Optimizing ribavirin dose in HIV/hepatitis C (HCV) co-infected individuals treated for HCV

Hepatitis C (HCV) and HIV share common transmission pathways and the acquisition of both viruses are relatively common. Concurrent treatment for HCV with highly active anti-retroviral therapy (HAART) should be considered in HIV co-infected individuals to decrease the progression of liver damage. Adverse effects and less satisfactory treatment outcomes are often concerns when treating co-infected individuals. Although, direct acting antivirals (DAAs) may increase SVR, they may not be possible because of drug-drug interactions. he objective of this study is to investigate the difference in response rates of HCV treatment in HIV co-infected inmates with varying doses of ribavirin. Retrospective medical chart reviews of 52 HCV/HIV co-infected inmates who underwent HCV therapy between 2003 and 2010. All received standard doses of pegylated interferon alpha 2a or 2b and 800–1600 mg of ribavirin depending on weight. The recommended dosage for genotypes 2 and 3 is 800 mg/day. For other genotypes, if weight is<75 kg, the recommended ribavirin dose is 1000 mg/day or 1200 mg/day if>75 kg. Efficacy was defined as attaining sustained virological response (SVR) six months post treatment. Univariate analyses was performed using SPSS-18; Chi-square test with p-value<0.05 was defined significant. 52 co-infected (3 females & 49 males) were identified. Mean age was 40±7 years. Caucasians accounted for 84.6%; First Nations for 13.5% and Asians 1.9%. 36 were concurrently on HAART. The genotype distribution was: geno 1, 66.0%; geno 2, 7.5%; geno 3, 26.4%. SVR by ribavirin dosage ratio (actual dosage/recommended dosage):=1.0; 41.2% (14/34),>1.0; 58.8% (20/34). Doses greater than 1.5 times were associated with higher adverse events and lower SVR. Suboptimal doses of weight-based ribavirin may be contributing to a lower treatment response in HCV/HIV co-infectants. In our experience, the optimal dose of ribavirin is between 1 and 1.2 times the current recommended dose. We recommend that ribavirin dose be individualized in co-infected in order to enhance the likelihood of achieving SVR. Dual therapy is more practical in many of our population because of chaotic lifestyle. Therefore optimizing the ribavirin dose should be initially undertaken

Mechanical Control of Spin States in Spin-1 Molecules and the Underscreened Kondo Effect

The ability to make electrical contact to single molecules creates opportunities to examine fundamental processes governing electron flow on the smallest possible length scales. We report experiments in which we controllably stretch individual cobalt complexes having spin S = 1, while simultaneously measuring current flow through the molecule. The molecule's spin states and magnetic anisotropy were manipulated in the absence of a magnetic field by modification of the molecular symmetry. This control enabled quantitative studies of the underscreened Kondo effect, in which conduction electrons only partially compensate the molecular spin. Our findings demonstrate a mechanism of spin control in single-molecule devices and establish that they can serve as model systems for making precision tests of correlated-electron theories.Comment: main text: 5 pages, 4 figures; supporting information attached; to appear in Science

Measuring the coherence of healthy and aphasic discourse production in Chinese using Rhetorical Structure Theory (RST)

INTRODUCTION: Discourse coherence refers to the semantic connectedness of propositions in a connected speech. Various theoretical bases, narrative elicitation tasks, and sample quantifications as well as small sample sizes in most studies resulted in a substantial disparity in findings regarding the micro-linguistic and macro-linguistic aspects of aphasic discourse (Armstrong, 2000). Specifically, while some reports claimed macro-linguistic skills in aphasia to be well-preserved despite lexical, grammatical, and phonological impairments, other studies demonstrated reduced discourse coherence due to omission of important content and higher proportion of irrelevant propositions. In this study we analyzed the discourse structure in aphasic ...postprin

Magnetic Bistability and Nucleation of Magnetic Bubbles in a Layered 2D Organic-Based Magnet [Fe(TCNE)(NCMe)(2)][FeCl(4)]

The 2D layered organic-based magnet [Fe(TCNE)(NCMe)2][FeC 14] (TCNE=tetracyanoethylene) exhibits a unique macroscopic magnetic bistability between the field-cooled and zero-field-cooled states, which cannot be explained by either superparamagnetic behavior or spin freezing due to spin glass order. This magnetic bistability is described through consideration of the ensemble of uncoupled 2D Ising layers and their magnetization reversal initiated by a field-induced nucleation of magnetic bubbles in individual layers. The bubble nucleation rate strongly depends on the external field and temperature resulting in anomalous magnetic relaxation.open7

Visualizing internetworked argumentation

In this chapter, we outline a project which traces its source of inspiration back to the grand visions of Vannevar Bush (scholarly trails of linked concepts), Doug Engelbart (highly interactive intellectual tools, particularly for argumentation), and Ted Nelson (large scale internet publishing with recognised intellectual property). In essence, we are tackling the age-old question of how to organise distributed, collective knowledge. Specifically, we pose the following question as a foil: In 2010, will scholarly knowledge still be published solely in prose, or can we imagine a complementary infrastructure that is ‘native’ to the emerging semantic, collaborative web, enabling more effective dissemination and analysis of ideas

CPU, GPU i FPGA implementacija MALD algoritma za otkrivanje nepravilnosti na površini keramičkih pločica

This paper addresses adjustments, implementation and performance comparison of the Moving Average with Local Difference (MALD) method for ceramic tile surface defects detection. Ceramic tile production process is completely autonomous, except the final stage where human eye is required for defects detection. Recent computational platform development and advances in machine vision provides us with several options for MALD algorithm implementation. In order to exploit the shortest execution time for ceramic tile production process, the MALD method is implemented on three different platforms: CPU, GPU and FPGA, and it is implemented on each platform in at least two ways. Implementations are done in MATLAB’s MEX/C++, C++, CUDA/C++, VHDL and Assembly programming languages. Execution times are measured and compared for different algorithms and their implementations on different computational platforms.U ovom radu razmatra se prilagodba, implementacija i usporedba performansi metode pomičnog usrednjavanja s lokalnom diferencijom (MALD) s primjenom u otkrivanju površinskih nedostataka na keramičkim pločicama. Proizvodna linija keramičkih pločica je autonomna sve do zadnje faze u kojoj je potreban ljudski vid kako bi se otkrili eventualni nedostaci na keramičkim pločicama. Nedavnim razvojem računalnih platformi i razvojem metoda računalnog vida omogućena je implementacija MALD metode na nekoliko načina. U nastojanju skraćenja vremena potrebnog za proizvodnju keramičkih pločica, MALD metoda je implementirana u trima različitim platformama: CPU (central processing unit), GPU (graphic processing unit) i FPGA (field programmable gate array), te s barem dva različita algoritma. Implementacija je izvršena sa MATLAB MEX/C++, C++, CUDA/C++, VHDL te Asembler programskim jezicima. Izmjerena vremena obrade su me.usobno uspore.ena za različite algoritme i njihove implementacije na različitim računalnim platformama

Evidence for directional selection at a novel major histocompatibility class I marker in wild common frogs (Rana temporaria) exposed to a viral pathogen (Ranavirus).

(c) 2009 Teacher et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Whilst the Major Histocompatibility Complex (MHC) is well characterized in the anuran Xenopus, this region has not previously been studied in another popular model species, the common frog (Rana temporaria). Nor, to date, have there been any studies of MHC in wild amphibian host-pathogen systems. We characterise an MHC class I locus in the common frog, and present primers to amplify both the whole region, and specifically the antigen binding region. As no more than two expressed haplotypes were found in over 400 clones from 66 individuals, it is likely that there is a single class I locus in this species. This finding is consistent with the single class I locus in Xenopus, but contrasts with the multiple loci identified in axolotls, providing evidence that the diversification of MHC class I into multiple loci likely occurred after the Caudata/Anura divergence (approximately 350 million years ago) but before the Ranidae/Pipidae divergence (approximately 230 mya). We use this locus to compare wild populations of common frogs that have been infected with a viral pathogen (Ranavirus) with those that have no history of infection. We demonstrate that certain MHC supertypes are associated with infection status (even after accounting for shared ancestry), and that the diseased populations have more similar supertype frequencies (lower F(ST)) than the uninfected. These patterns were not seen in a suite of putatively neutral microsatellite loci. We interpret this pattern at the MHC locus to indicate that the disease has imposed selection for particular haplotypes, and hence that common frogs may be adapting to the presence of Ranavirus, which currently kills tens of thousands of amphibians in the UK each year

Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.J.L.Z. and A.M. were supported by a BU Nano Cross-disciplinary fellowship from the BU Nano center at Boston University. J.L.Z. was supported by a Presidential Postdoctoral Fellowship from Nanyang Technological University, Grant/Award Number: 021229-00001. C.H.L. was supported by Dean’s Postdoctoral Fellowship, Nanyang Technological University, Lee Kong Chian School of Medicine, Grant/Award Number: 021207-00001. E.A. was supported by Azrieli Fellowship (The Azrieli Foundation). This work was also supported in part by funding from the National Institutes of Health (R01AA026914, OSS ML; R21AG063373, MWG OSS; and R21AG06045, OSS

The Selective Personalized Radio-Immunotherapy for Locally Advanced NSCLC Trial (SPRINT)

Purpose/Objective(s): Standard therapy for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy (chemoRT), which is usually followed by adjuvant durvalumab. We performed a prospective trial testing sequential pembrolizumab and risk-adapted radiotherapy without chemotherapy for biomarker-selected LA-NSCLC patients. Materials/Methods: Patients with AJCC version 8 stage III NSCLC or unresectable stage II NSCLC and ECOG performance status 0-1 were eligible for this trial. Subjects with PD-L1 tumor proportion score (TPS) ≥ 50% received three cycles of induction pembrolizumab (200 mg, every 21 days), underwent restaging FDG-PET/CT, received risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic tumor volume exceeding 20 cc and 48 Gy delivered to smaller lesions, all in 20 daily fractions), and then received up to 13 cycles of additional pembrolizumab. Subjects with PD-L1 TPS \u3c 50% received concurrent chemoRT, and adjuvant durvalumab was recommended for patients without disease progression. The primary study endpoint was one-year progression-free survival (PFS) for subjects treated with pembrolizumab and radiotherapy (pembroRT), which we hypothesized would exceed 65%. Other study endpoints included 1-year overall survival (OS) and rates of clinician-scored (CTCAE v. 4.03) and patient-reported (PRO-CTCAE) adverse events observed over one year. Results: Twenty-five subjects with PD-L1 TPS ≥ 50% and 12 subjects with PD-L1 TPS \u3c 50% from three institutions were enrolled between August 2018 and November 2021. Median age was 70. Twenty-four subjects had stage II-IIIA disease, and 13 had stage IIIB-IIIC disease. Except for PD-L1 TPS, subject characteristics did not differ significantly across treatment groups. Ten out of the 12 subjects with ChemoRT received adjuvant durvalumab, and one received adjuvant osimertinib for EGFR mutation. The median follow-up duration is 15 months. Compared to patients treated with chemoRT, treatment with pembroRT has yielded numerically higher 1-year PFS (72% v. 46%, log rank p=0.232) and OS (91% v. 73%, log rank p=0.213) rates. Similar rates of grade 3 physician-scored adverse events have been observed with pembroRT (24%) and chemoRT (25%). Less severe patient-reported adverse events occurred with pembroRT compared to chemoRT (See Table). Conclusion: Treatment with pembrolizumab and risk-adapted radiotherapy without chemotherapy is a promising approach for LA-NSCLC patients with PD-L1 TPS ≥ 50%. In addition to yielding high disease control rates, this strategy appears to reduce patient-reported adverse events compared to standard chemoRT and adjuvant therapy

Environmental DNA persistence and fish detection in captive sponges.

Large and hyper-diverse marine ecosystems pose significant challenges to biodiversity monitoring. While environmental DNA (eDNA) promises to meet many of these challenges, recent studies suggested that sponges, as 'natural samplers' of eDNA, could further streamline the workflow for detecting marine vertebrates. However, beyond pilot studies demonstrating the ability of sponges to capture eDNA, little is known about the dynamics of eDNA particles in sponge tissue, and the effectiveness of the latter compared to water samples. Here, we present the results of a controlled aquarium experiment to examine the persistence and detectability of eDNA captured by three encrusting sponge species and compare the sponge's eDNA capturing ability with established water filtration techniques. Our results indicate that sponges and water samples have highly similar detectability for fish of different sizes and abundances, but different sponge species exhibit considerable variance in performance. Interestingly, one sponge appeared to mirror the eDNA degradation profile of water samples, while another sponge retained eDNA throughout the experiment. A third sponge yielded virtually no DNA sequences at all. Overall, our study suggests that some sponges will be suitable as natural samplers, while others will introduce significant problems for laboratory processing. We suggest that an initial optimization phase will be required in any future studies aiming to employ sponges for biodiversity assessment. With time, factoring in technical and natural accessibility, it is expected that specific sponge taxa may become the 'chosen' natural samplers in certain habitats and regions