Church Island : a Description

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Outcomes of out-of-hospital cardiac arrest in Ireland 2012-2020: Protocol for an observational study [version 2; peer review: 1 approved, 3 approved with reservations]

Background Out-of-hospital cardiac arrest (OHCA) is a leading cause of preventable mortality that now affects almost 3,000 people each year in Ireland. Survival is low at 6–7%, compared to a European average of 8%. The Irish Out-of-Hospital Cardiac Registry (OHCAR) prospectively gathers data on all OHCA in Ireland where emergency medical services attempted resuscitation. The Irish health system has undergone several developments that are relevant to OHCA care in the period 2012–2020. OHCAR data provides a means of exploring temporal trends in OHCA incidence, care, and outcomes over time. It also provides a means of exploring whether system developments were associated with a change in key outcomes. This research aims to summarise key trends in available OHCAR data from the period 2012 – 2020, to explore and model predictors of bystander CPR, bystander defibrillation, and survival, and to explore the hypothesis that significant system level temporal developments were associated with improvements in these outcomes. Methods The following protocol sets out the relevant background and research approach for an observational study that will address the above aims. Key trends in available OHCAR data (2012 – 2020) will be described and evaluated using descriptive summaries and graphical displays. Multivariable logistic regression will be used to model predictors of ‘bystander CPR’, ‘bystander defibrillation’ and ‘survival to hospital discharge’ and to explore the effects (if any) of system level developments in 2015/2016 and the COVID-19 pandemic (2020) on these outcomes. Discussion The findings of this research will be used to understand temporal trends in the care processes and outcomes for OHCA in Ireland over the period 2012-2020. The results can further be used to optimise future health system developments for OHCA in both Ireland and internationally

Multiplexed and High-Throughput Label-Free Detection of RNA/Spike Protein/IgG/IgM Biomarkers of SARS-CoV-2 Infection Utilizing Nanoplasmonic Biosensors

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.To tackle the COVID-19 outbreak, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an unmet need for highly accurate diagnostic tests at all stages of infection with rapid results and high specificity. Here, we present a label-free nanoplasmonic biosensor-based, multiplex screening test for COVID-19 that can quantitatively detect 10 different biomarkers (6 viral nucleic acid genes, 2 spike protein subunits, and 2 antibodies) with a limit of detection in the aM range, all within one biosensor platform. Our newly developed nanoplasmonic biosensors demonstrate high specificity, which is of the upmost importance to avoid false responses. As a proof of concept, we show that our detection approach has the potential to quantify both IgG and IgM antibodies directly from COVID-19-positive patient plasma samples in a single instrument run, demonstrating the high-throughput capability of our detection approach. Most importantly, our assay provides receiving operating characteristics, areas under the curve of 0.997 and 0.999 for IgG and IgM, respectively. The calculated p-value determined through the Mann-Whitney nonparametric test is 96% (77/80), a positive predictive value of 98% at 5% prevalence, and a negative predictive value of 100% at 5% prevalence. We believe that our very sensitive, multiplex, high-throughput testing approach has potential applications in COVID-19 diagnostics, particularly in determining virus progression and infection severity for clinicians for an appropriate treatment, and will also prove to be a very effective diagnostic test when applied to diseases beyond the COVID-19 pandemic

Development of CCDs for REXIS on OSIRIS-REx

The Regolith x-ray Imaging Spectrometer (REXIS) is a coded-aperture soft x-ray imaging instrument on the OSIRIS-REx spacecraft to be launched in 2016. The spacecraft will fly to and orbit the near-Earth asteroid Bennu, while REXIS maps the elemental distribution on the asteroid using x-ray fluorescence. The detector consists of a 2×2 array of backilluminated 1k×1k frame transfer CCDs with a flight heritage to Suzaku and Chandra. The back surface has a thin p[superscript +]-doped layer deposited by molecular-beam epitaxy (MBE) for maximum quantum efficiency and energy resolution at low x-ray energies. The CCDs also feature an integrated optical-blocking filter (OBF) to suppress visible and near-infrared light. The OBF is an aluminum film deposited directly on the CCD back surface and is mechanically more robust and less absorptive of x-rays than the conventional free-standing aluminum-coated polymer films. The CCDs have charge transfer inefficiencies of less than 10[superscript -6], and dark current of 1e-/pixel/second at the REXIS operating temperature of –60 °C. The resulting spectral resolution is 115 eV at 2 KeV. The extinction ratio of the filter is ~10[superscript 12] at 625 nm.United States. National Aeronautics and Space Administration. Strategic Astrophysics Technology Program (Grant NNX12AF22G)United States. National Aeronautics and Space Administration (Contract NNG12FD70C)United States. National Aeronautics and Space Administration (IPR NNG12FC01I)United States. National Aeronautics and Space Administration. Strategic Astrophysics Technology Program (IPR NNH12AU04I)United States. Air Force (Contract FA8721-05-C-0002

Varieties of developmental dyslexia in Greek children

The current study aimed to investigate in a group of nine Greek children with dyslexia (mean age 9.9 years) whether the surface and phonological dyslexia subtypes could be identified. A simple regression was conducted using printed word naming latencies and nonword reading accuracy for 33 typically developing readers. Ninety per cent confidence intervals were established and dyslexic children with datapoints lying outside the confidence intervals were identified. Using this regression-based method three children with the characteristic of phonological dyslexia (poor nonword reading), two with surface dyslexia (slow word naming latencies) and four with a mixed profile (poor nonword reading accuracy and slow word naming latencies) were identified. The children were also assessed in spelling to dictation, phonological ability, rapid naming, visual memory and multi-character processing (letter report). Results revealed that the phonological dyslexia subtype children had difficulties in tasks of phonological ability, and the surface subtype children had difficulties in tasks of multi-character simultaneous processing ability. Dyslexic children with a mixed profile showed deficits in both phonological abilities and multi-character processing. In addition, one child with a mixed profile showed a rapid naming deficit and another showed a difficulty in visual memory for abstract designs. Overall the results confirm that the surface and phonological subtypes of developmental dyslexia can be found in Greek-speaking children. They also indicate that different subtypes are associated with different underlying disorders

Calcitonin gene-related peptide inhibits Langerhans cell-mediated HIV-1 transmission.

International audienceUpon its mucosal entry, human immunodeficiency virus type 1 (HIV-1) is internalized by Langerhans cells (LCs) in stratified epithelia and transferred locally to T cells. In such epithelia, LCs are in direct contact with peripheral neurons secreting calcitonin gene-related peptide (CGRP). Although CGRP has immunomodulatory effects on LC functions, its potential influence on the interactions between LCs and HIV-1 is unknown. We show that CGRP acts via its receptor expressed by LCs and interferes with multiple steps of LC-mediated HIV-1 transmission. CGRP increases langerin expression, decreases selected integrins, and activates NF-κB, resulting in decreased HIV-1 intracellular content, limited formation of LC-T cell conjugates, and elevated secretion of the CCR5-binding chemokine CCL3/MIP-1α. These mechanisms cooperate to efficiently inhibit HIV-1 transfer from LCs to T cells and T cell infection. In vivo, HIV-1 infection decreases CGRP plasma levels in both vaginally SHIV-challenged macaques and HIV-1-infected individuals. CGRP plasma levels return to baseline after highly active antiretroviral therapy. Our results reveal a novel path by which a peripheral neuropeptide acts at the molecular and cellular levels to limit mucosal HIV-1 transmission and suggest that CGRP receptor agonists might be used therapeutically against HIV-1

The GPI-Phospholipase C of Trypanosoma brucei Is Nonessential But Influences Parasitemia in Mice

In the mammalian host, the cell surface of Trypanosoma brucei is protected by a variant surface glycoprotein that is anchored in the plasma membrane through covalent attachment of the COOH terminus to a glycosylphosphatidylinositol. The trypanosome also contains a phospholipase C (GPI-PLC) that cleaves this anchor and could thus potentially enable the trypanosome to shed the surface coat of VSG. Indeed, release of the surface VSG can be observed within a few minutes on lysis of trypanosomes in vitro. To investigate whether the ability to cleave the membrane anchor of the VSG is an essential function of the enzyme in vivo, a GPI-PLC null mutant trypanosome has been generated by targeted gene deletion. The mutant trypanosomes are fully viable; they can go through an entire life cycle and maintain a persistent infection in mice. Thus the GPI-PLC is not an essential activity and is not necessary for antigenic variation. However, mice infected with the mutant trypanosomes have a reduced parasitemia and survive longer than those infected with control trypanosomes. This phenotype is partially alleviated when the null mutant is modified to express low levels of GPI-PLC

A multidisciplinary program for achieving lipid goals in chronic hemodialysis patients

BACKGROUND: There is little information on how target lipid levels can be achieved in end stage renal disease (ESRD) patients in a systematic, multidisciplinary fashion. METHODS: We retrospectively reviewed a pharmacist-directed hyperlipidemia management program for chronic hemodialysis (HD) patients. All 26 adult patients on chronic HD at a tertiary care medical facility were entered into the program. A clinical pharmacist was responsible for laboratory monitoring, patient counseling, and the initiation and dosage adjustment of an appropriate 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) using a dosing algorithm and monitoring guidelines. The low-density lipoprotein (LDL) cholesterol goal was ≤ 100 mg/dl. A renal dietitian provided nutrition counseling and the nephrologist was notified of potential or existing drug interactions or adverse drug reactions (ADRs). Patients received a flyer containing lipid panel results to encourage compliance. Data was collected at program initiation and for 6 months thereafter. RESULTS: At the start of the program, 58% of patients were at target LDL cholesterol. At 6 months, 88% had achieved target LDL (p = 0.015). Mean LDL cholesterol decreased from 96 ± 5 to 80 ± 3 mg/dl (p < 0.01), and mean total cholesterol decreased from 170 ± 7 to 151 ± 4 mg/dl (p < 0.01). Fifteen adjustments in drug therapy were made. Eight adverse drug reactions were identified; 2 required drug discontinuation or an alternative agent. Physicians were alerted to 8 potential drug-drug interactions, and appropriate monitoring was performed. CONCLUSIONS: Our findings demonstrate both feasibility and efficacy of a multidisciplinary approach in management of hyperlipidemia in HD patients

ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody–drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug–antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G2–M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors