (Asia Minor Current; AMC) coincide with reduced cross-shelf transport. Subsequent studies are recommended to concentrate on the variability in the frontal intensity of the AMC and associated cross-shelf transports, which are important for the oligotrophic Levantine Basin.

Microbiota and the volatile profile of avian nests are associated with each other and with the intensity of parasitism.

Bacteria have been suggested as being partially responsible for avian nest odours and, thus, volatiles from their metabolism could influence the intensity of selection pressures due to parasites detecting olfactory cues of their hosts. Here, we tested this hypothesis by exploring intraspecific and interspecific variability in microbial environments, volatile profiles and intensity of ectoparasitism by Carnus hemapterus in the nests of 10 avian species. As expected, we found that (i) alpha and beta diversity of microbial and volatile profiles were associated with each other. Moreover, (ii) alpha diversity of bacteria and volatiles of the nest environment, as well as some particular bacteria and volatiles, was associated with the intensity of parasitism at early and late stages of the nestling period. Finally, (iii) alpha diversity of the nest microbiota, as well as some particular bacteria and volatiles, was correlated with fledging success. When considering them together, the results support the expected links between the microbial environment and nest odours in different bird species, and between the microbial environment and both ectoparasitism intensity and fledging success. Relative abundances of particular volatiles and bacteria predicted ectoparasitism and/or fledging success. Future research should prioritise experimental approaches directed to determine the role of bacteria and volatiles in the outcomes of host-ectoparasite interactions.

A Systematic Review and Bayesian Meta-Analysis of Acoustic Measures of Prosody in Parkinson's Disease.

Linguistic prosody is affected in Parkinson's disease (PD), which implicates the basal ganglia's role in the production of prosody. However, there is no recent systematic synthesis of the available acoustic evidence of prosodic impairment in PD. This study aimed to identify the acoustic features of linguistic prosody that are consistently affected in PD. The authors systematically reviewed articles that reported acoustic features of prosodic production in PD. Articles focused on fundamental frequency (F0) and its variability, intensity and its variability, speech and articulation rate, and pause duration and ratio. From a total of 648 records identified, 36 met criteria for inclusion and exclusion. For each acoustic measurement and task, data from people with PD (PwPD) were compared with those from controls to extract effect sizes. Pooled effect sizes were estimated using robust Bayesian hierarchical regression models. PD was associated with decreased F0 variability and increased pause duration. There was limited evidence of reduced intensity variability and speech rate in PwPD. No evidence was found to suggest that PD affects articulation rate or pause ratio. The primary acoustic parameters of prosody affected by PD are F0 variability and pause duration. The identification of these acoustic parameters has important clinical implications for the selection of PD management strategies. The association of F0 variability and pause duration with PD suggests that the neural circuits controlling these parameters are at least partly shared and might include the basal ganglia. While the current study focused on the phonetic realization of prosodic cues, future studies should examine whether and how PD affects prosody at higher levels of processing. https://doi.org/10.23641/asha.25892923.

Utility of a brief measure of cannabis demand: Day-level associations with cannabis use

BackgroundCannabis demand (i.e., relative value) is usually assessed as a trait-level risk-factor for cannabis use and consequences. This study examined within-person variability in day-level intensity (i.e., amount consumed at zero cost) and Omax (i.e., maximum cannabis expenditure) and tested hypotheses that demand would be positively associated with day-level cannabis use. MethodsYoung adults (n=85) reporting past-month simultaneous alcohol and cannabis use completed two daily surveys for 30 days. Morning surveys assessed prior-day cannabis use and evening surveys assessed day-level demand (i.e., intensity, Omax). Multilevel models tested day-level effects of intensity and Omax on any cannabis use and flower use frequency and quantity (i.e., grams). ResultsApproximately 52 % and 46 % of variability in intensity and Omax, respectively, was due to within-person change. At the day-level, higher intensity and Omax were associated with higher likelihood of any cannabis use, regardless of formulation; Omax was associated with use of flower in particular; and intensity was associated with the highest quantity of use. At the person-level, only Omax was associated with flower use likelihood, and only intensity was associated with flower quantity across days. ConclusionsCannabis demand demonstrated day-to-day variability, conceivably in response to various internal states and external factors. Intensity and Omax were related to elevated likelihood of using any cannabis, particularly flower, at the day-level. Overall, these data illustrate the validity and utility of brief cannabis demand measures, which might be used to further understand cannabis’ reinforcing value at a fine-grained level.

High-resolution analysis of 3D fracture networks from Digital Outcrop Models, correlation to plate-tectonic events and calibration of subsurface models (Jurassic, Arabian Plate)

The performance of different reservoirs, both hydrocarbon and gas storage, is significantly influenced by the presence of natural fracture networks mainly originated in response to tectonic deformation. However, adequate characterization of fracture networks in the subsurface is often difficult since most of the used techniques are either spatially sparse (well and log data) or have limited resolution (seismic and well tests). In this study, we use UAV-based digital photogrammetry to reconstruct a 3D Digital Outcrop Model and characterize natural fracture sets of the late Jurassic Hanifa Formation (Tuwaiq Escarpment, Saudi Arabia). We analyzed the exposed fracture patterns in terms of fracture distribution, intensity, and lateral variability. The fracture dataset was collected using manual sampling approaches since the automatic sampling techniques are highly influenced by outcrop morphology thus not yet reliable to quantify and interpret fracture networks along reservoir outcrop analogues. The well-exposed late Jurassic outcrops in Wadi Birk, southern central Saudi Arabia, are considered analogous in depositional facies to subsurface reservoirs in the region. The observed fracture patterns are congruent with patterns reported from same-age formations in other parts of the Arabian Plate and hence can be related to plate-wide tectonic events that impacted Arabia during the Late Cretaceous (Alpine I) and the late Tertiary Period (Alpine II). This association provides support for using outcrop-based fracture studies as analogue scenarios for the orientation, distribution and intensity of fractures in subsurface reservoirs. The applied methodology for fracture network characterization have potential implications for hydrocarbon development, gas storage (H2) and Carbon Capture Utilization and Storage (CCUS).

Feasibility of MALDI-MSI-Based Proteomics Using Bouin-Fixed Pathology Samples: Untapping the Goldmine of Nephropathology Archives.

The application of innovative spatial proteomics techniques, such as those based upon matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technology, has the potential to impact research in the field of nephropathology. Notwithstanding, the possibility to apply this technology in more routine diagnostic contexts remains limited by the alternative fixatives employed by this ultraspecialized diagnostic field, where most nephropathology laboratories worldwide use bouin-fixed paraffin-embedded (BFPE) samples. Here, the feasibility of performing MALDI-MSI on BFPE renal tissue is explored, evaluating variability within the trypsin-digested proteome as a result of different preanalytical conditions and comparing them with the more standardized formalin-fixed paraffin-embedded (FFPE) counterparts. A large proportion of the features (270, 68.9%) was detected in both BFPE and FFPE renal samples, demonstrating only limited variability in signal intensity (10.22-10.06%). Samples processed with either fixative were able to discriminate the principal parenchyma regions along with diverse renal substructures, such as glomeruli, tubules, and vessels. This was observed when performing an additional "stress test", showing comparable results in both BFPE and FFPE samples when the distribution of several amyloid fingerprint proteins was mapped. These results suggest the utility of BFPE tissue specimens in MSI-based nephropathology research, further widening their application in this field.

Deep learning-based localization algorithms on fluorescence human brain 3D reconstruction: a comparative study using stereology as a reference

3D reconstruction of human brain volumes at high resolution is now possible thanks to advancements in tissue clearing methods and fluorescence microscopy techniques. Analyzing the massive data produced with these approaches requires automatic methods able to perform fast and accurate cell counting and localization. Recent advances in deep learning have enabled the development of various tools for cell segmentation. However, accurate quantification of neurons in the human brain presents specific challenges, such as high pixel intensity variability, autofluorescence, non-specific fluorescence and very large size of data. In this paper, we provide a thorough empirical evaluation of three techniques based on deep learning (StarDist, CellPose and BCFind-v2, an updated version of BCFind) using a recently introduced three-dimensional stereological design as a reference for large-scale insights. As a representative problem in human brain analysis, we focus on a 4-cm3\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$4~\ ext {-cm}^3$$\\end{document} portion of the Broca’s area. We aim at helping users in selecting appropriate techniques depending on their research objectives. To this end, we compare methods along various dimensions of analysis, including correctness of the predicted density and localization, computational efficiency, and human annotation effort. Our results suggest that deep learning approaches are very effective, have a high throughput providing each cell 3D location, and obtain results comparable to the estimates of the adopted stereological design.

Probabilistic fragility assessment of slopes considering uncertainty associated with temporal patterns of rainfall intensity

The temporal patterns of rainfall intensity, characterized by the variability of rainfall intensity over time during a single rainfall event, play a crucial role in landslide triggering and evolution. However, the influence of temporal patterns of rainfall intensity on the fragility and reliability assessment of slope instability has received limited attention. This study presents a novel methodology for probabilistic slope fragility assessment accounting for uncertainty associated with the temporal patterns of rainfall intensity. Hourly-scale random time series for the rainfall event are generated, considering uncertainties in temporal patterns of rainfall intensity, using the statistical concepts of skewness and kurtosis within the Pearson system of distributions. A time-dependent seepage-stability mechanical model coupling the finite element method and limit equilibrium method for the slope under hourly-scale rainfall time series is established. Slope fragility assessment under rainfall is conducted, accounting for uncertainties in temporal patterns of rainfall intensity based on Monte Carlo simulation. An illustrative example is provided, focusing on a hypothetical soil slope in the southeastern coastal area of China, susceptible to rainfall-induced landslides. The impact of skewness and kurtosis of rainfall time series on the slope failure probability and failure time are examined.

Diversity of the tropical easterly jet’s core location

The upper-tropospheric tropical easterly jet (TEJ) is one of the most important systems in modulating the Asian summer monsoon rainfall. In addition to the intensity variability that has been extensively studied, the TEJ’s core experiences remarkable changes in the zonal and meridional directions. The TEJ can be identified as three locational patterns using the cluster analysis: the east, northwest, and southwest modes. The frequencies of the three locational modes exhibit discernable changes on the monthly and the interannual-decadal time scales. While the anomalous zonal divergent circulation with the convergent/divergent center over the tropical Indian Ocean (IO) determines the zonal location of the TEJ’s core, the meridional temperature gradient between the Eurasian continent and the tropical IO distinguishes the meridional location of the TEJ’s core. It reflects the fundamental role of the large-scale east-west and north-south thermal contrasts in the movement of the TEJ’s core location. The variability of the TEJ’s core location has distinct impacts on the summer monsoon precipitation via redistributing the upper-level divergence and modulating the monsoon meridional circulation, especially in South, Southeast, and East Asia. In conjunction with the thermal effect of the Tibetan Plateau, the meridional shift of the TEJ’s core can affect the precipitation along the south slope of the Tibetan Plateau. These findings highlight the cause of the diversified TEJ’s core location and the significant impacts on the summer monsoon rainfall.

Associations between pain intensity, psychosocial factors, and pain-related disability in 4285 patients with chronic pain

Pain, a widespread challenge affecting daily life, is closely linked with psychological and social factors. While pain clearly influences daily function in those affected, the complete extent of its impact is not fully understood. Given the close connection between pain and psychosocial factors, a deeper exploration of these aspects is needed. In this study, we aim to examine the associations between psychosocial factors, pain intensity, and pain-related disability among patients with chronic pain. We used data on 4285 patients from the Oslo University Hospital Pain Registry, and investigated pain-related disability, pain intensity, pain catastrophizing, psychological distress, perceived injustice, insomnia, fatigue, and self-efficacy. We found significant associations between all psychosocial variables and pain-related disability, even after adjusting for demographic factors. In the multiple regression model, sleep problems and pain intensity were identified as primary contributors, alongside psychological distress, and fatigue. Combined, these factors accounted for 26.5% of the variability in pain-related disability, with insomnia and pain intensity exhibiting the strongest associations. While the direction of causation remains unclear, our findings emphasize the potential of interventions aimed at targeting psychosocial factors. Considering the strong link between psychosocial factors and pain-related disability, interventions targeting these factors—particularly insomnia—could reduce disability and enhance quality of life in those who suffer.

Segmentation of THz holograms for homogenous illumination

This paper investigates the feasibility of applying the hologram segmentation method for homogeneous illumination. Research focuses on improving the uniformity of the illumination obtained from diffractive optical elements in the THz range. The structures are designed with a modified Ping-Pong algorithm and a neural network-based solution. This method allows for the improvement of uniform illumination distribution with the desired shape. Additionally, the phase modulations of the structures are divided into segments, each responsible for imaging at different distances. Various segment combination methods are investigated, differing in shapes, image plane distances, and illumination types. The obtained image intensity maps allow for the identification of the performance of each combination method. Each of the presented structures shows significant improvements in the uniformity of imaged targets compared to the reference Ping-Pong structure. The presented structures were designed for a narrow band case—260 GHz frequency, which corresponds to 1.15 mm wavelength. The application of diffractive structures for homogenization of illumination shows promise. The created structures perform designed beamforming task with variability of intensity improved up to 23% (standard deviation) or 45% (interquartile range) compared with reference structure.

Variability and trends in tropical precipitation intensity in observations and climate models

Variability and trends in tropical precipitation intensity in observations and climate models

Global Flash Droughts Characteristics: Onset, Duration, and Extent at Watershed Scales

AbstractAddressing impacts of flash droughts (FDs) on the water‐food nexus requires a understanding of FD mechanisms and drivers at the watershed level. Examining climatic drivers, dry and wet spell lengths from 1980 to 2019, we analyzed FD spatial and temporal characteristics, emphasizing areal extent, onset time, and duration. Our findings reveal substantial variations in FDs among different watersheds. Notably, watersheds in the Southern Hemisphere are witnessing expanding, faster‐developing, and longer‐lasting FDs, aligning with climate variations in precipitation and temperature. Additionally, at the watershed scale, the onset and duration of FDs are more influenced by the intensity (magnitude and variability) of climatic drivers than the average length of wet and dry periods. FD‐extents, however, correlate with both climatic conditions and wet and dry periods, underscoring watershed connectivity. Ultimately, our results underscore the necessity for research to comprehend the interplay between FDs and watershed characteristics and how it manifests in overall water resource management.

Impact of Randomized Soil Properties and Rock Motion Intensities on Ground Motion

Seismic site response is inevitably influenced by natural variability of soil properties and anticipated earthquake intensity. This study presents the influence of variability in shear wave velocity (Vs) and amplitude of input rock motion on seismic site response analysis. Monte Carlo simulations were employed to randomize the Vs profile for different scenarios. A series of 1-D equivalent linear (EQL) seismic site response analyses were conducted by combining the randomized Vs profile with different levels of rock motion intensities. The results of the analyses are presented in terms of surface spectral acceleration, amplification factors (AFs), and peak ground acceleration (PGA). The mean and standard deviation of these parameters are thoroughly discussed for a wide range of randomized Vs profile, number of Vs randomizations, and intensities of input rock motions. The results demonstrate that both the median PGA and its standard deviations across different number of Vs profile realization exhibit a slight variation. As few as twenty Vs profile realizations are sufficient to compute reliable response parameters. Both rock motion intensity and standard deviation of Vs variability cause significant variation in computed surface parameters. However, the variability in the number of records used to conduct site response has no significant impact on ground response if the records closely match the target spectrum. Incorporating the multiple sources of variabilities can reduce uncertainty when conducting ground response simulations.

Generalizable Approach to Quantifying Guideline-Directed Medical Therapy.

Quantifying guideline-directed medical therapy (GDMT) intensity is foundational for improving heart failure (HF) care. Existing measures discount dose intensity or use inconsistent weighting. The Kansas City Medical Optimization (KCMO) score is the average of total daily to target dose percentages for eligible GDMT, reflecting the percentage of optimal GDMT prescribed (range, 0-100). In Change the Management of Patients With HF, we computed KCMO, HF collaboratory (0-7), and modified HF Collaboratory (0-100) scores for each patient at baseline and for 1-year change in established GDMT at the time (mineralocorticoid receptor antagonist, β-blocker, ACE [angiotensin-converting enzyme] inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor). We compared baseline and 1-year change distributions and the coefficient of variation (SD/mean) across scores. Among 4532 patients at baseline, mean KCMO, HF collaboratory, and modified HF Collaboratory scores were 38.8 (SD, 25.7), 3.4 (1.7), and 42.2 (22.2), respectively. The mean 1-year change (n=4061) for KCMO was -1.94 (17.8); HF collaborator, -0.11 (1.32); and modified HF Collaboratory, -1.35 (19.8). KCMO had the highest coefficient of variation (0.66), indicating greater variability around the mean than the HF collaboratory (0.49) and modified HF Collaboratory (0.53) scores, reflecting higher resolution of the variability in GDMT intensity across patients. KCMO measures GDMT intensity by incorporating dosing and treatment eligibility, provides more granularity than existing methods, is easily interpretable (percentage of ideal GDMT), and can be adapted as performance measures evolve. Further study of its association with outcomes and its usefulness for quality assessment and improvement is needed.

Biological variability hampers the use of skeletal staining methods in zebrafish embryo developmental toxicity assays

Zebrafish embryo assays are used by pharmaceutical and chemical companies as new approach methodologies (NAMs) in developmental toxicity screening. Despite an overall high concordance of zebrafish embryo assays with in vivo mammalian studies, false negative and false positive results have been reported. False negative results in risk assessment models are of particular concern for human safety, as developmental anomalies may be missed. Interestingly, for several chemicals and drugs that were reported to be false negative in zebrafish, skeletal findings were noted in the in vivo studies. As the number of skeletal endpoints assessed in zebrafish is very limited compared to the in vivo mammalian studies, the aim of this study was to investigate whether the sensitivity could be increased by including a skeletal staining method. Three staining methods were tested on zebrafish embryos that were exposed to four teratogens that caused skeletal anomalies in rats and/or rabbits and were false negative in zebrafish embryo assays. These methods included a fixed alizarin red-alcian blue staining, a calcein staining, and a live alizarin red staining. The results showed a high variability in staining intensity of larvae exposed to mammalian skeletal teratogens, as well as variability between control larvae originating from the same clutch of zebrafish. Hence, biological variability in (onset of) bone development in zebrafish hampers the detection of (subtle) treatment-related bone effects that are not picked-up by gross morphology. In conclusion, the used skeletal staining methods did not increase the sensitivity of zebrafish embryo developmental toxicity assays.