Blood-based kinetic analysis of PET data relies on an accurate estimate of the arterial plasma input function (PIF). An alternative to invasive measurements from arterial sampling is an image-derived ...input function (IDIF). However, an IDIF provides the whole blood radioactivity concentration, rather than the required free tracer radioactivity concentration in plasma. To estimate the tracer PIF, we corrected an IDIF from the carotid artery with estimates of plasma parent fraction (PF) and plasma-to-whole blood (PWB) ratio obtained from five venous samples. We compared the combined IDIF+venous approach to gold standard data from arterial sampling in 10 healthy volunteers undergoing 18FGE-179 brain PET imaging of the NMDA receptor. Arterial and venous PF and PWB ratio estimates determined from 7 patients with traumatic brain injury (TBI) were also compared to assess the potential effect of medication. There was high agreement between areas under the curves of the estimates of PF (r = 0.99, p<0.001), PWB ratio (r = 0.93, p<0.001), and the PIF (r = 0.92, p<0.001) as well as total distribution volume (VT) in 11 regions across the brain (r = 0.95, p<0.001). IDIF+venous VT had a mean bias of −1.7% and a comparable regional coefficient of variation (arterial: 21.3 ± 2.5%, IDIF+venous: 21.5 ± 2.0%). Simplification of the IDIF+venous method to use only one venous sample provided less accurate VT estimates (mean bias 9.9%; r = 0.71, p<0.001). A version of the method that avoids the need for blood sampling by combining the IDIF with population-based PF and PWB ratio estimates systematically underestimated VT (mean bias −20.9%), and produced VT estimates with a poor correlation to those obtained using arterial data (r = 0.45, p<0.001). Arterial and venous blood data from 7 TBI patients showed high correlations for PF (r = 0.92, p = 0.003) and PWB ratio (r = 0.93, p = 0.003). In conclusion, the IDIF+venous method with five venous samples provides a viable alternative to arterial sampling for quantification of 18FGE-179 VT.
Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the
locus. ETMRs predominantly ...occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on nine consecutive patients and review the role of initiation/timing of radiotherapy on survival. Between 2006 and 2018, nine patients were diagnosed with ETMR. Diagnosis was confirmed histopathologically, immunohistochemically and molecularly. Median age was 25 months (5-38). Location was supratentorial in five, pineal in three, and brainstem in one. Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis. Chemotherapy augmented with intrathecal therapy started a median of 10 days (7-20) after surgery. Only two patients who after gross total resection received radiotherapy very early on (six weeks after diagnosis) are alive and in complete remission 56 and 50 months after diagnosis. All remaining patients for whom radiotherapy was deferred until the end of chemotherapy recurred, albeit none with leptomeningeal disease. A literature research identified 228 patients with ETMR. Including our patients only 26 (11%) of 237 patients survived >36 months with no evidence of disease at last follow-up. All but two long-term (>36 months) survivors received radiotherapy, ten of whom early on following gross total resection (GTR). GTR followed by early focal radiotherapy and intrathecal therapy to prevent leptomeningeal disease are potentially important to improve survival of ETMR in the absence of effective targeted therapies.
Objective
The objective of this study was to assess the effectiveness of a low‐dose intravenous S‐ketamine treatment on refractory pain in patients with Complex Regional Pain Syndrome (CRPS).
Methods
...In this retrospective study, patients with CRPS who received intravenous S‐ketamine from March 2010 to April 2019 were included. According to our inpatient protocol, S‐ketamine dose was increased until pain reduction was achieved or side effects were observed. Maximum dose was 14 mg/h and treatment duration was 7 days. Primary outcome parameters were pain scores (Numeric Rating Scale) at baseline (T0), end of infusion (T1), and approximately 4 weeks postinfusion (T2). Patients were categorized as responder/nonresponder at T1 and T2. Patients were considered a responder in case there was pain score reduction of greater than or equal to 2 points or if treatment was reported as successful.
Results
Forty‐eight patients were included. Mean disease duration was 5 years (interquartile range IQR = 6 years). Median pain score significantly decreased from 8 (IQR = 2) at T0 to 6 (IQR = 4) at T1 (p < 0.001). At T1, 62% of the patients were responders. At T2, 48% of the patients remained a responder. A significant proportion of the responders at T1 turned into nonresponders at T2 (p = 0.03).
Conclusion
In a group of patients with CRPS with refractory pain, low‐dose intravenous S‐ketamine treatment resulted in effective pain relief during infusion. Although a significant proportion of initial responders became nonresponders at follow‐up, half of the patients were still a responder at ~ 4 weeks postinfusion. Further research is needed to investigate mechanisms responsible for pain relief by S‐ketamine infusions and to ascertain possible predictors of response to the treatment.
We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing d
Cas9 (i.e., "dead"
Cas9, in which the Cas9 nuclease ...activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1×10
vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.).
Objective
This study was undertaken to estimate the cost‐effectiveness of add‐on cenobamate in the UK when used to treat drug‐resistant focal seizures in adults who are not adequately controlled with ...at least two prior antiseizure medications, including at least one used adjunctively.
Methods
We estimated the cost per quality‐adjusted life‐year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long‐term studies of cenobamate. A network meta‐analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short‐Form six‐dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses.
Results
In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators.
Significance
Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost‐effective adjunctive antiseizure medication for people with drug‐resistant focal seizures.
Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein–Barr virus (EBV) seems to avoid ...recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viral- and exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5′ppp, in vitro transcripts, and coculture experiments, we established that 5′pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV-microRNAs, but no intact EBV-DNA, linking non–cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host–pathogen stand-off and may promote inflammatory diseas
Recent developments in performance and practicality of optically-pumped magnetometers (OPMs) have enabled new capabilities in non-invasive brain function mapping through magnetoencephalography. In ...particular, the lack of cryogenic operating conditions allows for more flexible placement of sensor heads closer to the brain, leading to improved spatial resolution and source localisation capabilities. Through recording visually evoked brain fields (VEFs), we demonstrate that the closer sensor proximity can be exploited to improve temporal resolution. We use OPMs, and superconducting quantum interference devices (SQUIDs) for reference, to measure brain responses to flash and pattern reversal stimuli. We find highly reproducible signals with consistency across multiple participants, stimulus paradigms and sensor modalities. The temporal resolution advantage of OPMs is manifest in a twofold improvement, compared to SQUIDs. The capability for improved spatio-temporal signal tracing is illustrated by simultaneous vector recordings of VEFs in the primary and associative visual cortex, where a time lag on the order of 10-20 ms is consistently found. This paves the way for further spatio-temporal studies of neurophysiological signal tracking in visual stimulus processing, and other brain responses, with potentially far-reaching consequences for time-critical mapping of functionality in healthy and pathological brains.
Conventional vaccines are very efficient in the prevention of bacterial infections caused by extracellular pathogens due to effective stimulation of pathogen-specific antibodies. In contrast, ...considering that intracellular surveillance by antibodies is not possible, they are typically less effective in preventing or treating infections caused by intracellular pathogens such as
. The objective of the current study was to use so-called photochemical internalization (PCI) to deliver a live bacterial vaccine to the cytosol of antigen-presenting cells (APCs) for the purpose of stimulating major histocompatibility complex (MHC) I-restricted CD8 T-cell responses. For this purpose,
BCG (BCG) was combined with the photosensitiser tetraphenyl chlorine disulfonate (TPCS2a) and injected intradermally into mice. TPCS2a was then activated by illumination of the injection site with light of defined energy. Antigen-specific CD4 and CD8 T-cell responses were monitored in blood, spleen, and lymph nodes at different time points thereafter using flow cytometry, ELISA and ELISPOT. Finally, APCs were infected and PCI-treated
for analysis of their activation of T cells
or
after autologous vaccination of mice. Combination of BCG with PCI induced stronger BCG-specific CD4 and CD8 T-cell responses than treatment with BCG only or with BCG and TPCS2a without light. The overall T-cell responses were multifunctional as characterized by the production of IFN-γ, TNF-α, IL-2 and IL-17. Importantly, PCI induced cross-presentation of BCG proteins for stimulation of antigen-specific CD8 T-cells that were particularly producing IFN-γ and TNF-α. PCI further facilitated antigen presentation by causing up-regulation of MHC and co-stimulatory proteins on the surface of APCs as well as their production of TNF-α and IL-1β
. Furthermore, PCI-based vaccination also caused local inflammation at the site of vaccination, showing strong infiltration of immune cells, which could contribute to the stimulation of antigen-specific immune responses. This study is the first to demonstrate that a live microbial vaccine can be combined with a photochemical compound and light for cross presentation of antigens to CD8 T cells. Moreover, the results revealed that PCI treatment strongly improved the immunogenicity of
BCG.
Land application of sewage sludge has a number of advantages over other alternatives, but is also associated with environmental impacts. To make proper assessments of different sludge treatments, it ...is crucial to have reliable estimates of emissions after the application of different sludge types. However, because of the complexity of the agricultural production system, it is difficult to estimate emissions consistently under different conditions. In the current paper, a mechanistic agro-ecosystem model was calibrated to be able to simulate different sludge types stabilized using different techniques. Subsequently, 100 year model simulations were used to provide emission factors as well as harvest and carbon sequestration factors (collectively called environmental inventory factors) under a variety of environmental conditions. Environmental inventory factors were calculated under both high crop response conditions (i.e. when nitrogen was limiting) and low crop response conditions (i.e. when nitrogen was not limiting). The average high response nitrogen harvest factor over the tested environmental conditions was ranging from 0.06 to 0.30 for the different sludge types included. This means that if an additional 1 kg of nitrogen is applied with sludge, between 0.06 and 0.30 kg additional nitrogen is harvested. This is considerably lower than for mineral fertilizer with an average value of 0.63. The low response harvest factors were considerably lower, ranging from 0.03 to 0.13. The emission factor for nitrous oxide nitrogen was ranging from 0.024 to 0.034, consistently being higher under high response conditions. For nitrogen leaching to the groundwater, the high response emission factor ranged from 0.20 to 0.50 for the different sludge types while the low response were slightly higher ranging from 0.18 to 0.55. The average carbon sequestration factor across the different environmental conditions ranged from 0.03 to 0.05 for the different sludge types. In conclusion, the approach using an agro-ecosystem model to estimate inventory factors associated with land application of sludge under varying conditions proved very powerful and would have been virtually impossible by experimental means.
•Environmental inventory factors for sewage sludge land application were estimated.•Harvest and N2O factors were highest under high crop response (low N) conditions.•Factors for N leaching were higher under low crop response conditions.•The modelling approach proved viable for estimation of inventory factors.
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