Higher viral loads in SARS-CoV-2 infections may be linked to more rapid spread of emerging variants of concern (VOC). Rapid detection and isolation of cases with highest viral loads, even in pre- or ...asymptomatic individuals, is essential for the mitigation of community outbreaks.
In this study, we analyze Ct values from 1297 SARS-CoV-2 positive patient saliva samples collected at the Clemson University testing lab in upstate South Carolina. Samples were identified as positive using RT-qPCR, and clade information was determined via whole genome sequencing at nearby commercial labs. We also obtained patient-reported information on symptoms and exposures at the time of testing. The lowest Ct values were observed among those infected with Delta (median: 22.61, IQR: 16.72-28.51), followed by Alpha (23.93, 18.36-28.49), Gamma (24.74, 18.84-30.64), and the more historic clade 20G (25.21, 20.50-29.916). There was a statistically significant difference in Ct value between Delta and all other clades (all p.adj<0.01), as well as between Alpha and 20G (p.adj<0.05). Additionally, pre- or asymptomatic patients (n = 1093) showed the same statistical differences between Delta and all other clades (all p.adj<0.01); however, symptomatic patients (n = 167) did not show any significant differences between clades. Our weekly testing strategy ensures that cases are caught earlier in the infection cycle, often before symptoms are present, reducing this sample size in our population.
COVID-19 variants Alpha and Delta have substantially higher viral loads in saliva compared to more historic clades. This trend is especially observed in individuals who are pre- or asymptomatic, which provides evidence supporting higher transmissibility and more rapid spread of emerging variants. Understanding the viral load of variants spreading within a community can inform public policy and clinical decision making.
Therapeutic hypothermia significantly improves outcomes after neonatal hypoxic-ischemic (HI) encephalopathy but is only partially protective. There is evidence that cortical inhibitory interneuron ...circuits are particularly vulnerable to HI and that loss of interneurons may be an important contributor to long-term neurological dysfunction in these infants. In the present study, we examined the hypothesis that the duration of hypothermia has differential effects on interneuron survival after HI. Near-term fetal sheep received sham ischemia or cerebral ischemia for 30 min, followed by cerebral hypothermia from 3 h after ischemia end and continued up to 48 h, 72 h, or 120 h recovery. Sheep were euthanized after 7 days for histology. Hypothermia up to 48 h recovery resulted in moderate neuroprotection of glutamate decarboxylase (GAD)
and parvalbumin
interneurons but did not improve survival of calbindin
cells. Hypothermia up to 72 h recovery was associated with significantly increased survival of all three interneuron phenotypes compared with sham controls. By contrast, while hypothermia up to 120 h recovery did not further improve (or impair) GAD
or parvalbumin
neuronal survival compared with hypothermia up to 72 h, it was associated with decreased survival of calbindin
interneurons. Finally, protection of parvalbumin
and GAD
interneurons, but not calbindin
interneurons, with hypothermia was associated with improved recovery of electroencephalographic (EEG) power and frequency by day 7 after HI. The present study demonstrates differential effects of increasing the duration of hypothermia on interneuron survival after HI in near-term fetal sheep. These findings may contribute to the apparent preclinical and clinical lack of benefit of very prolonged hypothermia.
Children who survive preterm birth exhibit persistent unexplained disturbances in cerebral cortical growth with associated cognitive and learning disabilities. The mechanisms underlying these ...deficits remain elusive. We used ex vivo diffusion magnetic resonance imaging to demonstrate in a preterm large-animal model that cerebral ischemia impairs cortical growth and the normal maturational decline in cortical fractional anisotropy (FA). Analysis of pyramidal neurons revealed that cortical deficits were associated with impaired expansion of the dendritic arbor and reduced synaptic density. Together, these findings suggest a link between abnormal cortical FA and disturbances of neuronal morphological development. To experimentally investigate this possibility, we measured the orientation distribution of dendritic branches and observed that it corresponds with the theoretically predicted pattern of increased anisotropy within cases that exhibited elevated cortical FA after ischemia. We conclude that cortical growth impairments are associated with diffuse disturbances in the dendritic arbor and synapse formation of cortical neurons, which may underlie the cognitive and learning disabilities in survivors of preterm birth. Further, measurement of cortical FA may be useful for noninvasively detecting neurological disorders affecting cortical development.
Background
NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large ...series of pediatric and adolescent patients with advanced cancers.
Procedure
Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions.
Results
Total of nine cases (0.44%) harbored NTRK fusions, including novel partners. Four of these cases were in children less than 2 years old for which infantile fibrosarcoma was considered as a diagnosis, and two harbored the canonical ETV6‐NTRK3. The remaining cases carried other diagnoses, at least one that carried the diagnosis of inflammatory myofibroblastic tumor.
Conclusions
NTRK fusions occur in a subset of young patients with mesenchymal or sarcoma‐like tumors at a low frequency, and are eminently druggable targets via either investigational agents or approved drugs.
•Preterm newborns are at significant risk impaired brain development.•Impaired neurodevelopment can result from injury and/or impaired maturation of brain cells such as oligodendrocytes.•The causes ...of impaired neurodevelopment are multifactorial but a pathway common to many insults is inflammation.•Acute inflammation after insults such as hypoxia-ischemia and chorioamnionitis is associated with brain injury and impaired brain development.•Increasing evidence suggests that For some infants, inflammation be chronic in nature. Inflammation is thus a target for neuroprotection treatments like stem cells.
The preterm newborn is at significant risk of neural injury and impaired neurodevelopment. Infants with mild or no evidence of injury may also be at risk of altered brain development, with evidence impaired cell maturation. The underlying causes are multifactorial and include exposure of both the fetus and newborn to hypoxia-ischemia, inflammation (chorioamnionitis) and infection, adverse maternal lifestyle choices (smoking, drug and alcohol use, diet) and obesity, as well as the significant demand that adaptation to post-natal life places on immature organs. Further, many fetuses and infants may have combinations of these events, and repeated (multi-hit) events that may induce tolerance to injury or sensitize to greater injury. Currently there are no treatments to prevent preterm injury or impaired neurodevelopment. However, inflammation is a common pathway for many of these insults, and clinical and experimental evidence demonstrates that acute and chronic inflammation is associated with impaired brain development. This review examines our current knowledge about the relationship between inflammation and preterm brain development, and the potential for stem cell therapy to provide neuroprotection and neurorepair through reducing inflammation and release of trophic factors, which promote cell maturation and repair.
Children surviving preterm birth have a high risk of disability, particularly cognitive and learning problems. There is extensive clinical and experimental evidence that disability is now primarily ...related to dysmaturation of white and gray matter, defined by failure of oligodendrocyte maturation and neuronal dendritic arborization, rather than cell death alone. The etiology of this dysmaturation is multifactorial, with contributions from hypoxia‐ischemia, infection/inflammation and barotrauma. Intriguingly, these factors can interact to both increase and decrease damage. In this review we summarize preclinical and clinical evidence that all of these factors trigger secondary or chronic inflammation and gliosis. Thus, we hypothesize that these shared pathological features play a key role in a final common pathway that leads to the impaired neural maturation and connectivity and cognitive/motor impairments that are commonly observed in infants born preterm. This raises the possibility that secondary or chronic inflammation may be a viable therapeutic target for delayed interventions to improve neurodevelopmental outcomes after preterm birth.
What this paper adds
Hypoxia‐ischemia, infection/inflammation, and barotrauma/volutrauma all contribute to preterm brain injury.
Multiple different triggers of preterm brain injury are associated with central nervous system dysmaturation.
Secondary brain inflammation may be a viable target to improve neurodevelopment after preterm birth.
Resumen
Interacciones complejas entre la hipoxia‐isquemia y la inflamación en la lesión cerebral de niños prematuros
Los niños que sobreviven a un parto prematuro tienen un alto riesgo de discapacidad, en particular desafíos cognitivos y de aprendizaje. Existe una amplia evidencia clínica y experimental de que ahora la discapacidad se relaciona principalmente con la dismaturidad de la sustancia blanca y gris, definida por el fracaso de la maduración de los oligodendrocitos y de la arborización dendrítica neuronal. Por lo tanto, la discapacidad relacionada a la prematurez no resulta solamente de la muerte celular. La etiología de esta dismaturidad es multifactorial, con contribuciones de hipoxia‐isquemia, infección / inflamación y barotrauma. Curiosamente, estos factores pueden interactuar tanto para aumentar como para disminuir el daño. En esta revisión, resumimos la evidencia clínica y preclínica de todos los factores que desencadenan la inflamación y gliosis secundaria o crónica. Por lo tanto, planteamos la hipótesis de que estas características patológicas compartidas desempeñan un papel clave en una vía final común que conduce a la alteración de la maduración y la conectividad neuronal y las discapacidades cognitivas / motoras que se observan comúnmente en los recién nacidos prematuros. Esto plantea la posibilidad de que la inflamación secundaria o crónica pueda ser un objetivo terapéutico viable para las intervenciones tardías para mejorar los resultados del desarrollo neurológico posterior al parto prematuro.
Resumo
Interações complexas entre hipoxia‐isquemia e inflamação na lesão cerebral do prematuro
Crianças que sobrevivem ao parto prematuro têm alto risco de incapacidades, em especial problemas cognitivos e de aprendizagem. Há agora extensivas evidências clínicas e experimentais de que a incapacidade é primariamente relacionada a imaturidade da substância branca e cinzenta, definida pela falha da maturação de oligodendrócitos e arborização dendrítica neuronal, e não à morte celular por si só. A etiologia desta imaturidade é multifatorial, com contribuições da hipoxia‐isquemia, infecção/inflamação e barotrauma. Intrigantemente, estes fatores podem interagir tanto para aumentar quanto para diminuir o dano. Nesta revisão, sintetizamos evidências clínicas e pré‐clínicas de que todos estes fatores disparam inflamação e gliose secundária ou crônica. Assim, hipotetizamos que estes mecanismos patológicos compartilhados desempenham papel central em uma via final comum que leva a maturação neural e conectividade deficientes e às deficiências cognitivas/motoras que são comumente observadas em prematuros. Isso levanta a possibilidade de que a inflamação secundária ou crônica possa ser um alvo terapêutico viável para intervenções tardias para melhorar os resultados de neurodesenvolvimento após o nascimento prematuro.
What this paper adds
Hypoxia‐ischemia, infection/inflammation, and barotrauma/volutrauma all contribute to preterm brain injury.
Multiple different triggers of preterm brain injury are associated with central nervous system dysmaturation.
Secondary brain inflammation may be a viable target to improve neurodevelopment after preterm birth.
This article is commented on by Paneth on page 115 of this issue.
This article's has been translated into Spanish and Portuguese.
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Therapeutic hypothermia is now well established to partially reduce disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Preclinical and clinical studies ...have confirmed that current protocols for therapeutic hypothermia are near optimal. The challenge is now to identify complementary therapies that can further improve outcomes, in combination with therapeutic hypothermia. Overall, anti-excitatory and anti-apoptotic agents have shown variable or even no benefit in combination with hypothermia, suggesting overlapping mechanisms of neuroprotection. Inflammation appears to play a critical role in the pathogenesis of injury in the neonatal brain, and thus, there is potential for drugs with immunomodulatory properties that target inflammation to be used as a therapy in neonates. In this review, we examine the evidence for neuroprotection with immunomodulation after hypoxia-ischemia. For example, stem cell therapy can reduce inflammation, increase cell survival, and promote cell maturation and repair. There are also encouraging preclinical data from small animals suggesting that stem cell therapy can augment hypothermic neuroprotection. However, there is conflicting evidence, and rigorous testing in translational animal models is now needed.
Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 ...receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS).
Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n = 9). Sheep were euthanized 4 days after starting infusions for histology.
LPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P < 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival.
IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.
Alzheimer's disease biomarkers are widely accepted as surrogate markers of underlying neuropathological changes. However, few studies have evaluated whether preclinical Alzheimer's disease biomarkers ...predict Alzheimer's neuropathology at autopsy. We sought to determine whether amyloid PET imaging or CSF biomarkers accurately predict cognitive outcomes and Alzheimer's disease neuropathological findings. This study included 720 participants, 42-91 years of age, who were enrolled in longitudinal studies of memory and aging in the Washington University Knight Alzheimer Disease Research Center and were cognitively normal at baseline, underwent amyloid PET imaging and/or CSF collection within 1 year of baseline clinical assessment, and had subsequent clinical follow-up. Cognitive status was assessed longitudinally by Clinical Dementia Rating®. Biomarker status was assessed using predefined cut-offs for amyloid PET imaging or CSF p-tau181/amyloid-β42. Subsequently, 57 participants died and underwent neuropathologic examination. Alzheimer's disease neuropathological changes were assessed using standard criteria. We assessed the predictive value of Alzheimer's disease biomarker status on progression to cognitive impairment and for presence of Alzheimer's disease neuropathological changes. Among cognitively normal participants with positive biomarkers, 34.4% developed cognitive impairment (Clinical Dementia Rating > 0) as compared to 8.4% of those with negative biomarkers. Cox proportional hazards modelling indicated that preclinical Alzheimer's disease biomarker status, APOE ɛ4 carrier status, polygenic risk score and centred age influenced risk of developing cognitive impairment. Among autopsied participants, 90.9% of biomarker-positive participants and 8.6% of biomarker-negative participants had Alzheimer's disease neuropathological changes. Sensitivity was 87.0%, specificity 94.1%, positive predictive value 90.9% and negative predictive value 91.4% for detection of Alzheimer's disease neuropathological changes by preclinical biomarkers. Single CSF and amyloid PET baseline biomarkers were also predictive of Alzheimer's disease neuropathological changes, as well as Thal phase and Braak stage of pathology at autopsy. Biomarker-negative participants who developed cognitive impairment were more likely to exhibit non-Alzheimer's disease pathology at autopsy. The detection of preclinical Alzheimer's disease biomarkers is strongly predictive of future cognitive impairment and accurately predicts presence of Alzheimer's disease neuropathology at autopsy.
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