We present a new modeling framework for recognition memory and repetition priming based on signal detection theory. We use this framework to specify and test the predictions of 4 models: (a) a ...single-system (SS) model, in which one continuous memory signal drives recognition and priming; (b) a multiple-systems-1 (MS1) model, in which completely independent memory signals (such as explicit and implicit memory) drive recognition and priming; (c) a multiple-systems-2 (MS2) model, in which there are also 2 memory signals, but some degree of dependence is allowed between these 2 signals (and this model subsumes the SS and MS1 models as special cases); and (d) a dual-process signal detection (DPSD1) model, 1 possible extension of a dual-process theory of recognition (Yonelinas, 1994) to priming, in which a signal detection model is augmented by an independent recollection process. The predictions of the models are tested in a continuous-identification-with-recognition paradigm in both normal adults (Experiments 1-3) and amnesic individuals (using data from Conroy, Hopkins, & Squire, 2005). The SS model predicted numerous results in advance. These were not predicted by the MS1 model, though could be accommodated by the more flexible MS2 model. Importantly, measures of overall model fit favored the SS model over the others. These results illustrate a new, formal approach to testing theories of explicit and implicit memory. (Contains 13 footnotes, 9 tables, and 16 figures.)
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly ...delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD.
In this open-label, dose-escalation phase 1–2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24S-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range.
Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423).
Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD.
National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Selenium (Se) is an essential micronutrient known for its antioxidant properties and health benefits, attributed to its presence in selenoproteins as the amino acid, selenocysteine. Selenocysteine ...lyase (Scly) catalyzes hydrolysis of selenocysteine to selenide and alanine, facilitating re-utilization of Se for de novo selenoprotein synthesis. Previously, it was reported that male Scly
mice develop increased body weight and body fat composition, and altered lipid and carbohydrate metabolism, compared to wild type mice. Strikingly, females appeared to present with a less severe phenotype, suggesting the relationship between Scly and energy metabolism may be regulated in a sex-specific manner. Here, we report that while body weight and body fat gain occur in both male and female Scly
mice, strikingly, males are susceptible to developing glucose intolerance, whereas female Scly
mice are protected. Because Se is critical for male reproduction, we hypothesized that castration would attenuate the metabolic dysfunction observed in male Scly
mice by eliminating sequestration of Se in testes. We report that fasting serum insulin levels were significantly reduced in castrated males compared to controls, but islet area was unchanged between groups. Finally, both male and female Scly
mice exhibit reduced hypothalamic expression of selenoproteins S, M, and glutathione peroxidase 1.
Many river basins have a weak in-situ hydrometeorological monitoring infrastructure. However, water resources practitioners depend on reliable hydrological models for management purposes. Remote ...sensing (RS) data have been recognized as an alternative to in-situ hydrometeorological data in remote and poorly monitored areas and are increasingly used to force, calibrate, and update hydrological models. In this study, we evaluate the potential of informing a river basin model with real-time radar altimetry measurements over reservoirs. We present a lumped, conceptual, river basin water balance modeling approach based entirely on RS and reanalysis data: precipitation was obtained from the Tropical Rainfall Measuring Mission (TRMM) Multisatellite Precipitation Analysis (TMPA), temperature from the European Centre for Medium-Range Weather Forecast's (ECMWF) Operational Surface Analysis dataset and reference evapotranspiration was derived from temperature data. The Ensemble Kalman Filter was used to assimilate radar altimetry (ERS2 and Envisat) measurements of reservoir water levels. The modeling approach was applied to the Syr Darya River Basin, a snowmelt-dominated basin with large topographical variability, several large reservoirs and scarce hydrometeorological data that is located in Central Asia and shared between 4 countries with conflicting water management interests. The modeling approach was tested over a historical period for which in-situ reservoir water levels were available. Assimilation of radar altimetry data significantly improved the performance of the hydrological model. Without assimilation of radar altimetry data, model performance was limited, probably because of the size and complexity of the model domain, simplifications inherent in model design, and the uncertainty of RS and reanalysis data. Altimetry data assimilation reduced the mean absolute error of the simulated reservoir water levels from 4.7 to 1.9 m, and overall model RMSE from 10.3 m to 6.7 m. Model performance was variable for the different reservoirs in the system. The RMSE ranged from 10% to 76% of the mean seasonal reservoir level variation. Because of its easy accessibility and immediate availability, radar altimetry lends itself to being used in real-time hydrological applications. As an impartial source of information about the hydrological system that can be updated in real time, the modeling approach described here can provide useful medium-term hydrological forecasts to be used in water resources management.
Abstract The purpose of this study was to evaluate concordance between administrative and clinical diagnosis and procedure codes for revision total joint arthroplasty (TJA). Concordance between ...administrative and clinical records was determined for 764 consecutive revision TJA procedures from 4 hospitals. For revision total hip arthroplasty, concordance between clinical diagnoses and administrative claims was very good for dislocation, mechanical loosening, and periprosthetic joint infection (all κ > 0.6), but considerably lower for prosthetic implant failure/breakage and other mechanical complication (both κ < 0.25). Similarly, for revision total knee arthroplasty diagnoses, concordance was very good for periprosthetic fracture, periprosthetic joint infection, mechanical loosening, and osteolysis (all κ > 0.60), but much lower for implant failure/breakage and other mechanical complication (both κ < 0.24). Concordance for TJA-specific procedure codes was very good only for revision total knee arthroplasty patellar component revisions and tibial insert exchange procedures. Total (all-component) revisions were overcoded for hips (00.70) and undercoded for knees (00.80). Improved clinical documentation and continued education are needed to enhance the value of these codes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the ...process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE
and RefSeq
launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequences of an Ensembl/GENCODE transcript and its counterpart in RefSeq such that the identifiers can be used synonymously. We have now released MANE Select transcripts for 97% of human protein-coding genes, including all American College of Medical Genetics and Genomics Secondary Findings list v3.0 (ref.
) genes. MANE transcripts are accessible from major genome browsers and key resources. Widespread adoption of these transcript sets will increase the consistency of reporting, facilitate the exchange of data regardless of the annotation source and help to streamline clinical interpretation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Human rhinovirus is a key viral trigger for asthma exacerbations. To date, murine studies investigating rhinovirus-induced exacerbation of allergic airways disease have employed systemic ...sensitisation/intranasal challenge with ovalbumin. In this study, we combined human-rhinovirus infection with a clinically relevant mouse model of aero-allergen exposure using house-dust-mite in an attempt to more accurately understand the links between human-rhinovirus infection and exacerbations of asthma. Adult BALB/c mice were intranasally exposed to low-dose house-dust-mite (or vehicle) daily for 10 days. On day 9, mice were inoculated with human-rhinovirus-1B (or UV-inactivated human-rhinovirus-1B). Forty-eight hours after inoculation, we assessed bronchoalveolar cellular inflammation, levels of relevant cytokines/serum antibodies, lung function and responsiveness/sensitivity to methacholine. House-dust-mite exposure did not result in a classical TH2-driven response, but was more representative of noneosinophilic asthma. However, there were significant effects of house-dust-mite exposure on most of the parameters measured including increased cellular inflammation (primarily macrophages and neutrophils), increased total IgE and house-dust-mite-specific IgG1 and increased responsiveness/sensitivity to methacholine. There were limited effects of human-rhinovirus-1B infection alone, and the combination of the two insults resulted in additive increases in neutrophil levels and lung parenchymal responses to methacholine (tissue elastance). We conclude that acute rhinovirus infection exacerbates house-dust-mite-induced lung disease in adult mice. The similarity of our results using the naturally occurring allergen house-dust-mite, to previous studies using ovalbumin, suggests that the exacerbation of allergic airways disease by rhinovirus infection could act via multiple or conserved mechanisms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dark respiration measurements with open-flow gas exchange analyzers are often questioned for their low accuracy as their low values often reach the precision limit of the instrument. Respiration was ...measured in five species, two hypostomatous (Vitis Vinifera L. and Acanthus mollis) and three amphistomatous, one with similar amount of stomata in both sides (Eucalyptus citriodora) and two with different stomata density (Brassica oleracea and Vicia faba). CO2 differential (ΔCO2) increased two-fold with no change in apparent Rd, when the two leaves with higher stomatal density faced outside. These results showed a clear effect of the position of stomata on ΔCO2. Therefore, it can be concluded that leaf position is important to guarantee the improvement of respiration measurements increasing ΔCO2 without affecting the respiration results by leaf or mass units. This method will help to increase the accuracy of leaf respiration measurements using gas exchange analyzers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is ...unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab.
A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound.
Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval CI 0.30–1.16) and 0.94 (95% CI 0.72–1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab.
Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb.
This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.
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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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