Problems undermining the health-related quality of life of people living with HIV in Spain: a qualitative study to inform the development of a novel clinic screening tool.

BACKGROUND: In settings with high antiretroviral therapy coverage, numerous health-related issues continue to undermine the health and health-related quality of life (HRQoL) of people living with HIV (PLHIV). As part of a larger study to develop and validate a new patient-reported outcome measure for use in HIV clinical care in Spain, we sought to identify the most burdensome health-related issues experienced by PLHIV in order to determine which issues should be addressed in the new instrument. METHODS: We conducted a literature review and a qualitative study based on four focus group discussions (FGDs) with key informants in Spain. Participants were selected via purposive sampling. Two FGDs convened 16 expert HIV service providers, and two convened 15 PLHIV with diverse epidemiological profiles. FGDs followed semi-structured interview scripts and incorporated an exercise to prioritise the most critical health-related issues among those named in the discussions. Content analysis was conducted using MAXQDA 12. RESULTS: The analysis of FGD data identified several broad categories of issues that were perceived to negatively affect PLHIV. The most frequently named issues fell within the categories of social problems; physical symptoms; psychological problems; and sexuality-related problems. Regarding social problems, stigma/discrimination was by far the issue raised the most frequently. In the prioritisation exercise, stigma/discrimination was also ranked as the most burdensome issue by both service providers and PLHIV. Within the physical symptoms category, the issues named most frequently were sleep-related problems, fatigue, physical pain and body fat changes. Regarding psychological problems, FGD participants most commonly spoke of emotional distress in general terms, and also called attention to depression and anxiety. In the prioritisation exercise, both service providers and PLHIV ranked psychological well-being as the second-most important issue following stigma. Sexuality-related problems that were reported included sexually transmitted infections, hormonal problems, lack of libido, and general sexual dissatisfaction. CONCLUSIONS: PLHIV are negatively affected by a wide range of health-related issues. HIV-related stigma and psychological well-being remain major challenges. Identifying and addressing these and other issues in routine clinical care supports healthy aging and may ultimately contribute to better health and HRQoL outcomes in this population.

Development of a Clinic Screening Tool to Identify Burdensome Health-Related Issues Affecting People Living With HIV in Spain.

BACKGROUND: Numerous health-related issues continue to undermine the health and health-related quality of life (HRQoL) of people living with HIV (PLHIV). We developed a clinic screening tool (CST-HIV) for the purpose of identifying these issues in routine specialist clinical care in Spain. METHODS: We used the following established instrument development procedures: (1) a literature review; (2) four focus group discussions (FGDs), two that convened 16 expert HIV care providers, and two that convened 15 PLHIV; (3) prioritisation, selection and definition of constructs (health-related issues) to include in the CST-HIV and drafting of initial item pool; and (4) a pilot study to analyse psychometric properties and validity of items and to determine which to retain in the final CST-HIV. The FGD interview scripts incorporated an exercise to prioritise the health-related issues perceived to have the greatest negative effect on HRQoL. The online questionnaire used for the pilot study included the pool of CST-HIV items and validated measures of each construct. RESULTS: We identified 68 articles that reported on factors associated with the HRQoL of PLHIV. The most burdensome health-related issues identified in the FGDs related to stigma, socioeconomic vulnerability, sleep/fatigue, pain, body changes, emotional distress, and sexuality. Based on the literature review and FGD findings, we selected and defined the following constructs to include in the initial CST-HIV: anticipated stigma, emotional distress, sexuality, social support, material deprivation, sleep/fatigue, cognitive problems, and physical symptoms. Two researchers wrote six to eight items for each construct. Next, 18 experts rated 47 items based on their clarity, relevance, and representativeness. Pilot testing was carried out with 226 PLHIV in Spain. We retained 24 items based on empirical criteria that showed adequate psychometric properties. Confirmatory factor analysis confirmed the eight-factor structure with a good fit to the data (RMSEA = 0.035, AGFI = 0.97, CFI = 0.99). We found strong positive correlations between the instrument's eight dimensions and validated measures of the same constructs. Likewise, we found negative associations between the dimensions of the CST-HIV and HRQoL. CONCLUSION: The CST-HIV is a promising tool for use in routine clinical care to efficiently identify and address health-related issues undermining the HRQoL of PLHIV.

Lossen Rearrangement of p-Toluenesulfonates of N-Oxyimides in Basic Condition, Theoretical Study, and Molecular Docking.

The sulfonic esters of N-oxyimides are a group of compounds with a wide range of biological activities, as well as a unique reactivity toward amines. They undergo this reaction with primary amines and other nucleophilic reagents according to a Lossen-like rearrangement. The reaction is initiated by nucleophilic attack on a carbonyl group in the succinimide ring followed by isocyanate formation, which next interacts with another nucleophile molecule forming an addition product (e.g., ureido or urethane derivative). However, the secondary amines are also susceptible to other reactions leading to products containing the maleimide ring formed by sulphonic acid elimination. In the case of tertiary amines, this reaction is predominant. To explain the phenomenon of the reactivity of the N- oxyimides toward different types of amines, we employed various spectroscopic and X-ray approaches as well as DFT calculation. Results suggest that the basicity of the amine used for the reaction plays a crucial role in the reaction mechanism that eventually dominates the entire chemical process. Moreover, we applied molecular docking to investigate the ability of the products to act as serine protease inhibitors using human leukocyte elastase (HLE).

Solid-phase synthesis of peptides containing aminoadipic semialdehyde moiety and their cyclisations.

Pathological levels of oxidative stress (OS) have been implicated in many diseases including diabetes mellitus, neurodegenerative diseases, inflammatory diseases, atherosclerosis, and cancer. Studies of oxidative stress are however complicated by the low concentration of oxidation products. To resolve this problem, we tested a new derivative of aminoadipic semialdehyde (Fmoc-Aea-OH) in the solid-phase synthesis of carbonylated peptides. We prepared a series of peptides with free and acetylated N-terminal amino groups using the Fmoc-Aea-OH reagent. LC-MS, ESI-MS, and MS/MS spectra confirmed the sequences of the modified peptides, although the LC-MS and ESI-MS spectra were dominated by signals corresponding to dehydration products. NMR studies of acetylated products revealed that the dominant product formed in this reaction contains a 1,2,3,4-tetrahydropyridine-2-carboxylic acid residue. Another side reaction in this system was the cleavage of the amide bond between the Aea residue and the amino acid moiety preceding it resulting in the formation of a side product with a six-membered ring at the N-terminus (2,3,4,5-tetrahydropyridine-2-carboxylic acid residue). We found that, depending on the peptide sequence, one of those side products is predominant. Our work suggests new methods for the solid-state synthesis of peptides containing unnatural amino acids.

Self-Synthesizing Models of Helical Proteins Based on Aromatic Disulfide Chemistry.

A new method of synthesis of peptide conjugates with aromatic moieties substituted with two sulfhydryl groups at 1,3-positions is proposed. Amphiphilic peptides derivatized in such a way under oxidative conditions spontaneously form cyclic, covalent trimers and tetramers dominated by α-helical conformations. The tendency to form tri- or tetrahelical bundles depends on sequences of the peptides and on the oxidation conditions, pH, and additives.

DNA functionalization by dynamic chemistry.

Dynamic combinatorial chemistry (DCC) is an attractive method to efficiently generate libraries of molecules from simpler building blocks by reversible reactions under thermodynamic control. Here we focus on the chemical modification of DNA oligonucleotides with acyclic diol linkers and demonstrate their potential for the deoxyribonucleic acid functionalization and generation of libraries of reversibly interconverting building blocks. The syntheses of phosphoramidite building blocks derived from D-threoninol are presented in two variants with protected amino or thiol groups. The threoninol building blocks were successfully incorporated via automated solid-phase synthesis into 13mer oligonucleotides. The amino group containing phosphoramidite was used together with complementary single-strand DNA templates that influenced the Watson-Crick base-pairing equilibrium in the mixture with a set of aldehyde modified nucleobases. A significant fraction of all possible base-pair mismatches was obtained, whereas, the highest selectivity (over 80%) was found for the guanine aldehyde templated by the complementary cytosine containing DNA. The elevated occurrence of mismatches can be explained by increased backbone plasticity derived from the linear threoninol building block as a cyclic deoxyribose analogue.

The influence of glycation on a high pressure denaturation of ubiquitin.

The combination of deuterium-hydrogen exchange (DHX) and mass spectrometry (MS) can be used for studying a high pressure denaturation (HPD) of proteins. Herein we present the results of investigations of the influence of glycation on the HPD of ubiquitin. Application of various values of pressure causes different degrees of protein unfolding, resulting in molecules with a different number of protons available for exchange with deuterons. The dependence of this number on pressure gives information on the denaturation state of a protein. On the basis of the obtained results we can conclude that increasing number of fructosamine moieties in ubiquitin decreases the pressure required for its denaturation. It suggests that glycation moderately decreases the protein stability. The present study is the first example of application of hydrogen-deuterium exchange as a method of investigating the influence of posttranslational modification of protein on the HPD.

Metal coordination and tyrosinase inhibition studies with Kojic-ßAla-Kojic.

Kojic acid is a natural antifungal and antibacterial agent that has been extensively studied for its tyrosinase inhibitory and metal coordination properties. Tyrosinase is a metalloenzyme with two copper ions in the active site. It is widely accepted that the tyrosinase inhibitory activity of kojic acid is related to its ability to coordinate metals. Over the past five years, we have used kojic acid to synthesize new and efficient bis-kojic acid chelators of iron and aluminium. In parallel, we investigated whether the de novo designed ligands could interfere with proper tyrosinase functioning. The present study combines our experience with inhibition and coordination studies of the new ligand: Kojic-ßAla-Kojic. Research aimed at the assembly of a new potent tyrosinase inhibitor was based on the well-known crystal structure of the enzyme. Two questions were whether two kojic acids could act better than one and to what extent the length and kind of linker could ameliorate metal coordination, and inhibitory activity. Our results show that Kojic-ßAla-Kojic has high affinity for Fe(III), Al(III), Zn(II), and Cu(II) and strong tyrosinase inhibitory effect and it can be proposed for use in industrial and pharmaceutical applications.

Metallacrowns as products of the aqueous medium self-assembly of histidinehydroxamic acid-containing polypeptides.

Self-assembly is a widely studied, spontaneous, and reversible phenomenon leading to the formation of the ordered structures by non-covalent specific interactions among starting molecules. In this work, a new template for the self-assembly of polypeptides based on peptides containing the C-terminal histidinehydroxamic acid moiety and Cu(2+) ions is characterized. Two peptide (tripeptide and pentadecapeptide) hydroxamic acid systems were synthesized and their interactions with Cu(2+) ions were investigated, revealing a high stability of the supramolecular assemblies formed. The supramolecular metallacrown-based L4Cu5 complexes exist at physiological pH in the presence of Cu(2+) ions as is evidenced from the spectroscopic methods, ESI mass spectrometry, and physicochemical techniques.

The mass spectrometric study on aminohydroxamic acids-based metallacrowns.

Electrospray ionization mass spectrometry (MS) has been widely used to detect noncovalent interactions in supramolecular compounds, especially in biological systems. In our work, we present the application of the electrospray ionization MS technique to characterize the metallamacrocycles, known as metallacrowns. This project involves investigations of the aminohydroxamic acids structure and chirality influence on formation of ternary 12-metallacrown-4 complexes. For our experiments, we used a series of ß-aminohydroxamic acids and derivatives of histidinehydroxamic acid. A high stability of the studied supramolecular systems in the gas phase was confirmed by MS/MS experiments. We also proposed the fragmentation pathways for the studied compounds. Obtained results reveal that the ternary 12-metallacrown-4 formation process is not selective, and ligands of various structures and chiralities can be incorporated into these systems.

Solid phase synthesis of peptide hydroxamic acids on poly(ethylene glycol)-based support.

A novel resin designed for solid-phase synthesis of peptide hydroxamic acids (PHA) combining the trityl linker with poly(ethylene glycol)-based support, ChemMatrix® type, is described. The synthesis of PHA can be performed according to a standard protocol, providing products in excellent purity and reasonable yields.

One-pot efficient synthesis of N(α)-urethane-protected ß- and γ-amino acids.

1-[(4-Methylphenyl)oxy]pyrrolidine-2,5-dione and 1-[(4-methylphenyl)oxy]piperidine-2,6-dione react in a Lossen-type reaction with primary alcohols in the presence of triethylamine to furnish corresponding N(α)-urethane-protected ß-alanine and γ-aminopropionic acid (GABA), respectively, with excellent yields and purities, in an essentially "one-pot" procedure.