Background Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous ...administration of the N -methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days 2 weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline; at 40, 80, 110, and 230 minutes postinfusion; and on days 1, 2, 3, 7, 10, and 14 postinfusion. Results Within 40 minutes, depressive symptoms, as well as suicidal ideation, significantly improved in subjects receiving ketamine compared with placebo ( d = .89, 95% confidence interval = .61–1.16, and .98, 95% confidence interval = .64–1.33, respectively); this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time point. Conclusions This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Over the past few decades, the field of transparent conducting oxides has undergone tremendous advances. With the rapid growth of optoelectronic applications related to display technologies, ...traditional materials such as Sn-doped indium oxide (ITO) are now widely used as transparent electrodes. In addition, with the advent of
p-type transparent conductors, through the transparent
pn-junction building block, a wide range of functional transparent optoelectronic devices have been demonstrated including UV-emitting diodes, UV-detectors, and transparent thin film transistors. This paper will highlight the unique characteristics of oxide materials based on the delafossite structure with a focus on the interrelationship between the chemistry, crystal structure, process conditions, and electrical and optical properties. The delafossite structure (ABO
2) is characterized by a layer of linearly coordinated A cations stacked between edge-shared octahedral layers (BO
6). The A-site cation is comprised of Pt, Pd, Ag, or Cu ions nominally in a monovalent state. The B-site cation can consist of most trivalent transition metals, group III elements, rare earths, or charge compensated pairs (e.g. B
2+/B
4+). This layered structure leads to highly anisotropic physical properties. The crystal chemistry of the delafossite structure will be discussed in reference to phase stability, the stability of dopants, and the important physical properties such as the conductivity and optical transparency.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Clinical evidence that ketamine, a nonselective N -methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that ...modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine. Methods Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores. Results Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders. Conclusions These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Identifying the pathophysiology of posttraumatic stress disorder (PTSD) is a critical step toward reducing its debilitating impact. Spontaneous neural activity, measured at rest using various ...neuroimaging techniques (e.g., regional homogeneity ReHo, amplitude of low frequency fluctuations ALFF), can provide insight about baseline neurobiological factors influencing sensory, cognitive, or behavioral processes associated with PTSD. The present study used activation likelihood estimation (ALE) to conduct the largest-to-date quantitative meta-analysis of spontaneous neural activity in PTSD, including 457 PTSD cases, 292 trauma-exposed controls (TECs), and 293 non-traumatized controls (NTCs) across 22 published studies. Five regions-of-interest (ROIs) were identified where activity differed between PTSD cases and controls: one when compared to all controls (left globus pallidus), two when compared to TECs (left inferior parietal lobule IPL and right lingual gyrus), and two when compared to NTCs (left amygdala and right caudate head). To corroborate these results, a second analysis was conducted using resting-state functional magnetic resonance imaging on an independent sample of 205 previously-deployed US military veterans. In this analysis, converging evidence from ReHo and ALFF showed that spontaneous neural activity in the left IPL alone was positively correlated with PTSD symptom severity. This result is consistent with theoretical accounts that link left IPL activity with PTSD-relevant processes such as processing of emotional stimuli (e.g., fearful faces) and the extent that attention is captured by salient autobiographical memories. By modeling the neurobiological correlates of PTSD, we can increase our understanding of this debilitating disorder and guide the development of future clinical innovations.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
NADPH oxidases (NOX), catalyzing the reduction of molecular oxygen to form the superoxide radical anion (•O₂⁻) and hydrogen peroxide (H₂O₂), are involved in several pathological conditions, such as ...stroke, diabetes, atherosclerosis, but also in chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis. GKT136901 is a novel NOX-1/4 inhibitor with potential application in the areas of diabetic nephropathy, stroke, or neurodegeneration. In the present study, we investigated additional pharmacological activities of the compound with respect to direct free radical scavenging. GKT136901 did not interact with nitric oxide (•NO), •O₂⁻, or hydroxyl radicals (•OH), but it acted as selective scavenger of peroxynitrite (PON) already in the submicromolar concentration range. Alpha synuclein (ASYN) is a protein involved in the pathogenesis of Parkinson's disease and a known target for PON-dependent tyrosine nitration. Submicromolar concentrations of GKT136901 prevented tyrosine nitration and di-tyrosine-dependent dimer formation of ASYN by PON as indicated by Western blot and mass spectrometric analysis. GKT136901 itself was degraded when exposed to PON. In a human neuronal cell model, GKT136901 prevented both the depletion of reduced intracellular glutathione, and the degeneration of neurites when present during PON treatment of the cells. When GKT136901 was applied after PON treatment, no protective effect was observed, thus excluding an impact of GKT136901 on cellular death/survival pathways. In summary, selective scavenging of PON is an additional pharmacological property of the NOX-1/4 inhibitor GKT136901, and this may add to the efficiency of the drug in several disease models.
A nearly fully dense β stabilized γ-TiAl alloy was additively manufactured by electron beam melting. The as-fabricated specimen exhibited a fine structure consisting of α2/γ colonies (<5 μm), ...equiaxed γ (1 μm) and βo (<1 μm) grains. The unique microstructure rendered high strength (580 MPa) and high ductility (>50%) in the sample at 800 °C. Annealing and subsequent stabilization treatments resulted in α2/γ colonies (<50 μm) with an ultrafine (20–40 nm) lamellar structure, which gave rise to high strength (770 MPa) and good ductility (6%) levels superior to those of conventional counterparts and other γ-TiAl alloys at 800 °C.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Atmospheric rivers, or long but narrow regions of enhanced water vapor transport, are an important component of the hydrologic cycle as they are responsible for much of the poleward transport of ...water vapor and result in precipitation, sometimes extreme in intensity. Despite their importance, much uncertainty remains in the detection of atmospheric rivers in large datasets such as reanalyses and century scale climate simulations. To understand this uncertainty, the Atmospheric River Tracking Method Intercomparison Project (ARTMIP) developed tiered experiments, including the Tier 2 Reanalysis Intercomparison that is presented here. Eleven detection algorithms submitted hourly tags--binary fields indicating the presence or absence of atmospheric rivers--of detected atmospheric rivers in the Modern Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2) and European Centre for Medium-Range Weather Forecasts' Reanalysis Version 5 (ERA5) as well as six-hourly tags in the Japanese 55-year Reanalysis (JRA-55). Due to a higher climatological mean for integrated water vapor transport in MERRA-2, atmospheric rivers were detected more frequently relative to the other two reanalyses, particularly in algorithms that use a fixed threshold for water vapor transport. The finer horizontal resolution of ERA5 resulted in narrower atmospheric rivers and an ability to detect atmospheric rivers along resolved coastlines. The fraction of hemispheric area covered by ARs varies throughout the year in all three reanalyses, with different atmospheric river detection tools having different seasonal cycles.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This paper provides evidence on the characteristics of firms that include "pro forma" earnings information in their press releases, whether the usefulness of pro forma earnings to investors varies ...systematically with these characteristics, and whether the investor response to pro forma earnings is consistent with market efficiency or mispricing. Using a sample of 249 press releases from 1997-99, we find that firms with low GAAP earnings informativeness are more likely to disclose pro forma earnings than other firms. We also find that strategic considerations, measured using the direction of GAAP earnings surprises, are an important determinant of pro forma reporting. In addition, our examination of the relative and incremental information content of pro forma earnings shows that investors find pro forma earnings to be more useful when GAAP earnings informativeness is low or when strategic considerations are absent. Tests of the predictive ability of pro forma earnings for future profitability and returns are mixed, and we therefore cannot conclusively determine whether the investor reaction to pro forma earnings at the time of the press release is consistent with market efficiency or mispricing. The paper contributes to the growing literature on pro forma earnings and more generally to the literature on voluntary and strategic disclosure.
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BFBNIB, CEKLJ, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
BACKGROUND:
Tramadol is a unique analgesic that has been associated with seizures on overdose.
OBJECTIVE:
To determine the toxic effects associated with tramadol exposure.
METHODS:
A retrospective ...chart review of tramadol exposures reported to a multisite, state-wide poison control system over a 2.5-year period was performed.
RESULTS:
A total of 602 cases were retrieved; 190 had sufficient data for study evaluation. Cases with coingestants or unknown outcomes were eliminated. Of the 190 remaining cases, 55% were females. Acute ingestions represented 90.0%, chronic ingestions 7.9%, and acute on chronic 2.1% of the overdoses. Ages of the patients ranged from 9 months to 80 years. Suicide attempts represented the largest group of exposures. Main symptoms included central nervous system (CNS) depression (27.4%), nausea and vomiting (21.1%), tachycardia (17.4%), and seizures (13.7%). Dosage ranged from a taste amount to 5000 mg. The smallest amount of tramadol associated with seizure was 200 mg, and 84.6% of seizures occurred within 6 hours of time of ingestion. Logistic regression analysis showed an association between seizures and tramadol use in males, chronic use, suicide attempts, intentional abuse or misuse, and tachycardia (HR >100 beats/min). No effect was seen in 36.3% of patients, minor effects in 43.7%, moderate effects in 19.5%, and major effects in 0.5%. Symptoms resolved within 24 hours in 96.7% of the 121 patients who had symptoms. Naloxone improved CNS depression in 7 of 8 patients in whom a response was documented.
CONCLUSIONS:
Tramadol overdoses frequently cause CNS depression, nausea/vomiting, tachycardia, and seizures. Symptoms generally resolve within 24 hours. Accidental ingestions in children were well tolerated, primarily causing sedation.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
BackgroundTumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains ...challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.MethodsWe tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed “NeoExpand”, was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.ResultsWe show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.ConclusionsTaken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation.Trial registration numberNCT00068003, NCT01174121, and NCT03412877.
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