Mutations in presenilin-1 (PSEN1) cause autosomal dominant Alzheimer's disease and mutations in MAPT cause the familial tauopathy Frontotemporal dementia linked to chromosome 17 (FTDP-17). However, ...there have been reports of mutations in PSEN1 and MAPT associated with cases of FTD with ubiquitin-positive tau-negative inclusion pathology. Here, we demonstrate that the MAPT variants are almost certainly rare benign polymorphisms as all of these cases harbour mutations in Progranulin (PGRN). Mutations in PGRN were recently shown to cause ubiquitin-positive FTDP-17.
Concentrations of troponin measured with high sensitivity troponin assays are raised in a number of emergency department (ED) patients; however many are not diagnosed with acute myocardial infarction ...(AMI). Clinical comparisons between the early use (2h after presentation) of high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) assays for the diagnosis of AMI have not been reported.
Early (0h and 2h) hs-cTnT and hs-cTnI assay results in 1571 ED patients with potential acute coronary syndrome (ACS) without ST elevation on electrocardiograph (ECG) were evaluated. The primary outcome was diagnosis of index AMI adjudicated by cardiologists using the local cTnI assay results taken ≥6h after presentation, ECGs and clinical information. Stored samples were later analysed with hs-cTnT and hs-cTnI assays.
The ROC analysis for AMI (204 patients; 13.0%) for hs-cTnT and hs-cTnI after 2h was 0.95 (95% CI: 0.94–0.97) and 0.98 (95% CI: 0.97–0.99) respectively. The sensitivity, specificity, PLR, and NLR of hs-cTnT and hs-cTnI for AMI after 2h were 94.1% (95% CI: 90.0–96.6) and 95.6% (95% CI: 91.8–97.7), 79.0% (95% CI: 76.8–81.1) and 92.5% (95% CI: 90.9–93.7), 4.48 (95% CI: 4.02–5.00) and 12.86 (95% CI: 10.51–15.31), and 0.07 (95% CI: 0.04–0.13) and 0.05 (95% CI:0.03–0.09) respectively.
Exclusion of AMI 2h after presentation in emergency patients with possible ACS can be achieved using hs-cTnT or hs-cTnI assays. Significant differences in specificity of these assays are relevant and if using the hs-cTnT assay, further clinical assessment in a larger proportion of patients would be required.
•First study comparing hs-cTnT and hs-cTnI as diagnostic tool for ACS in ED•Significant differences between the two assays were found.•With hs-cTnT assay, significantly more patients would require further assessment.•Economic impact of differences between these assays is potentially large.
The importance of heparan sulfate proteoglycan has been highlighted by a number of human genetic disorders associated with mutations in genes encoding for heparan sulfate proteoglycan protein cores ...or biosynthetic enzymes required for heparan sulfate (HS) assembly. To study the functional role of HS in Caenorhabditis elegans development cosmid sequence C34F6.4 was identified as the C. elegans ortholog of vertebrate heparan 2-O-sulfotransferase (HS2ST) and the gene named hst-2. HS2ST activity is present in C. elegans and is completely absent in a deletion mutant of hst-2, ok595, and specifically reduced by hst-2 RNA interference. Expression of hst-2 in CHO cells deficient in HS2ST rescues enzyme activity and binding of FGF2 to cell surface HS. hst-2 expression is found in the hypodermis, muscle, distal tip cells (DTCs), and in neurons. A null mutation in hst-2 causes cell migration defects. This work demonstrates sulfotransferase activity in C. elegans and indicates that specific 2-O-sulfate modifications are critical for normal HS functions in controlling cell migration.
Universities are vulnerable to infectious disease outbreaks, making them ideal environments to study transmission dynamics and evaluate mitigation and surveillance measures. Here, we analyze ...multimodal COVID-19-associated data collected during the 2020–2021 academic year at Colorado Mesa University and introduce a SARS-CoV-2 surveillance and response framework.
We analyzed epidemiological and sociobehavioral data (demographics, contact tracing, and WiFi-based co-location data) alongside pathogen surveillance data (wastewater and diagnostic testing, and viral genomic sequencing of wastewater and clinical specimens) to characterize outbreak dynamics and inform policy. We applied relative risk, multiple linear regression, and social network assortativity to identify attributes or behaviors associated with contracting SARS-CoV-2. To characterize SARS-CoV-2 transmission, we used viral sequencing, phylogenomic tools, and functional assays.
Athletes, particularly those on high-contact teams, had the highest risk of testing positive. On average, individuals who tested positive had more contacts and longer interaction durations than individuals who never tested positive. The distribution of contacts per individual was overdispersed, although not as overdispersed as the distribution of phylogenomic descendants. Corroboration via technical replicates was essential for identification of wastewater mutations.
Based on our findings, we formulate a framework that combines tools into an integrated disease surveillance program that can be implemented in other congregate settings with limited resources.
This work was supported by the National Science Foundation, the Hertz Foundation, the National Institutes of Health, the Centers for Disease Control and Prevention, the Massachusetts Consortium on Pathogen Readiness, the Howard Hughes Medical Institute, the Flu Lab, and the Audacious Project.
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•Surveillance of SARS-CoV-2 transmission at a public university•Wi-Fi co-location data identified social behaviors associated with infection•Overdispersion in virus transmission consists of both social and biological components•Concurrent clinical sample sequencing led to wastewater variant-calling criteria
Understanding the factors that influence the transmission of SARS-CoV-2 and other pathogens is critical to mitigate outbreaks. Here, researchers at Colorado Mesa University and at the Broad Institute of MIT and Harvard designed and assessed an infectious disease surveillance program that included diagnostic testing and symptom reporting, wastewater surveillance, and digital contact tracing of students at a university. Viral spread on campus was a result of social behaviors, such as the number of contacts and the types of interactions an infected person had, and biological factors, such as the SARS-CoV-2 variant an infected person harbored. The authors’ findings highlight the need to design surveillance programs that capture social behaviors and viral lineage information in congregate communities.
Petros et al. studied SARS-CoV-2 transmission at a university by integrating epidemiological metadata, Wi-Fi-based location data, and viral sequences from wastewater and clinical samples. They identified a novel viral lineage and used digital contact tracing, genomics, and functional assays to delineate the social and biological factors contributing to its expansion.
Clustered presentation of sialyl Lewis X (sLe(X)) on tumor cell mucins is thought to facilitate metastasis through binding to selectin adhesion receptors expressed on platelets, leukocytes and ...endothelial cells. Thus, interfering with sLe(X) assembly might provide a chemotherapeutic method for treating metastatic disease. Prior studies have shown that peracetylated disaccharides can act in cells as substrates for the assembly of oligosaccharides related to sLe(X) synthesis, and the assembly of oligosaccharides on the disaccharides diverts the assembly of sLe(X) from endogenous cell surface glycoconjugates. Here, we show that treatment of cultured human adenocarcinoma cells with micromolar concentrations of the peracetylated disaccharide, (Ac)(6)GlcNAcbeta1,3Galbeta-O-naphthalenemethanol (AcGnG-NM) reduces the expression of sLe(X) and diminishes binding in vitro to selectin-coated dishes, thrombin-activated platelets, and tumor necrosis factor alpha-activated endothelial cells. Altering glycosylation in this way significantly reduced the ability of tumor cells to distribute to the lungs of wild-type mice over a 3-h period after i.v. injection. No significant difference in biodistribution was noted after the injection of AcGnG-NM-treated tumor cells into P-selectin deficient mice, although the extent of lung seeding was reduced compared with that in wild-type mice. In vitro, we demonstrate that normal mouse platelets, but not P-selectin-deficient platelets, bound to control tumor cells and protected them from leukocyte-mediated cytolysis. Conversely, treatment of tumor cells with disaccharide markedly reduced the ability of normal platelets to protect them from cytolysis. Finally, in an experimental metastasis model, we show that treatment of tumor cells with the disaccharide markedly reduced their lung colonization potential after injection into severe combined immunodeficient mice. These findings suggest that this compound may represent a novel class of chemotherapeutic agents for prevention and treatment of metastatic disease.
Cells depend on polyamines for growth and their depletion represents a strategy for the treatment of cancer. Polyamines assemble de novo through a pathway sensitive to the inhibitor, ...α-difluoromethylornithine (DFMO). However, the presence of cell-surface heparan sulfate proteoglycans may provide a salvage pathway for uptake of circulating polyamines, thereby sparing cells from the cytostatic effect of DFMO. Here we show that genetic or pharmacologic manipulation of proteoglycan synthesis in the presence of DFMO inhibits cell proliferation in vitro and in vivo. In cell culture, mutant cells lacking heparan sulfate were more sensitive to the growth inhibitory effects of DFMO than wild-type cells or mutant cells transfected with the cDNA for the missing biosynthetic enzyme. Moreover, extracellular polyamines did not restore growth of mutant cells, but completely reversed the inhibitory effect of DFMO in wild-type cells. In a mouse model of experimental metastasis, DFMO provided in the water supply also dramatically diminished seeding and growth of tumor foci in the lungs by heparan sulfate-deficient mutant cells compared with the controls. Wild-type cells also formed tumors less efficiently in mice fed both DFMO and a xylose-based inhibitor of heparan sulfate proteoglycan assembly. The effect seemed to be specific for heparan sulfate, because a different xyloside known to affect only chondroitin sulfate did not inhibit tumor growth. Hence, combined inhibition of heparan sulfate assembly and polyamine synthesis may represent an additional strategy for cancer therapy.
Abstract
The number of articles related to antimicrobial stewardship published each year has increased significantly over the last decade. Keeping up with the literature, particularly the most ...innovative, well-designed, or applicable to one’s own practice area, can be challenging. The Southeastern Research Group Endeavor (SERGE-45) network reviewed antimicrobial stewardship–related, peer-reviewed literature from 2020 that detailed actionable interventions. The top 13 publications were summarized following identification using a modified Delphi technique. This article highlights the selected interventions and may serve as a key resource for teaching and training, and to identify novel or optimized stewardship opportunities within one’s institution.
The Southeastern Research Group Endeavor (SERGE-45) network reviewed antimicrobial stewardship-related, peer-reviewed literature from 2020 that detailed actionable interventions. This article highlights the top 13 publications selected by the network.
Mucopolysaccharidosis type IIIB (MPS IIIB) or Sanfilippo Syndrome type B is a lysosomal storage disease resulting from the deficiency of N-acetyl glucosaminidase (NAGLU) activity. We previously ...showed that intracranial adeno-associated virus (AAV)-based gene therapy results in partial improvements of several aspects of the disease. In an attempt to further correct the disease, MPS IIIB mice were treated at 2-4 days of age with intracranial AAV2/5-NAGLU (IC-AAV), intravenous lentiviral-NAGLU (IV-LENTI) or the combination of both (BOTH). The BOTH group had the most complete biochemical and histological improvements of any treatment group. Compared with untreated MPS IIIB animals, all treatments resulted in significant improvements in motor function (rotarod) and hearing (auditory-evoked brainstem response). In addition, each treatment group had a significantly increased median life span compared with the untreated group (322 days). The combination arm had the greatest increase (612 days), followed by IC-AAV (463 days) and IV-LENTI (358 days). Finally, the BOTH group had nearly normal circadian rhythm measures with improvement in time to activity onset. In summary, targeting both the systemic and central nervous system disease of MPS IIIB early in life appears to be the most efficacious approach for this inherited metabolic disorder.
Early decompression may improve neurological outcome after spinal cord injury (SCI), but is often difficult to achieve because of logistical issues. The aims of this study were to 1) determine the ...time to decompression in cases of isolated cervical SCI in Australia and New Zealand and 2) determine where substantial delays occur as patients move from the accident scene to surgery. Data were extracted from medical records of patients aged 15-70 years with C3-T1 traumatic SCI between 2010 and 2013. A total of 192 patients were included. The median time from accident scene to decompression was 21 h, with the fastest times associated with closed reduction (6 h). A significant decrease in the time to decompression occurred from 2010 (31 h) to 2013 (19 h, p = 0.008). Patients undergoing direct surgical hospital admission had a significantly lower time to decompression, compared with patients undergoing pre-surgical hospital admission (12 h vs. 26 h, p < 0.0001). Medical stabilization and radiological investigation appeared not to influence the timing of surgery. The time taken to organize the operating theater following surgical hospital admission was a further factor delaying decompression (12.5 h). There was a relationship between the timing of decompression and the proportion of patients demonstrating substantial recovery (2-3 American Spinal Injury Association Impairment Scale grades). In conclusion, the time of cervical spine decompression markedly improved over the study period. Neurological recovery appeared to be promoted by rapid decompression. Direct surgical hospital admission, rapid organization of theater, and where possible, use of closed reduction, are likely to be effective strategies to reduce the time to decompression.
OBJECTIVES/SPECIFIC AIMS: The aim of this study is to examine if stable health insurance coverage is associated with improved type 2 diabetes (DM) control and with reduced racial/ethnic health ...disparities. METHODS/STUDY POPULATION: We utilized EMR data (2005–2013) from 2 large, urban academic health centers with a racially/ethnically diverse patient population to longitudinally examine insurance coverage, and diabetes outcomes (A1C, LDL cholesterol, BP) and management measures (e.g., A1C and BP monitoring). We categorized insurance stability status during each 6-month interval as 6 separate categories based upon type (private, public, uninsured) and continuity of insurance (continuous, switches, or gaps in coverage). We will examine the association between insurance stability status and DM outcomes adjusting for time, age, sex, comorbidities, site of care, education, and income. Additional analysis will examine if insurance stability moderates the impact of race/ethnicity on DM outcomes. RESULTS/ANTICIPATED RESULTS: Overall, we anticipate that stable health insurance coverage will improve measures for DM care, particularly for racially/ethnically diverse patients. DISCUSSION/SIGNIFICANCE OF IMPACT: The finding of an interaction between insurance stability status and race/ethnicity in improved diabetes management and control would inform the national health care policy debate on the impact of stable health insurance.
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