To support informed decisions on drug registration and prescription, clinical trials need tools to assess the efficacy and safety signals related to a given therapeutic intervention. Standardized ...assessment facilitates reproducibility of results. Furthermore, it enables weighted comparison between different interventions, instrumental to facilitate shared decisions. When focused on adverse events in clinical trials, tools are needed to assess seriousness, causality and severity. As part of such a toolbox, the international Neonatal Consortium (INC) developed a first version of the neonatal adverse event severity scale (NAESS). This version underwent subsequent validation in retro-and prospective trials to assess its applicability and impact on the inter-observer variability. Regulators, sponsors and academic researchers also reported on the use of the NAESS in regulatory documents, trial protocols and study reports. In this paper, we aim to report on the trajectory, current status and impact of the NAESS score, on how stakeholders within INC assess its relevance, and on perspectives to further develop this tool.
ABSTRACT
We measure the velocity dispersions of clusters of galaxies selected by the red-sequence Matched-filter Probabilistic Percolation (redMaPPer) algorithm in the first three years of data from ...the Dark Energy Survey (DES), allowing us to probe cluster selection and richness estimation, λ, in light of cluster dynamics. Our sample consists of 126 clusters with sufficient spectroscopy for individual velocity dispersion estimates. We examine the correlations between cluster velocity dispersion, richness, X-ray temperature, and luminosity, as well as central galaxy velocity offsets. The velocity dispersion–richness relation exhibits a bimodal distribution. The majority of clusters follow scaling relations between velocity dispersion, richness, and X-ray properties similar to those found for previous samples; however, there is a significant population of clusters with velocity dispersions that are high for their richness. These clusters account for roughly 22 per cent of the λ < 70 systems in our sample, but more than half (55 per cent) of λ < 70 clusters at z > 0.5. A couple of these systems are hot and X-ray bright as expected for massive clusters with richnesses that appear to have been underestimated, but most appear to have high velocity dispersions for their X-ray properties likely due to line-of-sight structure. These results suggest that projection effects contribute significantly to redMaPPer selection, particularly at higher redshifts and lower richnesses. The redMaPPer determined richnesses for the velocity dispersion outliers are consistent with their X-ray properties, but several are X-ray undetected and deeper data are needed to understand their nature.
Beyond the symptom: the biology of fatigue Raizen, David M; Mullington, Janet; Anaclet, Christelle ...
Sleep (New York, N.Y.),
09/2023, Letnik:
46, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Abstract
A workshop titled “Beyond the Symptom: The Biology of Fatigue” was held virtually September 27–28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of ...Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.
Abstract
The delayed diagnosis of tuberculous meningitis (TBM) leads to poor outcomes, yet the current diagnostic methods for identifying Mycobacterium tuberculosis in cerebrospinal fluid (CSF) are ...inadequate. The first comparative study of the new GeneXpert MTB/RIF Ultra (Xpert Ultra) for TBM diagnosis suggested increased sensitivity of Xpert Ultra. Two subsequent studies have shown Xpert Ultra has improved sensitivity, but has insufficient negative predictive value to exclude TBM. Collecting and processing large volumes of CSF for mycobacterial testing are important for optimal diagnostic test performance. But clinical, radiological, and laboratory parameters remain essential for TBM diagnosis and empiric therapy is often needed. We therefore caution against the use of Xpert Ultra as a single diagnostic test for TBM; it cannot be used to “rule out” TBM.
Xpert Ultra may be superior to Xpert for detecting Mycobacterium tuberculosis in cerebrospinal fluid. However, Xpert Ultra has insufficient negative predictive value to exclude Tuberculous Meningitis (TBM). We caution against using Xpert Ultra as a single diagnostic test for TBM.
Autism spectrum disorder (ASD) is heritable, and younger siblings of ASD probands are at higher likelihood of developing ASD themselves. Prospective MRI studies of siblings report that atypical brain ...development precedes ASD diagnosis, although the link between brain maturation and genetic factors is unclear. Given that familial recurrence of ASD is predicted by higher levels of ASD traits in the proband, the authors investigated associations between proband ASD traits and brain development among younger siblings.
In a sample of 384 proband-sibling pairs (89 pairs concordant for ASD), the authors examined associations between proband ASD traits and sibling brain development at 6, 12, and 24 months in key MRI phenotypes: total cerebral volume, cortical surface area, extra-axial cerebrospinal fluid, occipital cortical surface area, and splenium white matter microstructure. Results from primary analyses led the authors to implement a data-driven approach using functional connectivity MRI at 6 months.
Greater levels of proband ASD traits were associated with larger total cerebral volume and surface area and larger surface area and reduced white matter integrity in components of the visual system in siblings who developed ASD. This aligned with weaker functional connectivity between several networks and the visual system among all siblings during infancy.
The findings provide evidence that specific early brain MRI phenotypes of ASD reflect quantitative variation in familial ASD traits. Multimodal anatomical and functional convergence on cortical regions, fiber pathways, and functional networks involved in visual processing suggest that inherited liability has a role in shaping the prodromal development of visual circuitry in ASD.
Background:
Femoroacetabular impingement (FAI) is one of the most common causes of early cartilage and labral damage in the nondysplastic hip. Biomarkers of cartilage degradation and inflammation are ...associated with osteoarthritis. It was not known whether patients with FAI have elevated levels of biomarkers of cartilage degradation and inflammation.
Hypothesis:
Compared with athletes without FAI, athletes with FAI would have elevated levels of the inflammatory C-reactive protein (CRP) and cartilage oligomeric matrix protein (COMP), a cartilage degradation marker.
Study Design:
Controlled laboratory study.
Methods:
Male athletes with radiographically confirmed FAI (n = 10) were compared with male athletes with radiographically normal hips with no evidence of FAI or hip dysplasia (n = 19). Plasma levels of COMP and CRP were measured, and subjects also completed the Short Form–12 (SF-12) and Hip Disability and Osteoarthritis Outcome Score (HOOS) surveys.
Results:
Compared with controls, athletes with FAI had a 24% increase in COMP levels and a 276% increase in CRP levels as well as a 22% decrease in SF-12 physical component scores and decreases in all of the HOOS subscale scores.
Conclusion:
Athletes with FAI demonstrate early biochemical signs of increased cartilage turnover and systemic inflammation.
Clinical Relevance:
Chondral injury secondary to the repetitive microtrauma of FAI might be reliably detected with biomarkers. In the future, these biomarkers might be used as screening tools to identify at-risk patients and assess the efficacy of therapeutic interventions such as hip preservation surgery in altering the natural history and progression to osteoarthritis.
Early diagnosis of gestational diabetes can lead to greater optimization of glucose control. We evaluated associations between maternal serum analytes (alpha-fetoprotein AFP, free beta-human ...chorionic gonadotropin beta-hCG, inhibin, and estriol) and the development of gestational diabetes mellitus (GDM).
This retrospective cohort study identified single-ton pregnancies with available second trimester serum analytes between 2009 and 2017. GDM was identified by ICD-9 and -10 codes. We examined the associations between analyte levels and GDM and to adjust for potential confounders routinely collected during genetic serum screening (maternal age, BMI, and race) using logistic regression. Optimal logistic regression predictive modeling for GDM was then performed using the analyte levels and the above mentioned potential confounders. The performance of the model was assessed by receiver operator curves.
Out of 5,709 patients, 660 (11.6%) were diagnosed with GDM. Increasing AFP and estriol were associated with decreasing risk of GDM, aOR 0.76 95% CI 0.60-0.95 and aOR 0.67 95% CI 0.50-0.89 respectively. Increasing beta-hCG was associated with a decreasing risk for GDM(aOR 0.84 95% CI 0.73-0.97). There was no association with inhibin. The most predictive GDM predictive model included beta-hCG and estriol in addition to the clinical variables of age, BMI, and race (area under the curve (AUC 0.75), buy this was not statistically different than using clinical variables alone (AUC 0.74) (p=0.26).
Increasing second trimester AFP, beta-hCG, and estriol are associated with decreasing risks of GDM, though do not improve the predictive ability for GDM when added to clinical risk factors of age, BMI, and race.
To determine if clozapine can be safely utilized in psychiatric patients with benign neutropenia.
A single-center, retrospective chart review study of records from 2001 to 2014 was conducted in an ...inpatient psychiatric hospital. Patients included had benign neutropenia prior to receiving clozapine and received clozapine using modified monitoring guidelines. All available laboratory values for absolute neutrophil count (ANC) before initiation and during treatment were evaluated. The primary endpoint was difference in ANC after initiation of clozapine from before clozapine.
A total of 26 patients were reviewed. The mean age at clozapine initiation was 34 years. The majority were African-American (73% n = 19), with more men than women (73% n = 19 vs 27% n = 7). The mean lowest ANC value was not significantly different after clozapine initiation compared to before (1.5× 10³ cells/mm³ and 1.4 × 10³ cells/mm³, respectively; P = .22). The overall mean ANC was significantly higher after initiation than before (2.63 × 10³ cells/mm³ and 2.13 × 10³ cells/mm³, respectively; P < .001). There were no cases of severe neutropenia (ANC < 0.5 × 10³ cells/mm³), and no patient was discontinued for falling below modified guideline limits. There were fewer occurrences of mild neutropenia (ANC < 2.0 × 10³ cells/mm³) after clozapine initiation than before (16.0% and 31.4%, respectively; P < .001). There were also fewer occurrences of moderate neutropenia (ANC < 1.5 × 10³ cells/mm³), with 2.1% after clozapine and 13.3% before (P < .001).
Twenty-six patients with benign neutropenia were safely treated with clozapine. Pre-clozapine neutropenia did not predict increased risk for severe neutropenia with clozapine. Patients had significantly fewer episodes of mild and moderate neutropenia after receiving clozapine compared to before.
West Nile virus (WNV) is a globally distributed mosquito-borne virus of great public health concern. The number of WNV human cases and mosquito infection patterns vary in space and time. Many ...statistical models have been developed to understand and predict WNV geographic and temporal dynamics. However, these modeling efforts have been disjointed with little model comparison and inconsistent validation. In this paper, we describe a framework to unify and standardize WNV modeling efforts nationwide. WNV risk, detection, or warning models for this review were solicited from active research groups working in different regions of the United States. A total of 13 models were selected and described. The spatial and temporal scales of each model were compared to guide the timing and the locations for mosquito and virus surveillance, to support mosquito vector control decisions, and to assist in conducting public health outreach campaigns at multiple scales of decision-making. Our overarching goal is to bridge the existing gap between model development, which is usually conducted as an academic exercise, and practical model applications, which occur at state, tribal, local, or territorial public health and mosquito control agency levels. The proposed model assessment and comparison framework helps clarify the value of individual models for decision-making and identifies the appropriate temporal and spatial scope of each model. This qualitative evaluation clearly identifies gaps in linking models to applied decisions and sets the stage for a quantitative comparison of models. Specifically, whereas many coarse-grained models (county resolution or greater) have been developed, the greatest need is for fine-grained, short-term planning models (m-km, days-weeks) that remain scarce. We further recommend quantifying the value of information for each decision to identify decisions that would benefit most from model input.
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