Determinants of adherence to highly active antiretroviral therapy for HIV-infected children: A research synthesis

Highly active antiretroviral therapy (HAART) has taken HIV-infection from a rapidly terminal illness to one that is a slowly progressive, chronic illness. HIV-infected children can now live long, normal lives. Today, four classes of antiretroviral medications are widely used and several antiretrovirals are available in each class, but resistance and cross-resistance to these medications can occur very quickly if the patient does not adhere to strict medication dosing guidelines. One method to improve pediatric adherence to antiretrovirals is to focus on identified determinants of adherence at clinical visits, but very few studies have been conducted to identify determinants of adherence to antiretrovirals and the best methods to measure adherence in the pediatric population. This research synthesis found adherence factors related to children can be divided into child-identified factors and caregiver-identified factors. Child identified factors include medication-related, demographic-related, cognitive-related, psychosocial-related, and biological marker-related barriers to adherence. Caregiver identified factors include medication-related, cognitive-related, relationship-related, and psychosocial-related barriers to adherence. More randomized clinical trials are needed to identify determinants to adherence, identify methods to best measure adherence, and to identify the best interventions to improve adherence in HIV-infected children and adolescents. ^

Effect of age on in vivo rates of mitochondrial protein synthesis in human skeletal muscle

A progressive decline in muscle performance in the rapidly expanding aging population is causing a dramatic increase in disability and health care costs. A decrease in muscle endurance capacity due to mitochondrial decay likely contributes to this decline in muscle performance. We developed a novel stable isotope technique to measure in vivo rates of mitochondrial protein synthesis in human skeletal muscle using needle biopsy samples and applied this technique to elucidate a potential mechanism for the age-related decline in the mitochondrial content and function of skeletal muscle. The fractional rate of muscle mitochondrial protein synthesis in young humans (24 ± 1 year) was 0.081 ± 0.004%·h−1, and this rate declined to 0.047 ± 0.005%·h−1 by middle age (54 ± 1 year; P < 0.01). No further decline in the rate of mitochondrial protein synthesis (0.051 ± 0.004%·h−1) occurred with advancing age (73 ± 2 years). The mitochondrial synthesis rate was about 95% higher than that of mixed protein in the young, whereas it was approximately 35% higher in the middle-aged and elderly subjects. In addition, decreasing activities of mitochondrial enzymes were observed in muscle homogenates (cytochrome c oxidase and citrate synthase) and in isolated mitochondria (citrate synthase) with increasing age, indicating declines in muscle oxidative capacity and mitochondrial function, respectively. The decrease in the rates of mitochondrial protein synthesis is likely to be responsible for this decline in muscle oxidative capacity and mitochondrial function. These changes in muscle mitochondrial protein metabolism may contribute to the age-related decline in aerobic capacity and muscle performance.

Capture of a protein synthesis-dependent component of long-term depression

Hippocampal-based behavioral memories and hippocampal-based forms of synaptic plasticity, such as long-term potentiation, are divisible into short- and long-term phases, with the long-term phase requiring the synthesis of new proteins and mRNA for its persistence. By contrast, it is less clear whether long-term depression (LTD) can be divisible into phases. We here describe that in stable hippocampal organotypic cultures, LTD also is not a unitary event but a multiphase process. A prolonged stimulus of 900 stimuli spaced at 1 Hz for 15 min induces a late phase of LTD, which is protein- and mRNA synthesis-dependent. By contrast, a short train of the same 900 stimuli massed at 5 Hz for 3 min produces only a short-lasting LTD. This short-lasting LTD is capable of capturing late-phase LTD. The 5-Hz stimulus or the prolonged 1-Hz stimulus in the presence of protein synthesis inhibitors each can be transformed into an enduring late phase of depression when the prolonged stimulus is applied to another input in the same population of neurons.

Correlation of individual papilloma latency time with DNA adducts, 8-hydroxy-2'-deoxyguanosine, and the rate of DNA synthesis in the epidermis of mice treated with 7,12-dimethylbenz[alpha]anthracene.

The question was addressed whether the risk of cancer of an individual in a heterogeneous population can be predicted on the basis of measurable biochemical and biological variables postulated to be associated with the process of chemical carcinogenesis. Using the skin tumor model with outbred male NMRI mice, the latency time for the appearance of a papilloma was used as an indicator of the individual cancer risk. Starting at 8 weeks of age, a group of 29 mice was treated twice weekly with 20 nmol of 7,12-dimethylbenz[alpha]anthracene (DMBA) applied to back skin. The individual papilloma latency time ranged from 13.5 to 25 weeks of treatment. Two weeks after the appearance of the first papilloma in each mouse, an osmotic minipump delivering 5-bromo-2'-deoxyuridine was s.c. implanted and the mouse was killed 24 hr later. Levels of DMBA-DNA adducts, of 8-hydroxy-2'-deoxyguanosine, and various measures of the kinetics of cell division were determined in the epidermis of the treated skin area. The levels of 8-hydroxy-2'-deoxyguanosine and the fraction of cells in DNA replication (labeling index for the incorporation of 5-bromo-2'-deoxyuridine) were significantly higher in those mice that showed short latency times. On the other hand, the levels of DMBA-DNA adducts were lowest in animals with short latency times. The latter finding was rather unexpected but can be explained as a consequence of the inverse correlation seen for the labeling index: with each round of cell division, the adduct concentration is reduced to 50% because the new DNA strand is free of DMBA adducts until the next treatment. Under the conditions of this bioassay, therefore, oxygen radical-related genotoxicity and the rate of cell division, rather than levels of carcinogen-DNA adducts, were found to be of predictive value as indicators of an individual cancer risk.

Gaia-ESO Survey: Analysis of pre-main sequence stellar spectra

Context. The Gaia-ESO Public Spectroscopic Survey is obtaining high-quality spectroscopy of some 100 000 Milky Way stars using the FLAMES spectrograph at the VLT, down to V = 19 mag, systematically covering all the main components of the Milky Way and providing the first homogeneous overview of the distributions of kinematics and chemical element abundances in the Galaxy. Observations of young open clusters, in particular, are giving new insights into their initial structure, kinematics, and their subsequent evolution. Aims. This paper describes the analysis of UVES and GIRAFFE spectra acquired in the fields of young clusters whose population includes pre-main sequence (PMS) stars. The analysis is applied to all stars in such fields, regardless of any prior information on membership, and provides fundamental stellar atmospheric parameters, elemental abundances, and PMS-specific parameters such as veiling, accretion, and chromospheric activity. Methods. When feasible, different methods were used to derive raw parameters (e.g. line equivalent widths) fundamental atmospheric parameters and derived parameters (e.g. abundances). To derive some of these parameters, we used methods that have been extensively used in the past and new ones developed in the context of the Gaia-ESO survey enterprise. The internal precision of these quantities was estimated by inter-comparing the results obtained by these different methods, while the accuracy was estimated by comparison with independent external data, such as effective temperature and surface gravity derived from angular diameter measurements, on a sample of benchmarks stars. A validation procedure based on these comparisons was applied to discard spurious or doubtful results and produce recommended parameters. Specific strategies were implemented to resolve problems of fast rotation, accretion signatures, chromospheric activity, and veiling. Results. The analysis carried out on spectra acquired in young cluster fields during the first 18 months of observations, up to June 2013, is presented in preparation of the first release of advanced data products. These include targets in the fields of the ρ Oph, Cha I, NGC 2264, γ Vel, and NGC 2547 clusters. Stellar parameters obtained with the higher resolution and larger wavelength coverage from UVES are reproduced with comparable accuracy and precision using the smaller wavelength range and lower resolution of the GIRAFFE setup adopted for young stars, which allows us to provide stellar parameters with confidence for the much larger GIRAFFE sample. Precisions are estimated to be ≈120 K rms in Teff, ≈0.3 dex rms in log g, and ≈0.15 dex rms in [Fe/H] for the UVES and GIRAFFE setups.

Catalysing sustainable fuel and chemical synthesis

Concerns over the economics of proven fossil fuel reserves, in concert with government and public acceptance of the anthropogenic origin of rising CO2 emissions and associated climate change from such combustible carbon, are driving academic and commercial research into new sustainable routes to fuel and chemicals. The quest for such sustainable resources to meet the demands of a rapidly rising global population represents one of this century’s grand challenges. Here, we discuss catalytic solutions to the clean synthesis of biodiesel, the most readily implemented and low cost, alternative source of transportation fuels, and oxygenated organic molecules for the manufacture of fine and speciality chemicals to meet future societal demands.

Attributes of identity document credibility: A synthesis of expert knowledge

In broad terms — including a thief's use of existing credit card, bank, or other accounts — the number of identity fraud victims in the United States ranges 9-10 million per year, or roughly 4% of the US adult population. The average annual theft per stolen identity was estimated at $6,383 in 2006, up approximately 22% from $5,248 in 2003; an increase in estimated total theft from $53.2 billion in 2003 to $56.6 billion in 2006. About three million Americans each year fall victim to the worst kind of identity fraud: new account fraud. Names, Social Security numbers, dates of birth, and other data are acquired fraudulently from the issuing organization, or from the victim then these data are used to create fraudulent identity documents. In turn, these are presented to other organizations as evidence of identity, used to open new lines of credit, secure loans, “flip” property, or otherwise turn a profit in a victim's name. This is much more time consuming — and typically more costly — to repair than fraudulent use of existing accounts. ^ This research borrows from well-established theoretical backgrounds, in an effort to answer the question – what is it that makes identity documents credible? Most importantly, identification of the components of credibility draws upon personal construct psychology, the underpinning for the repertory grid technique, a form of structured interviewing that arrives at a description of the interviewee’s constructs on a given topic, such as credibility of identity documents. This represents substantial contribution to theory, being the first research to use the repertory grid technique to elicit from experts, their mental constructs used to evaluate credibility of different types of identity documents reviewed in the course of opening new accounts. The research identified twenty-one characteristics, different ones of which are present on different types of identity documents. Expert evaluations of these documents in different scenarios suggest that visual characteristics are most important for a physical document, while authenticated personal data are most important for a digital document. ^

The 4-aza-S-ribosyl-L-homocysteine derivatives and the related gamma-lactam and azahemiacetal analogs: Synthesis, inhibition and quorum sensing activity

Quorum sensing (QS) is a population-dependent signaling process bacteria use to control multiple processes including virulence, critical for establishing infection. There are two major pathways of QS systems. Type 1 is species specific or intra-species communication in which N-acylhomoserine lactones (Gram-negative bacteria) or oligopeptides (Gram-positive bacteria) are employed as signaling molecules (autoinducer one). Type 2 is inter-species communication in which S-4,5-dihydroxy-2,3-pentanedione (DPD) or its borate esters are used as signaling molecules. The DPD is biosynthesized by LuxS enzyme from S-ribosylhomocysteine (SRH). Recent increase in prevalence of bacterial strains resistant to antibiotics emphasizes the need for the development of new generation of antibacterial agents. Interruption of QS by small molecules is one of the viable options as it does not affect bacterial growth but only virulence, leading to less incidence of microbial resistance. Thus, in this work, inhibitors of both N-acylhomoserine lactone (AHL) mediated intra-species and LuxS enzyme, involved in inter-species QS are targeted. The γ-lactam and their reduced cyclic azahemiacetal analogs, bearing the additional alkylthiomethyl substituent, were designed and synthesized targeting AHL mediated QS systems in P. aeruginosa and Vibrio harveyi. The γ-lactams with nonylthio or dodecylthio chains acted as inhibitors of las signaling in P. aeruginosa with moderate potency. The cyclic azahemiacetal with shorter propylthio or hexylthio substituent were found to strongly inhibit both las and rhl signaling in P. aeruginosa at higher concentrations. However, lactam and their azahemiacetal analogs were found to be inactive in V. harveyi QS systems. The 4-aza-S-ribosyl-L-homocysteine (4-aza-SRH) analogs and 2-deoxy-2-substituted-S-ribosyl-L-homocysteine analogs were designed and synthesized targeting Bacillus subtilis LuxS enzyme. The 4-aza-SRH analogs in which oxygen in ribose ring is replaced by nitrogen were further modified at anomeric position to produce pyrrolidine, lactam, nitrone, imine and hemiaminal analogs. Pyrrolidine and lactam analogs which lack anomeric hydroxyl, acted as competitive inhibitors of LuxS enzyme with KI value of 49 and 37 µM respectively. The 2,3-dideoxy lactam analogs were devoid of activity. Such findings attested the significance of hydroxyl groups for LuxS binding and activity. Hemiaminal analog of SRH was found to be a time-dependent inhibitor with IC50 value of 60 µM.

A synthesis of long-term research by the Florida Coastal Everglades LTER Program

This paper synthesizes research conducted during the first 5–6 years of the Florida Coastal Everglades Long-Term Ecological Research Program (FCE LTER). My objectives are to review our research to date, and to present a new central theme and conceptual approach for future research. Our research has focused on understanding how dissolved organic matter (DOM) from upstream oligotrophic marshes interacted with a marine source of the limiting nutrient, phosphorus (P), to control productivity in the oligohaline estuarine ecotone. We have been working along freshwater to marine transects in two drainage basins located in Everglades National Park (ENP). The Shark River Slough transect (SRS) has a direct connection to the Gulf of Mexico, providing this estuarine ecotone with a source of marine P. The oligohaline ecotone along our southern Everglades transect (TS/Ph), however, is separated from this marine P source by the Florida Bay estuary. We originally hypothesized an ecosystem productivity peak in the SRS ecotone, driven by the interaction of marine P and Everglades DOM, but no such productivity peak in the TS/Ph ecotone because of this lack of marine P. Our research to date has tended to show the opposite pattern, however, with many ecosystem components showing enhanced productivity in the TS/Ph ecotone, but not in the SRS ecotone. Water column P concentrations followed a similar pattern, with unexpectedly high P in the TS/Ph ecotone during the dry season. Our organic geochemical research has shown that Everglades DOM is more refractory than originally hypothesized. We have also begun to understand the importance of detrital organic matter production and transport to ecotone dynamics and as the base of aquatic food webs. Our future research will build on this substantial body of knowledge about these oligotrophic estuaries. We will direct our efforts more strongly on biophysical dynamics in the oligohaline ecotone regions. Specifically, we will be focusing on inputs to these regions from four primary water sources: freshwater Everglades runoff, net precipitation, marine inputs, and groundwater. We are hypothesizing that dry season groundwater inputs of P will be particularly important to TS/Ph ecotone dynamics because of longer water residence times in this area. Our organic geochemical, biogeochemical, and ecosystem energetics work will focus more strongly on the importance of detrital organics and will take advantage of a key Everglades Restoration project, scheduled for 2008 or 2009, that will increase freshwater inputs to our SRS transect only. Finally, we will also begin to investigate the human dimensions of restoration, and of a growing population in south Florida that will become increasingly dependent on the Everglades for critical ecosystem services (including fresh water) even as its growth presents challenges to Everglades sustainability.

Attributes of Identity Document Credibility: A Synthesis of Expert Knowledge

In broad terms — including a thief's use of existing credit card, bank, or other accounts — the number of identity fraud victims in the United States ranges 9-10 million per year, or roughly 4% of the US adult population. The average annual theft per stolen identity was estimated at $6,383 in 2006, up approximately 22% from $5,248 in 2003; an increase in estimated total theft from $53.2 billion in 2003 to $56.6 billion in 2006. About three million Americans each year fall victim to the worst kind of identity fraud: new account fraud. Names, Social Security numbers, dates of birth, and other data are acquired fraudulently from the issuing organization, or from the victim then these data are used to create fraudulent identity documents. In turn, these are presented to other organizations as evidence of identity, used to open new lines of credit, secure loans, “flip” property, or otherwise turn a profit in a victim's name. This is much more time consuming — and typically more costly — to repair than fraudulent use of existing accounts. This research borrows from well-established theoretical backgrounds, in an effort to answer the question – what is it that makes identity documents credible? Most importantly, identification of the components of credibility draws upon personal construct psychology, the underpinning for the repertory grid technique, a form of structured interviewing that arrives at a description of the interviewee’s constructs on a given topic, such as credibility of identity documents. This represents substantial contribution to theory, being the first research to use the repertory grid technique to elicit from experts, their mental constructs used to evaluate credibility of different types of identity documents reviewed in the course of opening new accounts. The research identified twenty-one characteristics, different ones of which are present on different types of identity documents. Expert evaluations of these documents in different scenarios suggest that visual characteristics are most important for a physical document, while authenticated personal data are most important for a digital document.

Seasonal changes in Vitamin D-effective UVB availability in Europe and associations with population serum 25-Hydroxyvitamin D

Low vitamin D status is common in Europe. The major source of vitamin D in humans is ultraviolet B (UVB)-induced dermal synthesis of cholecalciferol, whereas food sources are believed to play a lesser role. Our objectives were to assess UVB availability (Jm−2) across several European locations ranging from 35° N to 69° N, and compare these UVB data with representative population serum 25-hydroxyvitamin D (25(OH)D) data from Ireland (51–54° N), Iceland (64° N) and Norway (69° N), as exemplars. Vitamin D-effective UVB availability was modelled for nine European countries/regions using a validated UV irradiance model. Standardized serum 25(OH)D data was accessed from the EC-funded ODIN project. The results showed that UVB availability decreased with increasing latitude (from 35° N to 69° N), while all locations exhibited significant seasonal variation in UVB. The UVB data suggested that the duration of vitamin D winters ranged from none (at 35° N) to eight months (at 69° N). The large seasonal fluctuations in serum 25(OH)D in Irish adults was much dampened in Norwegian and Icelandic adults, despite considerably lower UVB availability at these northern latitudes but with much higher vitamin D intakes. In conclusion, increasing the vitamin D intake can ameliorate the impact of low UVB availability on serum 25(OH)D status in Europe.

Characterization of the Galactic White Dwarf Population in the Next Generation Virgo Cluster Survey

Halo white dwarfs remain one of the least studied stellar populations in the Milky Way because of their faint luminosities. Recent work has uncovered a population of hot white dwarfs which are thought to be remnants of low-mass Population II stars. This thesis uses optical data from the Next Generation Virgo Cluster Survey (NGVS) and ultravoilet data from the GALEX Ultraviolet Virgo Cluster Survey (GUViCS) to select candidates which may belong to this population of recently formed halo white dwarfs. A colour selection was used to separate white dwarfs from QSOs and main-sequence stars. Photometric distances are calculated using model colour-absolute magnitude relations. Proper motions are calculated by using the difference in positions between objects from the Sloan Digital Sky Survey and the NGVS. The proper motions are combined with the calculated photometric distances to calculate tangential velocities, as well as approximate Galactic space velocities. White dwarf candidates are characterized as belonging to either the disk or the halo using a variety of methods, including calculated scale heights (z> 1 kpc), tangential velocities (vt >200 km/s), and their location in (V,U) space. The 20 halo white dwarf candidates which were selected using Galactic space velocities are analyzed, and their colours and temperatures suggest that these objects represent some of the youngest white dwarfs in the Galactic halo.

Volunteering for the Commonwealth Games: what can realist synthesis contribute to health policy making?

The aim of this thesis was to investigate, using the real-time test case of the 2014 Commonwealth Games, whether the realist synthesis methodology could contribute to the making of health policy in a meaningful way. This was done by looking at two distinct research questions: first, whether realist synthesis could contribute new insights to the health policymaking process, and second, whether the 2014 Commonwealth Games volunteer programme was likely to have any significant, measurable, impact on health inequalities experienced by large sections of the host population. The 2014 Commonwealth Games legacy laid out ambitious plans for the event, in which it was anticipated that it would provide explicit opportunities to impact positively on health inequalities. By using realist synthesis to unpick the theories underpinning the volunteer programme, the review identifies the population subgroups for whom the programme was likely to be successful, how this could be achieved and in what contexts. In answer to the first research question, the review found that while realist methods were able to provide a more nuanced exposition of the impacts of the Games volunteer programme on health inequalities than previous traditional reviews had been able to provide, there were several drawbacks to using the method. It was found to be resource-intensive and complex, encouraging the exploration of a much wider set of literatures at the expense of an in-depth grasp of the complexities of those literatures. In answer to the second research question, the review found that the Games were, if anything, likely to exacerbate health inequalities because the programme was designed in such a way that individuals recruited to it were most likely to be those in least need of the additional mental and physical health benefits that Games volunteering was designed to provide. The following thesis details the approach taken to investigate both the realist approach to evidence synthesis and the likelihood that the 2014 Games volunteer programme would yield the expected results.

An efficient Jeans modelling of axisymmetric galaxies with multiple stellar components

Dynamical models of stellar systems represent a powerful tool to study their internal structure and dynamics, to interpret the observed morphological and kinematical fields, and also to support numerical simulations of their evolution. We present a method especially designed to build axisymmetric Jeans models of galaxies, assumed as stationary and collisionless stellar systems. The aim is the development of a rigorous and flexible modelling procedure of multicomponent galaxies, composed of different stellar and dark matter distributions, and a central supermassive black hole. The stellar components, in particular, are intended to represent different galaxy structures, such as discs, bulges, halos, and can then have different structural (density profile, flattening, mass, scale-length), dynamical (rotation, velocity dispersion anisotropy), and population (age, metallicity, initial mass function, mass-to-light ratio) properties. The theoretical framework supporting the modelling procedure is presented, with the introduction of a suitable nomenclature, and its numerical implementation is discussed, with particular reference to the numerical code JASMINE2, developed for this purpose. We propose an approach for efficiently scaling the contributions in mass, luminosity, and rotational support, of the different matter components, allowing for fast and flexible explorations of the model parameter space. We also offer different methods of the computation of the gravitational potentials associated of the density components, especially convenient for their easier numerical tractability. A few galaxy models are studied, showing internal, and projected, structural and dynamical properties of multicomponent galaxies, with a focus on axisymmetric early-type galaxies with complex kinematical morphologies. The application of galaxy models to the study of initial conditions for hydro-dynamical and $N$-body simulations of galaxy evolution is also addressed, allowing in particular to investigate the large number of interesting combinations of the parameters which determine the structure and dynamics of complex multicomponent stellar systems.

Hydrodynamic simulations of multiple stellar populations in globular clusters

The presence of multiple stellar populations in globular clusters (GCs) is now well accepted, however, very little is known regarding their origin. In this Thesis, I study how multiple populations formed and evolved by means of customized 3D numerical simulations, in light of the most recent data from spectroscopic and photometric observations of Local and high-redshift Universe. Numerical simulations are the perfect tool to interpret these data: hydrodynamic simulations are suited to study the early phases of GCs formation, to follow in great detail the gas behavior, while N-body codes permit tracing the stellar component. First, we study the formation of second-generation stars in a rotating massive GC. We assume that second-generation stars are formed out of asymptotic giant branch stars (AGBs) ejecta, diluted by external pristine gas. We find that, for low pristine gas density, stars mainly formed out of AGBs ejecta rotate faster than stars formed out of more diluted gas, in qualitative agreement with current observations. Then, assuming a similar setup, we explored whether Type Ia supernovae affect the second- generation star formation and their chemical composition. We show that the evolution depends on the density of the infalling gas, but, in general, an iron spread is developed, which may explain the spread observed in some massive GCs. Finally, we focused on the long-term evolution of a GC, composed of two populations and orbiting the Milky Way disk. We have derived that, for an extended first population and a low-mass second one, the cluster loses almost 98 percent of its initial first population mass and the GC mass can be as much as 20 times less after a Hubble time. Under these conditions, the derived fraction of second-population stars reproduces the observed value, which is one of the strongest constraints of GC mass loss.