bluuebunny/crossref_metadata_2025 huggingface dataset:
Can light intensity influence the tolerance of Synedrellopsis grisebachii to glyphosate?
Authors: Santos Juciléia I. , Amaral Carita L. , Alves Pedro Luis C.A. , Gasparino Eduardo C.
Published: December 2015

Plant susceptibility to herbicides is related to several factors, including the environmental conditions under which the plants develop. Two experiments were carried out using Synedrellopsis grisebachii plants in two different developmental stages (vegetative and reproductive), with the goal of studying plant susceptibility to the herbicide, glyphosate, and the dependence of this susceptibility on light intensity (full sunlight and 70% shading), correlated with leaf anatomy. The experimental design for both experiments was completely randomized, with a 2 × 7 factorial scheme, with two light intensities and seven different doses of glyphosate (0D, 1/4D, 1/2D, D, 2D, 4D and 6D, where D is the recommended dose of 1800 g ae ha−1) as the factors and four replicates per treatment. The leaf anatomy was characterized with optical and scanning electron microscopy. The plants that were grown in full sunlight were more tolerant of glyphosate because of thickening of the adaxial epidermis, parenchyma and main vein structures, which required higher glyphosate doses for effective weed control. The plants that were in the reproductive stage were more tolerant of glyphosate, probably because of lower glyphosate absorption and translocation to the reproductive organs.
REVIEW ON SQL INJECTION PROTECTION METHODS AND TOOLS
Authors: Saidu Aliero Muhammad , Ghani Imran , Zainudden Syeed , Murad Khan Muhammad , Bello Munir
Published: December 2015

SQL injection vulnerability is one of the most common web-based application vulnerabilities that can be exploited by SQL injection attack. Successful SQL Injection Attacks (SQLIA) result in unauthorized access and unauthorized data modification. Researchers have proposed many methods to tackle SQL injection attack, however these methods fail to address the whole problem of SQL injection attack, because most of the approaches are vulnerable in nature, cannot resist sophisticated attack or limited to scope of subset of SQLIA type. In this paper we provide a detailed background of SQLIA together with vulnerable PHP code to demonstrate how attacks are being carried out, and discuss most commonly used method by programmers to defend against SQLIA and the disadvantages of such an approach. Lastly we reviewed most commonly use tools and methods that act a firewall for preventing SQLIA, finally wean alytically evaluated reviewed tools and methods based on our experience with respect to five different perspectives. Our evaluation results point out common trends on current SQLI prevention tools and methods. Most of these methods and tools have problems addressing store-procedure attacks, as well as problems addressing attacks that take advantage of second order SQLI vulnerability. Our evaluation also shows that only a few of these methods and tools considered can be deployed in all web-based application platforms.
COMPARISON OF HEAT TRANSFER PROPERTIES OF DRY SAND AND MAGNESIUM OXIDE POWDER BY SINGLE-PROBE METHOD
Authors: Ndenah Linah Markus , C. Meludu Osita , Elisha Kundwal Moses
Published: December 2015

The use of magnesium oxide (MgO) powder in electrical heating appliances is based on its thermal and electrical insulating properties. However, dry sand, which is readily available and free on the surface horizon than MgO powder also possesses good thermal and electrical insulating properties that could be utilized in the fabrication of electrical heating devices. In this study, we determined and compared heat transfer properties of dry fine-medium sand (0.125-0.50 mm) and dry coarse sand (0.50-1.00 mm) with those of MgO powder, using the single-probe method. Electrical heating equipment was designed and fabricated with a heating element that generated a heat flux of 18.05Wm-1. From the results obtained, the thermal conductivities of dry fine-medium sand, dry coarse sand and MgO powder were found to be 0.21 m-1K-1, 0.22 Wm-1K-1 and 0.36 Wm-1K-1 respectively. Temperature increase per second were also obtained and found to be 4.75 × 10-2 Ks-1 in dry fine-medium sand, 4.28 × 10-2  Ks-1 in dry coarse sand and 2.03 × 10-2  Ks-1 in MgO powder. Thus, while it took MgO powder 472 s to warm from 30 oC to 40 oC, it took dry coarse sand and dry fine-medium sand only 229 s and 205 s respectively to warm through the same temperature range.
APPRAISAL OF APPLICATION OF VALUE ENGINEERING METHODOLOGY IN MECHANICAL AND ELECTRICAL SERVICES INSTALLATIONS
Authors: Ganiyu Amuda–Yusuf , Afeez O. Sanni , Theophilus O.O. Olowa
Published: December 2015

Value engineering (VE) is a structured team-oriented problem solving approach that can be applied throughout the lifecycle of a building project. However, the methodology is rarely applied in mechanical and electrical services (M&E) installations in buildings because clients are not aware of the potential benefits of adopting VE and different members of design team lack the requisite knowledge about VE methodology. As a result, a great deal of unnecessary cost is created due to the increasingly complex nature of M&E services in buildings leading to cost overruns and unhappy clients. The purpose of this study is to investigate the level of adoption of VE methodology in the design and installations of M&E services in buildings in Malaysian construction industry. The research method adopted is questionnaire survey to industry practitioners and inferential statistics was adopted for data analysis. Findings from the study show that, VE is not well appreciated in the industry and there is no structured approach adopted for its adoption for the procurement of mechanical and electrical services. Practitioners are of the opinion that implementation of VE could lead to: significant capital and life cycle cost savings in buildings generally; alignment of stakeholders and construction process improvement; improved client satisfaction, and shared understanding among key participants. An implementation framework was developed which emphasised on the need for early involvement of consultants and collaboration between the downstream supply chain for effective implementation of VE methodology on mechanical and electrical services.
AN INTERACTIVE 3D ACUPRESSURE MODEL FOR SELF TREATMENT IN REDUCING PAIN
Authors: Abu Nur Azman , Norasikin Mohd Adili , Maksom Zulisman
Published: December 2015

There are many pressure points on a human body. The pressure points are specific sensitive areas on the surface of the human body going into deep tissue where the pain concentrate and accumulate on. Acupressure is an alternative way to relieve pain. This method is applied by using fingers. On medication, an effort to relieve pain by taking painkillers will cause many side effects to a human body. The objectives of this paper is to show acupressure points and its set of interconnection point in an interactive 3D visual model. This model will recommend a set of self-acupressure points for a natural self-curative therapy to relieve pain. The self-acupressure visual model has been embedded in a mobile application. This interactive 3D visual model provides an alternative way to relieve pain. It is an effective aid to help a user learn and apply self-acupressure treatment.
Pore dilatation increases the bicarbonate permeability of CFTR, ANO1 and glycine receptor anion channels
Authors: Jun Ikhyun , Cheng Mary Hongying , Sim Eunji , Jung Jinsei , Suh Bong Lim , Kim Yonjung , Son Hankil , Park Kyungsoo , Kim Chul Hoon , Yoon Joo‐Heon , Whitcomb David C. , Bahar Ivet , Lee Min Goo
Published: December 2015

Key points

Cellular stimuli can modulate the ion selectivity of some anion channels, such as CFTR, ANO1 and the glycine receptor (GlyR), by changing pore size.

Ion selectivity of CFTR, ANO1 and GlyR is critically affected by the electric permittivity and diameter of the channel pore.

Pore size change affects the energy barriers of ion dehydration as well as that of size‐exclusion of anion permeation.

Pore dilatation increases the bicarbonate permeability () of CFTR, ANO1 and GlyR.

Dynamic change in may mediate many physiological and pathological processes.

Chloride (Cl−) and bicarbonate (HCO3−) are two major anions and their permeation through anion channels plays essential roles in our body. However, the mechanism of ion selection by the anion channels is largely unknown. Here, we provide evidence that pore dilatation increases the bicarbonate permeability () of anion channels by reducing energy barriers of size‐exclusion and ion dehydration of HCO3− permeation. Molecular, physiological and computational analyses of major anion channels, such as cystic fibrosis transmembrane conductance regulator (CFTR), anoctamin‐1(ANO1/TMEM16A) and the glycine receptor (GlyR), revealed that the ion selectivity of anion channels is basically determined by the electric permittivity and diameter of the pore. Importantly, cellular stimuli dynamically modulate the anion selectivity of CFTR and ANO1 by changing the pore size. In addition, pore dilatation by a mutation in the pore‐lining region alters the anion selectivity of GlyR. Changes in pore size affected not only the energy barriers of size exclusion but that of ion dehydration by altering the electric permittivity of water‐filled cavity in the pore. The dynamic increase in by pore dilatation may have many physiological and pathophysiological implications ranging from epithelial HCO3− secretion to neuronal excitation.
Nerve–muscle activation by rotating permanent magnet configurations
Authors: Watterson Peter A. , Nicholson Graham M.
Published: December 2015

Key points

The standard method of magnetic nerve activation using pulses of high current in coils has drawbacks of high cost, high electrical power (of order 1 kW), and limited repetition rate without liquid cooling.

Here we report a new technique for nerve activation using high speed rotation of permanent magnet configurations, generating a sustained sinusoidal electric field using very low power (of order 10 W).

A high ratio of the electric field gradient divided by frequency is shown to be the key indicator for nerve activation at high frequencies.

Activation of the cane toad sciatic nerve and attached gastrocnemius muscle was observed at frequencies as low as 180 Hz for activation of the muscle directly and 230 Hz for curved nerves, but probably not in straight sections of nerve.

These results, employing the first prototype device, suggest the opportunity for a new class of small low‐cost magnetic nerve and/or muscle stimulators.

Conventional pulsed current systems for magnetic neurostimulation are large and expensive and have limited repetition rate because of overheating. Here we report a new technique for nerve activation, namely high‐speed rotation of a configuration of permanent magnets. Analytical solutions of the cable equation are derived for the oscillating electric field generated, which has amplitude proportional to the rotation speed. The prototype device built comprised a configuration of two cylindrical magnets with antiparallel magnetisations, made to rotate by interaction between the magnets’ own magnetic field and three‐phase currents in coils mounted on one side of the device. The electric field in a rectangular bath placed on top of the device was both numerically evaluated and measured. The ratio of the electric field gradient on frequency was approximately 1 V m−2 Hz−1 near the device. An exploratory series of physiological tests was conducted on the sciatic nerve and attached gastrocnemius muscle of the cane toad (Bufo marinus). Activation was readily observed of the muscle directly, at frequencies as low as 180 Hz, and of nerves bent around insulators, at frequencies as low as 230 Hz. Nerve–muscles, with the muscle elevated to avoid its direct activation, were occasionally activated, possibly in the straight section of the nerve, but more likely in the nerve where it curved up to the muscle, at radius of curvature 10 mm or more, or at the nerve end. These positive first results suggest the opportunity for a new class of small, low‐cost devices for magnetic stimulation of nerves and/or muscles.
Caracterización de las agendas mediática y pública en las provincias cubanas entre 2011 y 2014: el caso de Santiago de Cuba
Authors: Muñiz Zúñiga Viviana , Fonseca Valido Rafael Ángel
Published: December 2015

La presente investigación toma como referencia los estudios de agenda-setting desarrollados en diferentes universidades cubanas, para realizar a partir de ellos una caracterización de las agendas mediática y pública en Santiago de Cuba entre los años 2011 y 2014. Este estudio de caso longitudinal utiliza un enfoque de investigación mixto sobre la base de datos cuantificables.

Sus aportes principales son la demostración de la naturaleza cíclica de la agenda mediática y de la sincrónica de la agenda pública y el desarrollo de dos propuestas metodológicas para evaluar dichas agendas en el contexto territorial cubano. Se utilizan los métodos de análisis-síntesis, el inductivo-deductivo y la teoría fundada. De igual modo, se emplean técnicas de investigación como el coeficiente de correlación de Spearman y el análisis de contenido.
Gabriel García Márquez y la ética en Cien años de soledad – II
Authors: Molina Herrera, S.J. Luis Carlos
Published: December 2015

La esta segunda y última parte de esta colaboración, expone y justifica que Cien años de soledad condensa un planteamiento ético –de acento veterotestamentario: pecado/castigo–, acerca de las costumbres, hábitos, creencias y valoraciones propias del obrar humano en la historia de Macondo. Esta novela es un símbolo de la moral viviente no solo en la región sino en el mundo entero. Un matriarcado ético corre –en soledad desgraciada–, como un magma de miedos y premoniciones, conciencia moral rigorista y relajamiento escandaloso; homicidios, incestos y lujuria; explotación laboral, injusticia, dependencia y despilfarro, la irreversible pendiente de no poder contar ya con una segunda oportunidad sobre la tierra. 
A Systematic Determination Approach of Model's Base Using Gap Metric for Nonlinear Systems
Authors: Zribi Ali , Chtourou Mohamed , Djemal Mohamed
Published: December 2015

This paper proposes a novel gap metric based fuzzy decomposition approach resulting in a reduced model bank that provides enough information to design controllers. It requires, first, the determination of the model base. For this, the number of initial models is obtained via fuzzy c-means (FCM) algorithm. Then, a gap metric based method which aims to get a reduced model bank is developed. Based on the linear models bank, a set of linear controllers are designed and combined into a global controller for setpoint tracking control.
NiO/GaN heterojunction diode deposited through magnetron reactive sputtering
Authors: Li Liuan , Wang Xinzhi , Liu Yang , Ao Jin-Ping
Published: December 2015

NiO films were prepared with different O2/Ar reactive sputtering gas ratios. The morphology, crystalline structure, and optical properties of the as-deposited films are dependent on sputtering gas ratios. The NiO/GaN heterojunction diode was fabricated with NiO film obtained at medium O content (25%). Compared with the Ni/GaN Schottky diode, the NiO/GaN heterojunction diode shows a relatively higher turn-on voltage and lower reverse leakage current. The temperature-dependent current–voltage characteristics demonstrate that the thermionic emission dominated the reverse leakage current of the NiO/GaN diode.
Testing and verification of a scale-model acoustic propagation system
Authors: Sagers Jason D. , Ballard Megan S.
Published: December 2015

This paper discusses the design and operation of a measurement apparatus used to conduct scale-model underwater acoustic propagation experiments, presents experimental results for an idealized waveguide, and compares the measured results to data generated by two-dimensional (2D) and three-dimensional (3D) numerical models. The main objective of this paper is to demonstrate the capability of the apparatus for a simple waveguide that primarily exhibits 2D acoustic propagation. The apparatus contains a computer-controlled positioning system that accurately moves a receiving transducer in the water layer above a scale-model bathymetry while a stationary source transducer emits broadband pulsed waveforms. Experimental results are shown for a 2.133 m × 1.219 m bathymetric part possessing a flat-bottom bathymetry with a translationally invariant wedge of 10° slope along one edge. Beamformed results from a synthetic horizontal line array indicate the presence of strong in-plane arrivals along with weaker diffracted and horizontally refracted arrivals. A simulated annealing inversion method is applied to infer values for five waveguide parameters with the largest measurement uncertainty. The inferred values are then used in a 2D method of images model and a 3D adiabatic normal-mode model to simulate the measured acoustic data.
Ultrasensitive Detection and Quantification of Toxins for Optimized Diagnosis of Clostridium difficile Infection
Authors: Pollock Nira R.
Published: December 2015

Recently developed ultrasensitive and quantitative methods for detection of
Clostridium difficile
toxins provide new tools for diagnosis and, potentially, for management of
C. difficile
infection (CDI). Compared to methods that detect toxigenic organism, ultrasensitive toxin detection may allow diagnosis of CDI with increased clinical specificity, without sacrificing clinical sensitivity; measurement of toxin levels may also provide information relevant to disease prognosis. This minireview provides an overview of these new toxin detection technologies and considers what these new tools might add to the field.
Development and Validation of a PCR Assay To Detect the Prairie Epidemic Strain of Pseudomonas aeruginosa from Patients with Cystic Fibrosis
Authors: Workentine M. , Poonja A. , Waddell B. , Duong J. , Storey D. G. , Gregson D. , Somayaji R. , Rabin H. R. , Surette M. G. , Parkins M. D.
Published: December 2015

The monitoring of epidemic
Pseudomonas aeruginosa
is important for cystic fibrosis (CF) infection control. The prairie epidemic strain (PES) is common in western Canadian CF clinics. Using whole-genome sequencing, we identified a novel genomic island and developed a PCR assay for PES. Against a collection of 186
P. aeruginosa
isolates, the assay had 98% sensitivity and 100% specificity.
Does the Capsule Interfere with Performance of Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry for Identification of Cryptococcus neoformans and Cryptococcus gattii?
Authors: Thomaz Danilo Y. , Grenfell Rafaella C. , Vidal Monica S. M. , Giudice Mauro C. , Del Negro Gilda M. B. , Juliano Luiz , Benard Gil , de Almeida Júnior João N.
Published: December 2015

We described the impact of the capsule size for
Cryptococcus neoformans
and
Cryptococcus gattii
identification at the species level by Bruker matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). After experimental capsule size modulation, we observed that reducing the capsule size resulted in improved identification by Bruker MALDI-TOF MS across all of the reference strains analyzed.
Diagnostic Performance of Galactomannan Antigen Testing in Cerebrospinal Fluid
Authors: Chong G. M. , Maertens J. A. , Lagrou K. , Driessen G. J. , Cornelissen J. J. , Rijnders B. J. A.
Published: December 2015

Testing cerebrospinal fluid (CSF) for the presence of galactomannan (GM) antigen may help in diagnosing cerebral aspergillosis (CA). However, the use of the CSF GM test as a diagnostic test has been little studied. We evaluated its diagnostic performance by comparing the CSF GM optical density indexes (ODI) at different cutoffs in patients with probable and proven CA to those in patients without CA. Patients from 2 tertiary referral hospitals with suspected CA between 2004 and 2014 and in whom CSF GM ODI had been determined were selected. European Organization for Research and Treatment of Cancer/Invasive Infectious Diseases Study Mycoses Group (EORTC/MSG) definitions of invasive aspergillosis and CA were used, but with the exclusion of the test to be validated (i.e., the CSF GM test) as a microbiological EORTC/MSG criterion. The study population consisted of 44 patients (4 with proven CA, 13 with probable CA, and 27 with no CA). Of the 17 patients with CA, 15 had a CSF GM ODI of ≥2.0. Of 27 patients without CA, 26 had a CSF GM ODI of <0.5 and 1 had a CSF GM ODI of 8.2. When a GM CSF ODI cutoff of 1.0 was used, the sensitivity, specificity, and positive and negative predictive values were 88.2%, 96.3%, 93.8%, and 92.9%, respectively. The same results were found when a CSF GM ODI cutoff of 0.5 or 2.0 was used. Testing GM in CSF has a high diagnostic performance for diagnosing CA and may be useful to diagnose or virtually rule out the infection without the need for a cerebral biopsy.
A Single Amino Acid Substitution in the M Protein Attenuates Japanese Encephalitis Virus in Mammalian Hosts
Authors: de Wispelaere Mélissanne , Khou Cécile , Frenkiel Marie-Pascale , Desprès Philippe , Pardigon Nathalie
Published: December 2015

Japanese encephalitis virus (JEV) membrane (M) protein plays important structural roles in the processes of fusion and maturation of progeny virus during cellular infection. The M protein is anchored in the viral membrane, and its ectodomain is composed of a flexible N-terminal loop and a perimembrane helix. In this study, we performed site-directed mutagenesis on residue 36 of JEV M protein and showed that the resulting mutation had little or no effect on the entry process but greatly affected virus assembly in mammalian cells. Interestingly, this mutant virus had a host-dependent phenotype and could develop a wild-type infection in insect cells. Experiments performed on infectious virus as well as in a virus-like particle (VLP) system indicate that the JEV mutant expresses structural proteins but fails to form infectious particles in mammalian cells. Using a mouse model for JEV pathogenesis, we showed that the mutation conferred complete attenuation
in vivo
. The production of JEV neutralizing antibodies in challenged mice was indicative of the immunogenicity of the mutant virus
in vivo
. Together, our results indicate that the introduction of a single mutation in the M protein, while being tolerated in insect cells, strongly impacts JEV infection in mammalian hosts.

IMPORTANCE
JEV is a mosquito-transmitted flavivirus and is a medically important pathogen in Asia. The M protein is thought to be important for accommodating the structural rearrangements undergone by the virion during viral assembly and may play additional roles in the JEV infectious cycle. In the present study, we show that a sole mutation in the M protein impairs the JEV infection cycle in mammalian hosts but not in mosquito cells. This finding highlights differences in flavivirus assembly pathways among hosts. Moreover, infection of mice indicated that the mutant was completely attenuated and triggered a strong immune response to JEV, thus providing new insights for further development of JEV vaccines.
Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes
Authors: Edenborough Kathryn M. , Lowther Suzanne , Laurie Karen , Yamada Manabu , Long Fenella , Bingham John , Payne Jean , Harper Jennifer , Haining Jessica , Arkinstall Rachel , Gilbertson Brad , Middleton Deborah , Brown Lorena E.
Published: December 2015

Although avian H5N1 influenza virus has yet to develop the capacity for human-to-human spread, the severity of the rare cases of human infection has warranted intensive follow-up of potentially exposed individuals that may require antiviral prophylaxis. For countries where antiviral drugs are limited, the World Health Organization (WHO) has developed a risk categorization for different levels of exposure to environmental, poultry, or human sources of infection. While these take into account the infection source, they do not account for the likely mode of virus entry that the individual may have experienced from that source and how this could affect the disease outcome. Knowledge of the kinetics and spread of virus after natural routes of exposure may further inform the risk of infection, as well as the likely disease severity. Using the ferret model of H5N1 infection, we compared the commonly used but artificial inoculation method that saturates the total respiratory tract (TRT) with virus to upper respiratory tract (URT) and oral routes of delivery, those likely to be encountered by humans in nature. We show that there was no statistically significant difference in survival rate with the different routes of infection, but the disease characteristics were somewhat different. Following URT infection, viral spread to systemic organs was comparatively delayed and more focal than after TRT infection. By both routes, severe disease was associated with early viremia and central nervous system infection. After oral exposure to the virus, mild infections were common suggesting consumption of virus-contaminated liquids may be associated with seroconversion in the absence of severe disease.

IMPORTANCE
Risks for human H5N1 infection include direct contact with infected birds and frequenting contaminated environments. We used H5N1 ferret infection models to show that breathing in the virus was more likely to produce clinical infection than swallowing contaminated liquid. We also showed that virus could spread from the respiratory tract to the brain, which was associated with end-stage disease, and very early viremia provided a marker for this. With upper respiratory tract exposure, infection of the brain was common but hard to detect, suggesting that human neurological infections might be typically undetected at autopsy. However, viral spread to systemic sites was slower after exposure to virus by this route than when virus was additionally delivered to the lungs, providing a better therapeutic window. In addition to exposure history, early parameters of infection, such as viremia, could help prioritize antiviral treatments for patients most at risk of succumbing to infection.
High Degree of HIV-1 Group M (HIV-1M) Genetic Diversity within Circulating Recombinant Forms: Insight into the Early Events of HIV-1M Evolution
Authors: Tongo Marcel , Dorfman Jeffrey R. , Martin Darren P.
Published: December 2015

The existence of various highly divergent HIV-1 lineages and of recombination-derived sequence tracts of indeterminate origin within established circulating recombinant forms (CRFs) strongly suggests that HIV-1 group M (HIV-1M) diversity is not fully represented under the current classification system. Here we used a fully exploratory screen for recombination on a set of 480 near-full-length genomes representing the full known diversity of HIV-1M. We decomposed recombinant sequences into their constituent parts and then used maximum-likelihood phylogenetic analyses of this mostly recombination-free data set to identify rare divergent sequence lineages that fall outside the major named HIV-1M taxonomic groupings. We found that many of the sequence fragments occurring within CRFs (including CRF04_cpx, CRF06_cpx, CRF11_cpx, CRF18_cpx, CRF25_cpx, CRF27_cpx, and CRF49_cpx) are in fact likely derived from divergent unclassified parental lineages that may predate the current subtypes, even though they are presently identified as derived from currently defined HIV-1M subtypes. Our evidence suggests that some of these CRFs are descended predominantly from what were or are major previously unidentified HIV-1M lineages that were likely epidemiologically relevant during the early stages of the HIV-1M epidemic. The restriction of these divergent lineages to the Congo basin suggests that they were less infectious and/or simply not present at the time and place of the initial migratory wave that triggered the global epidemic.

IMPORTANCE
HIV-1 group M (HIV-1M) likely spread to the rest of the world from the Congo basin in the mid-1900s (N. R. Faria et al., Science
346:
56–61, 2014,
http://dx.doi.org/10.1126/science.1256739
) and is today the principal cause of the AIDS pandemic. Here, we show that large sequence fragments from several HIV-1M circulating recombinant forms (CRFs) are derived from divergent parental lineages that cannot reasonably be classified within the nine established HIV-1M subtypes. These lineages are likely to have been epidemiologically relevant in the Congo basin at the onset of the epidemic. Nonetheless, they appear not to have undergone the same explosive global spread as other HIV-1M subtypes, perhaps because they were less transmissible. Concerted efforts to characterize more of these divergent lineages could allow the accurate inference and chemical synthesis of epidemiologically key ancestral HIV-1M variants so as to directly test competing hypotheses relating to the viral genetic factors that enabled the present pandemic.
In Vitro
Reactivation of Replication-Competent and Infectious HIV-1 by Histone Deacetylase Inhibitors
Authors: Banga Riddhima , Procopio Francesco Andrea , Cavassini Matthias , Perreau Matthieu
Published: December 2015

The existence of long-lived HIV-1-infected resting memory CD4 T cells is thought to be the primary obstacle to HIV-1 eradication. In the search for novel therapeutic approaches that may reverse HIV-1 latency, inhibitors of histone deacetylases (HDACis) have been tested to reactivate HIV-1 replication with the objective of rendering HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In the present study, we evaluated the efficiency of HDACis to reactivate HIV-1 replication from resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. We demonstrate that following prolonged/repeated treatment of resting memory CD4 T cells with HDACis, HIV-1 replication may be induced from primary resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. More importantly, we demonstrate that HIV-1 reactivated in the cell cultures was not only replication competent but also infectious. Interestingly, givinostat, an HDACi that has not been investigated in clinical trials, was more efficient than vorinostat, panobinostat, and romidepsin in reversing HIV-1 latency
in vitro
. Taken together, these results support further evaluation of givinostat as a latency-reversing agent (LRA) in aviremic long-term-treated HIV-1-infected subjects.

IMPORTANCE
The major barrier to HIV cure is the existence of long-lived latently HIV-1-infected resting memory CD4 T cells. Latently HIV-1-infected CD4 T cells are transcriptionally silent and are therefore not targeted by conventional antiretroviral therapy (ART) or the immune system. In this context, one strategy to target latently infected cells is based on pharmacological molecules that may force the virus to replicate and would therefore render HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In this context, we developed an experimental strategy that would allow the evaluation of latency-reversing agent (LRA) efficiency
in vitro
using primary CD4 T cells. In the present study, we demonstrate that HDACis are potent inducers of replication-competent and infectious HIV-1 in resting memory CD4 T cells of long-term ART-treated patients and identify givinostat as the most efficient LRA tested.
Mutations in Pseudorabies Virus Glycoproteins gB, gD, and gH Functionally Compensate for the Absence of gL
Authors: Schröter Christina , Vallbracht Melina , Altenschmidt Jan , Kargoll Sabrina , Fuchs Walter , Klupp Barbara G. , Mettenleiter Thomas C.
Published: December 2015

Entry of herpesviruses depends on the combined action of viral glycoprotein B (gB) and the heterodimeric gH/gL complex, which are activated by binding of the virion to specific cellular receptors. While gB carries signatures of a bona fide fusion protein, efficient membrane fusion requires gH/gL. However, although gB and gH/gL are essential for entry, the alphaherpesvirus pseudorabies virus (PrV) is capable of limited cell-to-cell spread in the absence of gL. To understand gH/gL function in more detail, the limited spread of PrV-ΔgL was used for reversion analyses by serial cell culture passages. In a first experiment, an infectious gL-negative mutant in which gL function was replaced by generation of a gD-gH hybrid protein was isolated (B. G. Klupp and T. C. Mettenleiter, J Virol 73:3014–3022, 1999). In a second, independent experiment PrV-ΔgLPassB4.1, which also replicated productively without gL, was isolated. Sequence analysis revealed mutations in gH but also in gB and gD. In a transfection-based fusion assay, two amino acid substitutions in the N-terminal part of gH
B4.1
(L
70
P and W
103
R) were found to be sufficient to compensate for lack of gL, while mutations present in gB
B4.1
enhanced fusogenicity. Coexpression of gB
B4.1
with the homologous gH
B4.1
resulted in strongly increased syncytium formation, which was further augmented by truncation of the gB
B4.1
C-terminal 29 amino acids. Nevertheless, gH was still required for membrane fusion. Surprisingly, coexpression of gD
B4.1
blocked syncytium formation in the fusion assays, which could be attributed to a V
106
A substitution within the ectodomain of gD
B4.1
.

IMPORTANCE
In contrast to many other enveloped viruses, herpesviruses rely on the concerted action of four viral glycoproteins for membrane fusion during infectious entry. Although the highly conserved gB shows signatures of a fusion protein, for fusion induction it requires the gH/gL complex, whose role is still elusive. Here we demonstrated fusion activation by gH in the absence of gL after reversion analysis of gL-deleted pseudorabies virus. This gL-independent fusion activity depended on single amino acid exchanges affecting the gL-binding domain in gH, increasing fusogenicity in gB and allowing negative fusion regulation by gD. Thus, our results provide novel information on the interplay in the fusion machinery of herpesviruses.
Price elasticity of tobacco products among economic classes in India, 2011–2012
Authors: Selvaraj Sakthivel , Srivastava Swati , Karan Anup
Published: December 2015

Objectives

The objectives of this study are to: (1) examine the pattern of price elasticity of three major tobacco products (bidi, cigarette and leaf tobacco) by economic groups of population based on household monthly per capita consumption expenditure in India and (2) assess the effect of tax increases on tobacco consumption and revenue across expenditure groups.

Setting

Data from the 2011–2012 nationally representative Consumer Expenditure Survey from 101 662 Indian households were used.

Participants

Households which consumed any tobacco or alcohol product were retained in final models.

Primary outcome measures

The study draws theoretical frameworks from a model using the augmented utility function of consumer behaviour, with a two-stage two-equation system of unit values and budget shares. Primary outcome measures were price elasticity of demand for different tobacco products for three hierarchical economic groups of population and change in tax revenue due to changes in tax structure. We finally estimated price elasticity of demand forbidi, cigarette and leaf tobacco and effects of changes in their tax rates on demand for these tobacco products and tax revenue.

Results

Own price elasticities forbidiwere highest in the poorest group (−0.4328) and lowest in the richest group (−0.0815). Cigarette own price elasticities were −0.832 in the poorest group and −0.2645 in the richest group. Leaf tobacco elasticities were highest in the poorest (−0.557) and middle (−0.4537) groups.

Conclusions

Poorer group elasticities were the highest, indicating that poorer consumers are more price responsive. Elasticity estimates show positive distributional effects of uniformbidiand cigarette taxation on the poorest consumers, as their consumption is affected the most due to increases in taxation. Leaf tobacco also displayed moderate elasticities in poor and middle tertiles, suggesting that tax increases may result in a trade-off between consumption decline and revenue generation. A broad spectrum rise in tax rates across all products is critical for tobacco control.
Internet-delivered cognitive-behavioural therapy for concerned significant others of people with problem gambling: study protocol for a randomised wait-list controlled trial
Authors: Magnusson Kristoffer , Nilsson Anders , Hellner Gumpert Clara , Andersson Gerhard , Carlbring Per
Published: December 2015

Introduction

About 2.3% of the adult population in Sweden are considered to suffer from problem gambling, and it is estimated that only 5% of those seek treatment. Problem gambling can have devastating effects on the economy, health and relationship, both for the individual who gambles and their concerned significant other (CSO). No empirically supported treatment exists for the CSOs of people with problem gambling. Consequently, the aim of this study is to develop and evaluate a programme aimed at CSOs of treatment-refusing problem gamblers. The programme will be based on principles from cognitive behavioural therapy (CBT) and motivational interviewing. To benefit as many CSOs as possible, the programme will be delivered via the internet with therapist support via encrypted email and short weekly conversations via telephone.

Methods and analysis

This will be a randomised wait-list controlled internet-delivered treatment trial. A CBT programme for the CSOs of people with problem gambling will be developed and evaluated. The participants will work through nine modules over 10 weeks in a secure online environment, and receive support via secure emails and over the telephone. A total of 150 CSOs over 18 years of age will be included. Measures will be taken at baseline and at 3, 6 and 12 months. Primary outcomes concern gambling-related harm. Secondary outcomes include the treatment entry of the individual who gambles, the CSO's levels of depression, anxiety, as well as relationship satisfaction and quality of life.

Ethics and dissemination

The protocol has been approved by the regional ethics board of Stockholm, Sweden. This study will add to the body of knowledge on how to protect CSOs from gambling-related harm, and how to motivate treatment-refusing individuals to seek professional help for problem gambling.

Trial registration number

NCT02250586.
Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review
Authors: Cooper Janine A , Cadogan Cathal A , Patterson Susan M , Kerse Ngaire , Bradley Marie C , Ryan Cristín , Hughes Carmel M
Published: December 2015

Objective

To summarise the findings of an updated Cochrane review of interventions aimed at improving the appropriate use of polypharmacy in older people.

Design

Cochrane systematic review. Multiple electronic databases were searched including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (from inception to November 2013). Hand searching of references was also performed. Randomised controlled trials (RCTs), controlled clinical trials, controlled before-and-after studies and interrupted time series analyses reporting on interventions targeting appropriate polypharmacy in older people in any healthcare setting were included if they used a validated measure of prescribing appropriateness. Evidence quality was assessed using the Cochrane risk of bias tool and GRADE (Grades of Recommendation, Assessment, Development and Evaluation).

Setting

All healthcare settings.

Participants

Older people (≥65 years) with ≥1 long-term condition who were receiving polypharmacy (≥4 regular medicines).

Primary and secondary outcome measures

Primary outcomes were the change in prevalence of appropriate polypharmacy and hospital admissions. Medication-related problems (eg, adverse drug reactions), medication adherence and quality of life were included as secondary outcomes.

Results

12 studies were included: 8 RCTs, 2 cluster RCTs and 2 controlled before-and-after studies. 1 study involved computerised decision support and 11 comprised pharmaceutical care approaches across various settings. Appropriateness was measured using validated tools, including the Medication Appropriateness Index, Beers’ criteria and Screening Tool of Older Person's Prescriptions (STOPP)/ Screening Tool to Alert doctors to Right Treatment (START). The interventions demonstrated a reduction in inappropriate prescribing. Evidence of effect on hospital admissions and medication-related problems was conflicting. No differences in health-related quality of life were reported.

Conclusions

The included interventions demonstrated improvements in appropriate polypharmacy based on reductions in inappropriate prescribing. However, it remains unclear if interventions resulted in clinically significant improvements (eg, in terms of hospital admissions). Future intervention studies would benefit from available guidance on intervention development, evaluation and reporting to facilitate replication in clinical practice.
COGNITIVE-HD study: protocol of an observational study of neurocognitive functioning and association with clinical outcomes in adults with end-stage kidney disease treated with haemodialysis
Authors: Palmer Suetonia C , Ruospo Marinella , Barulli Maria Rosaria , Iurillo Annalisa , Saglimbene Valeria , Natale Patrizia , Gargano Letizia , Murgo Angelo M , Loy Clement , van Zwieten Anita , Wong Germaine , Tortelli Rosanna , Craig Jonathan C , Johnson David W , Tonelli Marcello , Hegbrant Jörgen , Wollheim Charlotta , Logroscino Giancarlo , Strippoli G F M
Published: December 2015

Introduction

The prevalence of cognitive impairment may be increased in adults with end-stage kidney disease compared with the general population. However, the specific patterns of cognitive impairment and association of cognitive dysfunction with activities of daily living and clinical outcomes (including withdrawal from treatment) among haemodialysis patients remain incompletely understood. The COGNITIVE impairment in adults with end-stage kidney disease treated with HemoDialysis (COGNITIVE-HD) study aims to characterise the age-adjusted and education-adjusted patterns of cognitive impairment (using comprehensive testing for executive function, perceptual-motor function, language, learning and memory, and complex attention) in patients on haemodialysis and association with clinical outcomes.

Methods and analysis

A prospective, longitudinal, cohort study of 750 adults with end-stage kidney disease treated with long-term haemodialysis has been recruited within haemodialysis centres in Italy (July 2013 to April 2014). Testing for neurocognitive function was carried out by a trained psychologist at baseline to assess cognitive functioning. The primary study factor is cognitive impairment and secondary study factors will be specific domains of cognitive function. The primary outcome will be total mortality. Secondary outcomes will be cause-specific mortality, major cardiovascular events, fatal and non-fatal myocardial infarction and stroke, institutionalisation, and withdrawal from treatment at 12 months.

Ethics and dissemination

This protocol was approved before study conduct by the following responsible ethics committees: Catania (approval reference 186/BE; 26/09/2013), Agrigento (protocol numbers 61–62; 28/6/2013), USL Roma C (CE 39217; 24/6/2013), USL Roma F (protocol number 0041708; 23/7/2013), USL Latina (protocol number 20090/A001/2011; 12/7/2013), Trapani (protocol number 3413; 16/7/2013) and Brindisi (protocol number 40259; 6/6/2013). All participants have provided written and informed consent and can withdraw from the study at any time. The findings of the study will be disseminated through peer-reviewed journals and national and international conference presentations and to the participants through communication within the dialysis network in which this study is conducted.
How do we deal with multiple goals for care within an individual patient trajectory? A document content analysis of health service research papers on goals for care
Authors: Berntsen G K R , Gammon D , Steinsbekk A , Salamonsen A , Foss N , Ruland C , Fønnebø V
Published: December 2015

Objectives

Patients with complex long-term needs experience multiple parallel care processes, which may have conflicting or competing goals, within their individual patient trajectory (iPT). The alignment of multiple goals is often implicit or non-existent, and has received little attention in the literature. Research questions: (1) What goals for care relevant for the iPT can be identified from the literature? (2) What goal typology can be proposed based on goal characteristics? (3) How can professionals negotiate a consistent set of goals for the iPT?

Design

Document content analysis of health service research papers, on the topic of ‘goals for care’.

Setting

With the increasing prevalence of multimorbidity, guidance regarding the identification and alignment of goals for care across organisations and disciplines is urgently needed.

Participants

70 papers that describe ‘goals for care’, ‘health’ or ‘the good healthcare process’ relevant to a general iPT, identified in a step-wise structured search of MEDLINE, Web of Science and Google Scholar.

Results

We developed a goal typology with four categories. Three categories are professionally defined: (1) Functional, (2) Biological/Disease and (3) Adaptive goals. The fourth category is the patient's personally defined goals. Professional and personal goals may conflict, in which case goal prioritisation by creation of a goal hierarchy can be useful. We argue that the patient has the moral and legal right to determine the goals at the top of such a goal hierarchy. Professionals can then translate personal goals into realistic professional goals such as standardised health outcomes linked to evidence-based guidelines. Thereby, when goals are aligned with one another, the iPT will be truly patient centred, while care follows professional guidelines.

Conclusions

Personal goals direct professional goals and define the success criteria of the iPT. However, making personal goals count requires brave and wide-sweeping attitudinal, organisational and regulatory transformation of care delivery.