A SARS-CoV-2 surveillance program conducted by the National Basketball Association identified 173 newly infected persons. The viral kinetics were systematically studied and are described.
Objective
Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is an mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of ...TSC. We report the first prospective human clinical trial to directly assess whether everolimus will also benefit epilepsy in TSC patients.
Methods
The effect of everolimus on seizure control was assessed using a prospective, multicenter, open‐label, phase I/II clinical trial. Patients ≥2 years of age with confirmed diagnosis of TSC and medically refractory epilepsy were treated for a total of 12 weeks. The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency over a 4‐week period before and after treatment. Secondary endpoints assessed impact on electroencephalography (EEG), behavior, and quality of life.
Results
Twenty‐three patients were enrolled, and 20 patients were treated with everolimus. Seizure frequency was reduced by ≥50% in 12 of 20 subjects. Overall, seizures were reduced in 17 of the 20 by a median reduction of 73% (p < 0.001). Seizure frequency was also reduced during 23‐hour EEG monitoring (p = 0.007). Significant reductions in seizure duration and improvement in parent‐reported behavior and quality of life were also observed. There were 83 reported adverse events that were thought to be treatment‐related, all of which were mild or moderate in severity.
Interpretation
Seizure control improved in the majority of TSC patients with medically refractory epilepsy following treatment with everolimus. Everolimus demonstrated additional benefits on behavior and quality of life. Treatment was safe and well tolerated. Everolimus may be a therapeutic option for refractory epilepsy in this population. Ann Neurol 2013;74:679–687
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Adult hippocampal neurogenesis is believed to maintain a range of cognitive functions, many of which decline with age. We recently reported that radial neural stem cells (rNSCs) in the hippocampus ...undergo activation-dependent conversion into astrocytes, a mechanism that over time contributes to a reduction in the rNSC population. Here, we injected low and high levels of kainic acid (KA) in the dentate gyrus to assess whether neuronal hyperexcitation, a hallmark of epileptic disorders, could accelerate this conversion. At low levels of KA, generating epileptiform activity without seizures, we indeed found increased rNSC activation and conversion into astrocytes. At high levels, generating sustained epileptic seizures, however, we find that rNSCs divide symmetrically and that both mother and daughter cells convert into reactive astrocytes. Our results demonstrate that a threshold response for neuronal hyperexcitation provokes a dramatic shift in rNSC function, which impairs adult hippocampal neurogenesis in the long term.
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•Kainic acid injections into hippocampus model neuronal hyperactivity in mice•At low doses, without seizure activity, rNSCs divide asymmetrically•At high doses, with seizures, rNSCs divide symmetrically into reactive astrocytes•Both models deplete rNSCs and impair hippocampal neurogenesis
Sierra et al. model neuronal hyperactivity in mice to show that seizures induce a massive activation of radial neural stem cells (rNSCs) and their conversion into reactive astrocytes, which exhausts adult hippocampal neurogenesis. In the absence of seizures, but with interictal epileptiform activity, they also show that rNSC activation and subsequent depletion mirror age-associated decline of neurogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Evolution of brown carbon in wildfire plumes Forrister, Haviland; Liu, Jiumeng; Scheuer, Eric ...
Geophysical research letters,
16 June 2015, Volume:
42, Issue:
11
Journal Article
Peer reviewed
Open access
Particulate brown carbon (BrC) in the atmosphere absorbs light at subvisible wavelengths and has poorly constrained but potentially large climate forcing impacts. BrC from biomass burning has ...virtually unknown lifecycle and atmospheric stability. Here, BrC emitted from intense wildfires was measured in plumes transported over 2 days from two main fires, during the 2013 NASA SEAC4RS mission. Concurrent measurements of organic aerosol (OA) and black carbon (BC) mass concentration, BC coating thickness, absorption Ångström exponent, and OA oxidation state reveal that the initial BrC emitted from the fires was largely unstable. Using back trajectories to estimate the transport time indicates that BrC aerosol light absorption decayed in the plumes with a half‐life of 9 to 15 h, measured over day and night. Although most BrC was lost within a day, possibly through chemical loss and/or evaporation, the remaining persistent fraction likely determines the background BrC levels most relevant for climate forcing.
Key Points
Biomass burning brown carbon has unknown lifecycle and atmospheric stability
Brown carbon and aerosol properties from two fires are measured for 50 h
Wildfire brown carbon lifetime was 9–15 h, but a small fraction is stable
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cortical dysplasia (CD) is a common cause for intractable epilepsy. Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway has been implicated in CD; however, the mechanisms by which ...mTOR hyperactivation contribute to the epilepsy phenotype remain elusive. Here, we investigated whether constitutive mTOR hyperactivation in the hippocampus is associated with altered voltage-gated ion channel expression in the neuronal subset-specific Pten knockout (NS-Pten KO) mouse model of CD with epilepsy. We found that the protein levels of Kv1.1, but not Kv1.2, Kv1.4, or Kvβ2, potassium channel subunits were increased, along with altered Kv1.1 distribution, within the hippocampus of NS-Pten KO mice. The aberrant Kv1.1 protein levels were present in young adult (≥postnatal week 6) but not juvenile (≤postnatal week 4) NS-Pten KO mice. No changes in hippocampal Kv1.1 mRNA levels were found between NS-Pten KO and WT mice. Interestingly, mTOR inhibition with rapamycin treatment at early and late stages of the pathology normalized Kv1.1 protein levels in NS-Pten KO mice to WT levels. Together, these studies demonstrate altered Kv1.1 protein expression in association with mTOR hyperactivation in NS-Pten KO mice and suggest a role for mTOR signaling in the modulation of voltage-gated ion channel expression in this model.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that ...in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis
. However, some people living with HIV ...who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance
. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections
. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence
. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log
-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
"Treatable traits" have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve ...outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.
Background
Use of acute care for mental health concerns has been increasing among youth in recent years. Improving access to outpatient mental health services may prevent downstream acute care ...visits.
Purpose
To examine differences in rates of acute mental health care visits among youth with-
versus
without prior outpatient mental health services.
Methodology
A total of 2,442 youth ages 14-17 years participated in a provincially representative cross-sectional epidemiological survey, the 2014 Ontario Child Health Study. This sample was individually linked to health administrative databases, with nearly universal coverage of all medically necessary physician and acute care visits. Our exposure was parent and youth reported outpatient mental health service use in the six-month period prior to completing the survey. Exposed youth (n=691) were matched with unexposed youth using a propensity score informed by a range of clinical and socio-demographic factors. Our outcome was acute mental health care visits in the 18-month period following completion of the survey, ascertained though the linked health administrative data.
Results
In our propensity score matched sample, we found no difference in rates of subsequent acute mental health care visits (HR= 1.14, 95%CI 0.44, 2.98) between youth with- versus without prior outpatient mental health services.
Conclusions
There is a need to further understand the types of services youth are receiving in outpatient settings to determine if, and for whom, outpatient mental health services reduces the likelihood of future acute mental health care visits.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Production advantages, environmental benefits and increasing parasite resistance are changing the composition of New Zealand pastures. Traditional ryegrass/clover pasture mixes are being replaced by ...forage herb crops such as lucerne, chicory and plantain that accumulate a higher concentration of contaminants such as cadmium (Cd). To explore the relationship between Cd in forage crops and the Cd concentration accumulated by animals, four-month-old lambs at four farms across the central North Island of New Zealand were grazed on different forage crops (ryegrass, chicory, lucerne and plantain) between weaning and slaughter. Soil and pasture samples, and sequential liver biopsies, were collected and analysed for total Cd. There were significant differences in Cd concentration between the forage crops (chicory > plantain > lucerne > ryegrass) and this ordering was repeated for Cd in liver. There was no exceedance of maximum limits (ML) for Cd in offal set by the EU and NZ/Australia food safety standards authorities for animals of this study, although the highest concentration of Cd in chicory (0.85 mg/kg DW) was considerably lower than has been recorded elsewhere in New Zealand (4.5 mg/kg DW). Provisional Soil Management Values (SMVs) were developed to explore compliance of liver with EU food standards as a function of grazing chicory. For a soil pH of 5, exceedance might occur at a soil cadmium concentration of 0.34 mg/kg. This concentration falls within Tier 0 of the New Zealand Tiered Fertiliser Management System which seeks to ensure soil Cd remains within acceptable limits over the next 100 years and beyond. Increased Cd uptake by fodder crops and its management in these Tier 0 pastoral soils is therefore an emerging issue for pastoral agriculture. The risk of ML exceedance for animals grazing forage crops such as chicory on low Cd soils should be further considered to ensure uninterrupted access to export markets.
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•The relationship between forage and liver Cd was investigated across four farms.•Liver cadmium is higher for sheep grazing chicory even from low cadmium soils.•Soil management values are advanced to manage cadmium exceedance from chicory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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