Early identification of cerebral palsy (CP) is important for early intervention, yet expert-based assessments do not permit widespread use, and conventional machine learning alternatives lack ...validity.
To develop and assess the external validity of a novel deep learning-based method to predict CP based on videos of infants' spontaneous movements at 9 to 18 weeks' corrected age.
This prognostic study of a deep learning-based method to predict CP at a corrected age of 12 to 89 months involved 557 infants with a high risk of perinatal brain injury who were enrolled in previous studies conducted at 13 hospitals in Belgium, India, Norway, and the US between September 10, 2001, and October 25, 2018. Analysis was performed between February 11, 2020, and September 23, 2021. Included infants had available video recorded during the fidgety movement period from 9 to 18 weeks' corrected age, available classifications of fidgety movements ascertained by the general movement assessment (GMA) tool, and available data on CP status at 12 months' corrected age or older. A total of 418 infants (75.0%) were randomly assigned to the model development (training and internal validation) sample, and 139 (25.0%) were randomly assigned to the external validation sample (1 test set).
Video recording of spontaneous movements.
The primary outcome was prediction of CP. Deep learning-based prediction of CP was performed automatically from a single video. Secondary outcomes included prediction of associated functional level and CP subtype. Sensitivity, specificity, positive and negative predictive values, and accuracy were assessed.
Among 557 infants (310 55.7% male), the median (IQR) corrected age was 12 (11-13) weeks at assessment, and 84 infants (15.1%) were diagnosed with CP at a mean (SD) age of 3.4 (1.7) years. Data on race and ethnicity were not reported because previous studies (from which the infant samples were derived) used different study protocols with inconsistent collection of these data. On external validation, the deep learning-based CP prediction method had sensitivity of 71.4% (95% CI, 47.8%-88.7%), specificity of 94.1% (95% CI, 88.2%-97.6%), positive predictive value of 68.2% (95% CI, 45.1%-86.1%), and negative predictive value of 94.9% (95% CI, 89.2%-98.1%). In comparison, the GMA tool had sensitivity of 70.0% (95% CI, 45.7%-88.1%), specificity of 88.7% (95% CI, 81.5%-93.8%), positive predictive value of 51.9% (95% CI, 32.0%-71.3%), and negative predictive value of 94.4% (95% CI, 88.3%-97.9%). The deep learning method achieved higher accuracy than the conventional machine learning method (90.6% 95% CI, 84.5%-94.9% vs 72.7% 95% CI, 64.5%-79.9%; P < .001), but no significant improvement in accuracy was observed compared with the GMA tool (85.9%; 95% CI, 78.9%-91.3%; P = .11). The deep learning prediction model had higher sensitivity among infants with nonambulatory CP (100%; 95% CI, 63.1%-100%) vs ambulatory CP (58.3%; 95% CI, 27.7%-84.8%; P = .02) and spastic bilateral CP (92.3%; 95% CI, 64.0%-99.8%) vs spastic unilateral CP (42.9%; 95% CI, 9.9%-81.6%; P < .001).
In this prognostic study, a deep learning-based method for predicting CP at 9 to 18 weeks' corrected age had predictive accuracy on external validation, which suggests possible avenues for using deep learning-based software to provide objective early detection of CP in clinical settings.
Abstract
Lomandra is the largest genus in Asparagaceae subfamily Lomandroideae and possesses economic, ecological, and ethnobotanical significance in Australia. Lomandra comprises four sections, L. ...section Capitatae, L. section Macrostachya, L. section Typhopsis and L. section Lomandra, the latter comprising series Lomandra and series Sparsiflorae, all recognized based solely on morphology. In this study, phylogenetic relationships were estimated for 79 Lomandroideae individuals, including 45 Lomandra species and subspecies (c. 63% of species and subspecies diversity). We generated genome-scale plastome sequence data and used maximum likelihood and Bayesian inference criteria for phylogenetic estimation. Lomandra was non-monophyletic, with Xerolirion divaricata nested within it. Two major clades were recovered: Capitatae–Macrostachya (CM) and Lomandra–Typhopsis (LT). The CM clade included a monophyletic Lomandra section Capitatae with a base chromosome number x = 7, and L. section Macrostachya (x = 8); the LT clade included L. sections Typhopsis and Lomandra, both x = 8. Section Lomandra series Lomandra and series Sparsiflorae were both recovered as non-monophyletic. Morphological characters were assessed to identify combinations of characters that characterize clades. A base chromosome number of x = 8 was plesiomorphic for Lomandra. The largest number of Lomandra species occupy the Mediterranean ecoregion and occupancy of sclerophyll vegetation was reconstructed as ancestral for the genus.
Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte ...network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14
CD24
macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14
CD24
mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.
During ischemic stroke, occlusion of the cerebrovasculature causes neuronal cell death (infarction), but naturally occurring genetic factors modulating infarction have been difficult to identify in ...human populations. In a surgically induced mouse model of ischemic stroke, we have previously mapped Civq1 to distal chromosome 7 as a quantitative trait locus determining infarct volume. In this study, genome-wide association mapping using 32 inbred mouse strains and an additional linkage scan for infarct volume confirmed that the size of the infarct is determined by ancestral alleles of the causative gene(s). The genetically isolated Civq1 locus in reciprocal recombinant congenic mice refined the critical interval and demonstrated that infarct size is determined by both vascular (collateral vessel anatomy) and non-vascular (neuroprotection) effects. Through the use of interval-specific SNP haplotype analysis, we further refined the Civq1 locus and identified integrin alpha L (Itgal) as one of the causative genes for Civq1. Itgal is the only gene that exhibits both strain-specific amino acid substitutions and expression differences. Coding SNPs, a 5-bp insertion in exon 30b, and increased mRNA and protein expression of a splice variant of the gene (Itgal-003, ENSMUST00000120857), all segregate with infarct volume. Mice lacking Itgal show increased neuronal cell death in both ex vivo brain slice and in vivo focal cerebral ischemia. Our data demonstrate that sequence variation in Itgal modulates ischemic brain injury, and that infarct volume is determined by both vascular and non-vascular mechanisms.
The murine paucity of lymph node T cell (plt) mutation leads to abnormalities in leukocyte migration and immune response. The causative defect is thought to be a loss of secondary lymphoid-organ ...chemokine (SLC) expression in lymphoid tissues. We now find that the plt defect is due to the loss of both SLC and EBI-1 ligand chemokine (ELC) expression in secondary lymphoid organs. In an examination of the plt locus, we find that commonly used inbred mouse strains demonstrate at least three different haplotypes. Polymorphism at this locus is due to duplications of at least four genes, three of them encoding chemokines. At least two cutaneous T cell-attracting chemokine (CTACK), three SLC, and four ELC genes or pseudogenes are present in some haplotypes. All haplotypes share a duplication that includes two SLC genes, which demonstrate different expression patterns, a single functional ELC gene, and an ELC pseudogene. The plt mutation represents a deletion that includes the SLC gene expressed in secondary lymphoid organs and the single functional ELC gene, leaving only an SLC gene that is expressed in lymphatic endothelium and an ELC pseudogene. This lack of CCR7 ligands in the secondary lymphoid organs of plt mice provides a basis for their severe abnormalities in leukocyte migration and immune response.
Background
Half of women undergoing mammography have dense breasts. Mandatory dense breast notification and educational materials have been shown to confuse women, rather than empower them.
Objective
...This study used a mixed method, multi-stakeholder approach to assess acceptability of an interactive, computer-animated agent that provided breast density information to women and changes in knowledge, satisfaction, and informational needs.
Design
A pre-post survey and qualitative focus groups assessed the acceptability of the computer-animated agent among women. An anonymous, online survey measuring acceptability was delivered to a multi-stakeholder group.
Participants
English-speaking, mammography-eligible women ages 40–74 were invited and 44 women participated in one of nine focus groups. In addition, 14 stakeholders representing primary care, radiology, patient advocates, public health practitioners, and researchers completed the online survey.
Interventions
A prototype of a computer-animated agent was delivered to women in a group setting; stakeholders viewed the prototype independently.
Main Measures
Data collected included open-ended qualitative questions that guided discussion about the content and form of the computer-animated agent. Structured surveys included domains related to knowledge, acceptability, and satisfaction. Stakeholder acceptability was measured with a series of statements about aspects of the intervention and delivery approach and are reported as the proportion of respondents who endorsed each statement.
Key Results
Six of 12 knowledge items demonstrated improvement post-intervention, satisfaction with the agent was high (81%), but the number of unanswered questions did not improve (67% vs. 54%,
p
= 0.37). Understanding of the distinction between connective and fatty tissue in the breast did not increase (30% vs. 26%,
p
= 0.48). Results of the multi-stakeholder survey suggest broad acceptability of the approach and agent.
Conclusions
Findings highlight the benefits of a brief interactive educational exposure as well as misperceptions that persisted. Results demonstrate the need for an evidence-based, accessible intervention that is easy to understand for patients.
In pulmonary arterial hypertension (PAH), there is overexpression of the chemokine, C-C chemokine ligand type 2 (CCL2), and infiltration of myeloid cells into the pulmonary vasculature. Inhibition of ...CCL2 in animals decreases PAH, suggesting that the CCL2 receptor (CCR2) plays a role in PAH development. To test this hypothesis, we exposed wild-type (WT) and CCR2-deficient (Ccr2(-/-)) mice to chronic hypobaric hypoxia to induce PAH. After hypoxic stress, Ccr2(-/-) mice displayed a more severe PAH phenotype, as demonstrated by increased right ventricular (RV) systolic pressures, RV hypertrophy, and tachycardia relative to WT mice. However, these mice also exhibited increased RV systolic pressures and increased pulmonary artery muscularization under normoxic conditions. Moreover, Ccr2(-/-) mice displayed decreased pulmonary vascular branching at 3 weeks of age and increased vascular muscularization at birth, suggesting that an abnormality in pulmonary vascular development leads to spontaneous PAH in these animals. No significant differences in cytokine responses were observed between WT and Ccr2(-/-) mice during either normoxia or hypoxia. However, Ccr2(-/-) mice displayed increased Notch-3 signaling and dysregulated Notch ligand expression, suggesting a possible cause for their abnormal pulmonary vascular development. Our findings imply that CCR2 does not directly contribute to the development of PAH, but does play a previously unrecognized role in pulmonary vasculature development and remodeling wherein the absence of CCR2 results in spontaneous PAH, most likely via dysregulation of Notch signaling. Our results demonstrate that CCR2 has impacts beyond leukocyte recruitment, and is required for the proper expression of Notch signaling molecules.
Secondary lymphoid organs (spleen, lymph nodes and Peyer's patches) are divided into compartments, such as B-cell zones (follicles) and T-cell zones, which provide specialized environments for ...specific steps of the immune response. Migration of lymphocyte subsets into these compartments is essential for normal immune function, yet the molecular cues guiding this cellular traffic are poorly defined. Chemokines constitute a family of chemotactic cytokines that have been shown to direct the migration of leukocytes during inflammation, and which may be involved in the constitutive homing of lymphocytes into follicles and T-cell zones. Here we describe a novel chemokine, B-lymphocyte chemoattractant (BLC), that is strongly expressed in the follicles of Peyer's patches, the spleen and lymph nodes. BLC strongly attracts B lymphocytes while promoting migration of only small numbers of T cells and macrophages, and therefore is the first chemokine to be identified that is selective towards B cells. An orphan chemokine receptor, Burkitt's lymphoma receptor 1 (BLR-1), has been found to be required for B-cell migration into lymphoid follicles. We show that BLC stimulates calcium influx into, and chemotaxis of, cells transfected with BLR-1. Our results indicate that BLC functions as a BLR-1 ligand and may guide B lymphocytes to follicles in secondary lymphoid organs.
Early prediction of cerebral palsy (CP) using the General Movement Assessment (GMA) during the fidgety movements (FM) period has been recommended as standard of care in high-risk infants. The aim of ...this study was to determine the accuracy of GMA, alone or in combination with neonatal imaging, in predicting cerebral palsy (CP).
Infants with increased risk of perinatal brain injury were prospectively enrolled from 2009-2014 in this multi-center, observational study. FM were classified by two certified GMA observers blinded to the clinical history. Abnormal GMA was defined as absent or sporadic FM. CP-status was determined by clinicians unaware of GMA results.
Of 450 infants enrolled, 405 had scorable video and follow-up data until at least 18-24 months. CP was confirmed in 42 (10.4%) children at mean age 3 years 1 month. Sensitivity, specificity, positive and negative predictive values, and accuracy of absent/sporadic FM for CP were 76.2, 82.4, 33.3, 96.8, and 81.7%, respectively. Only three (8.1%) of 37 infants with sporadic FM developed CP. The highest accuracy (95.3%) was achieved by a combination of absent FM and abnormal neonatal imaging.
In infants with a broad range of neonatal risk factors, accuracy of early CP prediction was lower for GMA than previously reported but increased when combined with neonatal imaging. Sporadic FM did not predict CP in this study.
Childhood obesity is a growing worldwide problem. In adults, lower cold-induced brown adipose tissue (BAT) activity is linked to obesity and metabolic dysfunction; this relationship remains uncertain ...in children. In this cross-sectional study, we compared cold-induced supraclavicular (SCV) BAT activity (percent change in proton density fat fraction PDFF) within the SCV region after 1 h of whole-body cold exposure (18°C), using MRI in 26 boys aged 8-10 years: 13 with normal BMI and 13 with overweight/obesity. Anthropometry, body composition, hepatic fat, visceral adipose tissue (VAT), and pre- and postcold PDFF of the subcutaneous adipose tissue (SAT) in the posterior neck region and the abdomen were measured. Boys with overweight/obesity had lower cold-induced percent decline in SCV PDFF compared with those with normal BMI (1.6 ± 0.8 vs. 4.7 ± 1.2%, P = 0.044). SCV PDFF declined significantly in boys with normal BMI (2.7 ± 0.7%, P = 0.003) but not in boys with overweight/obesity (1.1 ± 0.5%, P = 0.053). No cold-induced changes in the PDFF of either neck SAT (-0.89 ± 0.7%, P = 0.250, vs. 0.37 ± 0.3%, P = 0.230) or abdominal SAT (-0.39 ± 0.5%, P = 0.409, and 0.25 ± 0.2%, P = 0.139, for normal BMI and overweight/obesity groups, respectively) were seen. The cold-induced percent decline in SCV PDFF was inversely related to BMI (r = -0.39, P = 0.047), waist circumference (r = -0.48, P = 0.014), and VAT (r = -0.47, P = 0.014). Thus, in young boys, as in adults, BAT activity is lower in those with overweight/obesity, suggesting that restoring activity may be important for improving metabolic health.
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