473 research outputs found
Effects of Baseline Left Ventricular Hypertrophy and Decreased Renal Function on Cardiovascular and Renal Outcomes in Patients with Fabry Disease Treated with Agalsidase Alfa: A Fabry Outcome Survey Study
PURPOSE: The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment. METHODS: Eligible patients were males and females aged â„18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; â€50 g/m2.7 in males and â€48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events. FINDINGS: Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P < 0.001) compared with patients with a normal eGFR at baseline. IMPLICATIONS: In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065
Phylogenetic relationships of Indian caecilians (Amphibia: Gymnophiona) inferred from mitochondrial rRNA gene sequences
India has a diverse caecilian fauna, including representatives of three of the six currently recognized families, the Caeciliidae, Ichthyophiidae, the endemic Uraeotyphlidae, but previous molecular phylogenetic studies of caecilians have not included sequences for any Indian caecilians. Partial 12S and 16S mitochondrial gene sequences were obtained for a single representative of each of the caecilian families found in India and aligned against previously reported sequences for 13 caecilian species. The resulting alignment (16 taxa, 1200 sites, of which 288 cannot be aligned unambiguously) was analyzed using parsimony, maximum-likelihood, and distance methods. As judged by bootstrap proportions, decay indices, and leaf stabilities, well-supported relationships of the Indian caecilians are recovered from the alignment. The data (1) corroborate the hypothesis, based on morphology, that the Uraeotyphlidae and Ichthyophiidae are sister taxa, (2) recover a monophyletic Ichthyophiidae, including Indian and South East Asian representatives, and (3) place the Indian caeciliid Gegeneophis ramaswamii as the sister group of the caeciliid caecilians of the Seychelles. Rough estimates of divergence times suggest an origin of the Uraeotyphlidae and Ichthyophiidae while India was isolated from Laurasia and Africa and are most consistent with an Indian origin of these families and subsequent dispersal of ichthyophiids into South East Asia
Asymptotic Expansions for the Conditional Sojourn Time Distribution in the -PS Queue
We consider the queue with processor sharing. We study the
conditional sojourn time distribution, conditioned on the customer's service
requirement, in various asymptotic limits. These include large time and/or
large service request, and heavy traffic, where the arrival rate is only
slightly less than the service rate. The asymptotic formulas relate to, and
extend, some results of Morrison \cite{MO} and Flatto \cite{FL}.Comment: 30 pages, 3 figures and 1 tabl
Novel peptides of therapeutic promise from Indian conidae
Highly structured small peptides are the major toxic constituents of the venom of cone snails, a family of widely distributed predatory marine molluscs. These animals use the venom for rapid prey immobilization. The peptide components in the venom target a wide variety of membrane-bound ion channels and receptors. Many have been found to be highly selective for a diverse range of mammalian ion channels and receptors associated with pain-signaling pathways. Their small size, structural stability, and target specificity make them attractive pharmacologic agents. A select number of laboratories mainly from the United States, Europe, Australia, Israel, and China have been engaged in intense drug discovery programs based on peptides from a few snail species. Coastal India has an estimated 20-30% of the known cone species; however, few serious studies have been reported so far. We have begun a comprehensive program for the identification and characterization of peptides from cone snails found in Indian Coastal waters. This presentation reviews our progress over the last 2 years. As expected from the evolutionary history of these venom components, our search has yielded novel peptides of therapeutic promise from the new species that we have studied
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Understanding subjective well-being: perspectives from psychology and public health
Background
Individual subjective well-being (SWB) is essential for creating and maintaining healthy, productive societies. The literature on SWB is vast and dispersed across multiple disciplines. However, few reviews have summarized the theoretical and empirical tenets of SWB literature across disciplinary boundaries.
Methods
We cataloged and consolidated SWB-related theories and empirical evidence from the fields of psychology and public health using a combination of online catalogs of scholarly articles and online search engines to retrieve relevant articles. For both theories and determinants/correlates of SWB, PubMed, PsychINFO, and Google Scholar were used to obtain relevant articles. Articles for the review were screened for relevance, varied perspectives, journal impact, geographic location of study, and topicality. A core theme of SWB empirical literature was the identification of SWB determinants/correlates, and over 100 research articles were reviewed and summarized for this review.
Results
We found that SWB theories can be classified into four groups: fulfillment and engagement theories, personal orientation theories, evaluative theories, and emotional theories. A critical analysis of the conflicts and overlaps between these theories reveals the lack of a coherent theoretical and methodological framework that would make empirical research systematically comparable. We found that determinants/correlates of SWB can be grouped into seven broad categories: basic demographics, socioeconomic status, health and functioning, personality, social support, religion and culture, and geography and infrastructure. However, these are rarely studied consistently or used to test theories.
Conclusions
The lack of a clear, unifying theoretical basis for categorizing and comparing empirical studies can potentially be overcome using an operationalizable criterion that focuses on the dimension of SWB studied, measure of SWB used, design of the study, study population, and types of determinants and correlates. From our review of the empirical literature on SWB, we found that the seven categories of determinants/correlates identified may potentially be used to improve the link between theory and empirical research, and that the overlap in the determinant/correlates as they relate to multiple theory categories may enable us to test theories in unison. However, doing so in the future would require a conscious effort by researchers in several areas, which are discussed
Data Commons
Publicly available data from open sources (e.g., United States Census Bureau
(Census), World Health Organization (WHO), Intergovernmental Panel on Climate
Change (IPCC)) are vital resources for policy makers, students and researchers
across different disciplines. Combining data from different sources requires
the user to reconcile the differences in schemas, formats, assumptions, and
more. This data wrangling is time consuming, tedious and needs to be repeated
by every user of the data. Our goal with Data Commons (DC) is to help make
public data accessible and useful to those who want to understand this data and
use it to solve societal challenges and opportunities. We do the data
processing and make the processed data widely available via standard schemas
and Cloud APIs. Data Commons is a distributed network of sites that publish
data in a common schema and interoperate using the Data Commons APIs. Data from
different Data Commons can be joined easily. The aggregate of these Data
Commons can be viewed as a single Knowledge Graph. This Knowledge Graph can
then be searched over using Natural Language questions utilizing advances in
Large Language Models. This paper describes the architecture of Data Commons,
some of the major deployments and highlights directions for future work
A genome-wide resource for the analysis of protein localisation in Drosophila
The Drosophila genome contains >13000 protein-coding genes, the majority of which remain poorly investigated. Important reasons include the lack of antibodies or reporter constructs to visualise these proteins. Here, we present a genome-wide fosmid library of 10000 GFP-tagged clones, comprising tagged genes and most of their regulatory information. For 880 tagged proteins, we created transgenic lines, and for a total of 207 lines, we assessed protein expression and localisation in ovaries, embryos, pupae or adults by stainings and live imaging approaches. Importantly, we visualised many proteins at endogenous expression levels and found a large fraction of them localising to subcellular compartments. By applying genetic complementation tests, we estimate that about two-thirds of the tagged proteins are functional. Moreover, these tagged proteins enable interaction proteomics from developing pupae and adult flies. Taken together, this resource will boost systematic analysis of protein expression and localisation in various cellular and developmental contexts
The ALBI grade provides objective hepatic reserve phenotyping across each BCLC stage of hepatocellular carcinoma
BACKGROUND & AIMS: Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient's mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. METHODS: We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia. RESULTS: Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p<0.001), transarterial chemoembolization (p<0.001) and sorafenib (p<0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p<0.001). CONCLUSIONS: In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. LAY SUMMARY: Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC
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