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Dynamic Changes in White Matter Abnormalities Correlate With Late Improvement and Deterioration Following TBI: A Diffusion Tensor Imaging Study.

OBJECTIVE: Traumatic brain injury (TBI) is not a single insult with monophasic resolution, but a chronic disease, with dynamic processes that remain active for years. We aimed to assess patient trajectories over the entire disease narrative, from ictus to late outcome. METHODS: Twelve patients with moderate-to-severe TBI underwent magnetic resonance imaging in the acute phase (within 1 week of injury) and twice in the chronic phase of injury (median 7 and 21 months), with some undergoing imaging at up to 2 additional time points. Longitudinal imaging changes were assessed using structural volumetry, deterministic tractography, voxel-based diffusion tensor analysis, and region of interest analyses (including corpus callosum, parasagittal white matter, and thalamus). Imaging changes were related to behavior. RESULTS: Changes in structural volumes, fractional anisotropy, and mean diffusivity continued for months to years postictus. Changes in diffusion tensor imaging were driven by increases in both axial and radial diffusivity except for the earliest time point, and were associated with changes in reaction time and performance in a visual memory and learning task (paired associates learning). Dynamic structural changes after TBI can be detected using diffusion tensor imaging and could explain changes in behavior. CONCLUSIONS: These data can provide further insight into early and late pathophysiology, and begin to provide a framework that allows magnetic resonance imaging to be used as an imaging biomarker of therapy response. Knowledge of the temporal pattern of changes in TBI patient populations also provides a contextual framework for assessing imaging changes in individuals at any given time point

SKYSURF-4: Panchromatic HST All-Sky Surface-Brightness Measurement Methods and Results

The diffuse, unresolved sky provides most of the photons that the Hubble Space Telescope (HST) receives, yet remains poorly understood. HST Archival Legacy program SKYSURF aims to measure the 0.2-1.6 $\mu$m sky surface brightness (sky-SB) from over 140,000 HST images. We describe a sky-SB measurement algorithm designed for SKYSURF that is able to recover the input sky-SB from simulated images to within 1% uncertainty. We present our sky-SB measurements estimated using this algorithm on the entire SKYSURF database. Comparing our sky-SB spectral energy distribution (SED) to measurements from the literature shows general agreements. Our SKYSURF SED also reveals a possible dependence on Sun angle, indicating either non-isotropic scattering of solar photons off interplanetary dust or an additional component to Zodiacal Light. Finally, we update Diffuse Light limits in the near-IR based on the methods from Carleton et al. (2022), with values of 0.009 MJy sr$^{-1}$ (22 nW m$^{-2}$ sr$^{-1}$) at 1.25 $\mu$m, 0.015 MJy sr$^{-1}$ (32 nW m$^{-2}$ sr$^{-1}$) at 1.4 $\mu$m, and 0.013 MJy sr$^{-1}$ (25 nW m$^{-2}$ sr$^{-1}$) at 1.6 $\mu$m. These estimates provide the most stringent all-sky constraints to date in this wavelength range. SKYSURF sky-SB measurements are made public on the official SKYSURF website and will be used to constrain Diffuse Light in future papers.Comment: Revised based on helpful comments from the reviewer, and accepted to AJ on April 12th, 2023. Main paper: 18 pages, 9 figures, 4 tables. Appendices: 16 pages, 10 figures, 1 table. Main results shown in Figure 7 and Table

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Resistance to First-Line Anti-TB Drugs Is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis

Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known. Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO. Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment. Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions

SKYSURF: Constraints on Zodiacal Light and Extragalactic Background Light through Panchromatic HST All-Sky Surface-Brightness Measurements: I. Survey Overview and Methods

We give an overview and describe the rationale, methods, and testing of the Hubble Space Telescope (HST) Archival Legacy project "SKYSURF." SKYSURF uses HST's unique capability as an absolute photometer to measure the ~0.2-1.7 $\mu$m sky surface brightness (SB) from 249,861 WFPC2, ACS, and WFC3 exposures in ~1400 independent HST fields. SKYSURF's panchromatic dataset is designed to constrain the discrete and diffuse UV to near-IR sky components: Zodiacal Light (ZL; inner Solar System), Kuiper Belt Objects (KBOs; outer Solar System), Diffuse Galactic Light (DGL), and the discrete plus diffuse Extragalactic Background Light (EBL). We outline SKYSURF's methods to: (1) measure sky-SB levels between its detected objects; (2) measure the integrated discrete EBL, most of which comes from AB$\simeq$17-22 mag galaxies; and (3) estimate how much diffuse light may exist in addition to the extrapolated discrete galaxy counts. Simulations of HST WFC3/IR images with known sky-values and gradients, realistic cosmic ray (CR) distributions, and star plus galaxy counts were processed with nine different algorithms to measure the "Lowest Estimated Sky-SB" (LES) in each image between the discrete objects. The best algorithms recover the inserted LES values within 0.2% when there are no image gradients, and within 0.2-0.4% when there are 5-10% gradients. SKYSURF requires non-standard re-processing of these HST images that includes restoring the lowest sky-level from each visit into each drizzled image. We provide a proof of concept of our methods from the WFC3/IR F125W images, where any residual diffuse light that HST sees in excess of the Kelsall et al. (1998) Zodiacal model prediction does not depend on the total object flux that each image contains. This enables us to present our first SKYSURF results on diffuse light in Carleton et al. (2022).Comment: Accepted to AJ; see accompanying paper Carleton et al. 2022: arXiv:2205.06347. Comments welcome

Oncolytic Adenoviruses Armed with Thymidine Kinase Can Be Traced by PET Imaging and Show Potent Antitumoural Effects by Ganciclovir Dosing

Replication-competent adenoviruses armed with thymidine kinase (TK) combine the concepts of virotherapy and suicide gene therapy. Moreover TK-activity can be detected by noninvasive positron emission-computed tomography (PET) imaging, what could potentially facilitate virus monitoring in vivo. Here, we report the generation of a novel oncolytic adenovirus that incorporates the Tat8-TK gene under the control of the Major Late Promoter in a highly selective backbone thus providing selectivity by targeting the retinoblastoma pathway. The selective oncolytic TK virus, termed ICOVIR5-TK-L, showed reduced potency compared to a non-selective counterpart. However the combination of ICOVIR5-TK-L with ganciclovir (GCV) induced a potent antitumoural effect similar to that of wild type adenovirus in a preclinical model of pancreatic cancer. Although the treatment with GCV provoked a reduction in the viral yield, both in vitro and in vivo, a two-cycle treatment of virus and GCV resulted in an enhanced antitumoral response that correlated with high TK-activity, based on microPET measurements. Thus, TK-expressing oncolytic adenoviruses can be traced by PET imaging providing real time information on the activity of the virus and its antitumoral potency can be optimized by GCV dosing

Global, regional, and national burden of epilepsy, 1990 - 2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background: Seizures and their consequences contribute to the burden of epilepsy because they can cause health loss (premature mortality and residual disability). Data on the burden of epilepsy are needed for health-care planning and resource allocation. The aim of this study was to quantify health loss due to epilepsy by age, sex, year, and location using data from the Global Burden of Diseases, Injuries, and Risk Factors Study. Methods: We assessed the burden of epilepsy in 195 countries and territories from 1990 to 2016. Burden was measured as deaths, prevalence, and disability-adjusted life-years (DALYs; a summary measure of health loss defined by the sum of years of life lost [YLLs] for premature mortality and years lived with disability), by age, sex, year, location, and Socio-demographic Index (SDI; a compound measure of income per capita, education, and fertility). Vital registrations and verbal autopsies provided information about deaths, and data on the prevalence and severity of epilepsy largely came from population representative surveys. All estimates were calculated with 95% uncertainty intervals (UIs). Interpretation: Despite the decrease in the disease burden from 1990 to 2016, epilepsy is still an important cause of disability and mortality. Standardised collection of data on epilepsy in population representative surveys will strengthen the estimates, particularly in countries for which we currently have no or sparse data and if additional data is collected on severity, causes, and treatment. Sizeable gains in reducing the burden of epilepsy might be expected from improved access to existing treatments in low-income countries and from the development of new effective drugs worldwide