A Scoping Review of Non-Medical and Extra-Medical Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications worldwide and have analgesic, antipyretic and anti-inflammatory properties. Although NSAIDs are recognised as generally safe and effective, non-medical and extra-medical use of these products can occur. Unlike the use of illegal and many prescription drugs, which are subject to extensive research attention, inappropriate use of NSAIDs has been less well investigated. This scoping review collates and describes what is known regarding non-medical and extra-medical use of NSAIDs. In total, 72 studies were included in this scoping review. Three themes emerged from the review: (1) indicative profile of people who engage in non-medical or extra-medical use of NSAIDs; (2) antecedents for non-medical or extra-medical use; and (3) adverse health effects of non-medical and extra-medical use of NSAIDs. The review concluded that there is a need for enhanced patient education, including among sports people; pharmacovigilance in terms of clinician recognition of aberrance; and prescriber and pharmacist awareness of the potential for extra-medical and non-medical use and the related health harms.

"Saving Face": An Online Study of the Injecting Use of DIY Botox and Dermal Filler Kits.

This study reports on an empirically underdocumented practice in contemporary aesthetic enhancement culture, the self-injection of unregulated DIY Botox and dermal filler kits purchased online. Data were collected from 4 online discussion forums containing disclosures in relation to use of DIY kits and analyzed using ethnographic content analysis. Motivation to source DIY Botox and dermal fillers online was grounded in desire to avoid financial cost of professional services and a lack of confidence in practitioners. Future intentions to order online raw materials and "formulas" to prepare dermal fillers at home were expressed. Individuals taught themselves to inject through watching YouTube tutorials and downloading Botox injection maps from the Internet. Although individuals demonstrated awareness of the health risks involved with self-injection of unregulated products, this was not a deterrent. Future research is warranted to document the injecting practices and health outcomes of individuals who inject DIY Botox and dermal filler kits to inform targeted harm reduction interventions by health-care practitioners.

La présente étude rend compte d'une pratique empirique sous-attestée dans la culture de l'esthétique corporelle contemporaine, l'auto-injection de Botox non réglementé et l'utilisation de trousses de remplissage dermique après des achats en ligne. Les chercheurs ont compilé les données à partir de quatre forums de discussion en ligne où les usagers affirmaient utiliser des trousses personnelles, puis les ont évaluées à partir de l'analyse du contenu ethnographique (Krippendorf, 2004). La motivation pour utiliser soi-même le Botox et le remplissage dermique provenait d'un désir d'éviter les coûts des services professionnels et d'un manque de confiance envers les praticiens. Les usagers exprimaient l'intention de commander les produits bruts et les « formules ¼ en ligne afin de préparer des solutions de remplissage dermique à la maison. Ils apprenaient à se faire les injections en regardant des tutorats sur YouTube et en téléchargeant des diagrammes d'injection de Botox trouvés dans Internet. Même s'ils connaissaient les risques pour leur santé liés à l'auto-injection des produits non réglementés, ils ne les considéraient pas comme des éléments dissuasifs. D'autres recherches s'imposent pour répertorier les pratiques d'injection et les résultats cliniques des personnes qui s'injectent du Botox et qui utilisent des trousses de remplissage dermique afin d'orienter les interventions ciblées de réduction des risques qu'adopteront les professionnels de la santé.

"Blood letting"-Self-phlebotomy in injecting anabolic-androgenic steroids within performance and image enhancing drug (PIED) culture.

BACKGROUND: New evidence with regard to a previously undocumented practice - self phlebotomy, known as 'bloodletting' - incontemporary injecting performance and image enhancing drug (PIED) culture is the subject of this paper. While self phlebotomy has been evidenced in psychiatric patients previously, it was performed here in people who inject AAS as a self directed health care procedure. METHODS: Data was collected from five publicly accessible internet discussion forums and coded using NVivo software. For the purposes of this study, posts in relation to bloodletting were extracted from the final set of records for analysis RESULTS: Motivation to perform bloodletting or to 'self - bleed' was largely grounded in experiencing symptoms of high blood pressure or a high red blood cell count (RBC).Instructions on how to perform bloodletting were found within discussion threads. CONCLUSION: This study is intended to provide the first snapshot of online communal activity around practice of self-phlebotomy or bloodletting amongst people who inject AAS. Further research in this area is warranted, and will be of benefit to healthcare workers, treatment providers and policy makers particularly as this relates to evidence informed and targeted harm reduction policies and effective public health interventions.

The injecting use of image and performance-enhancing drugs (IPED) in the general population: a systematic review.

Injecting use of image and performance-enhancing drugs (IPED) in the general population is a public health concern. A wide and varied range of IPED are now easily accessible to all through the online market. A comprehensive literature review was undertaken according to Critical Appraisal Skills Programme (CASP) guidelines for systematic review, to identify the relevant literature. No date restrictions were placed on the database search in the case of human growth hormone melanotan I and II, and oil and cosmetic injectables. In the case of anabolic androgenic steroids search dates were restricted to January 2014-2015. Publications not in English and with a lack of specificity to the topic were excluded. The review yielded 133 relevant quantitative and qualitative papers, clinical trials, clinical case presentations and editorials/reports. Findings were examined/reviewed under emergent themes which identified/measured extent of use, user profiling, sourcing, product endorsement, risk behaviours and health outcomes in users. Motivation for IPED use may be grounded in appearance, pursuit of health and youth, and body image disturbance. IPED users can practice moderated use, with pathological use linked to high-risk behaviours, which may be normalised within IPED communities. Many IPED trajectories and pathways of use are not scientifically documented. Much of this information may be available online in IPED specific discussion forums, an underutilised setting for research, where uncensored discourse takes place among users. This review underscores the need for future internet and clinical research to investigate prevalence and patterns of injecting use, and to map health outcomes in IPED users. This paper provides community-based clinical practice and health promotion services with a detailed examination and analysis of the injecting use of IPED, highlighting the patterns of this public health issue. It serves to disseminate updated publication information to health and social policy makers and those in health service practice who are involved in harm reduction intervention.

Coinfection with Human Cytomegalovirus Genetic Variants in Transplant Recipients and Its Impact on Antiviral T Cell Immune Reconstitution.

UNLABELLED: Reconstitution of T cell immunity is absolutely critical for the effective control of virus-associated infectious complications in hematopoietic stem cell transplant (HSCT) recipients. Coinfection with genetic variants of human cytomegalovirus (CMV) in transplant recipients has been linked to clinical disease manifestation; however, how these genetic variants impact T cell immune reconstitution remains poorly understood. In this study, we have evaluated dynamic changes in the emergence of genetic variants of CMV in HSCT recipients and correlated these changes with reconstitution of antiviral T cell responses. In an analysis of single nucleotide polymorphisms within sequences encoding HLA class I-restricted CMV epitopes from the immediate early 1 gene of CMV, coinfection with genetically distinct variants of CMV was detected in 52% of patients. However, in spite of exposure to multiple viral variants, the T cell responses in these patients were preferentially directed to a limited repertoire of HLA class I-restricted CMV epitopes, either conserved, variant, or cross-reactive. More importantly, we also demonstrate that long-term control of CMV infection after HSCT is primarily mediated through the efficient induction of stable antiviral T cell immunity irrespective of the nature of the antigenic target. These observations provide important insights for the future design of antiviral T cell-based immunotherapeutic strategies for transplant recipients, emphasizing the critical impact of robust immune reconstitution on efficient control of viral infection. IMPORTANCE: Infection and disease caused by human cytomegalovirus (CMV) remain a significant burden in patients undergoing hematopoietic stem cell transplantation (HSCT). The establishment of efficient immunological control, primarily mediated by cytotoxic T cells, plays a critical role in preventing CMV-associated disease in transplant recipients. Recent studies have also begun to investigate the impact genetic variation in CMV has upon disease outcome in transplant recipients. In this study, we sought to investigate the role T cell immunity plays in recognizing and controlling genetic variants of CMV. We demonstrate that while a significant proportion of HSCT recipients may be exposed to multiple genetic variants of CMV, this does not necessarily lead to immune control mediated via recognition of this genetic variation. Rather, immune control is associated with the efficient establishment of a stable immune response predominantly directed against immunodominant conserved T cell epitopes.

Gamma-hydroxybutyrate (GHB): a scoping review of pharmacology, toxicology, motives for use, and user groups.

Gamma hydroxybutyrate (GHB) is a central nervous system depressant with euphoric and relaxant effects. Documentation of GHB prevalence and the underreporting of abuse remains problematic, given the availability of GHB and its precursors γ-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) and the ease of synthesis from kits available on the Internet. The continued abuse of and dependence on GHB, and associated fatalities, present an on-going public health problem. As the drug GHB remains an underresearched topic, a scoping review was chosen as a technique to map the available literature into a descriptive summarized account. PRISMA was used to assist in data retrieval, with subsequent data charting into three key themes (pharmacology and toxicology, outcomes, and user groups). Administered orally, GHB is dose-dependent and popular for certain uses (therapeutic, body enhancement, sexual assault) and amongst user sub groups (recreational party drug users, homosexual men). Despite the low prevalence of use in comparison to other club drugs, rising abuse of the drug is associated with dependence, withdrawal, acute toxicity, and fatal overdose. Clinical diagnosis and treatment is complicated by the co-ingestion of alcohol and other drugs. Limitations of the scoping review and potential for further research and harm reduction initiatives are discussed.

Molecular imprint of exposure to naturally occurring genetic variants of human cytomegalovirus on the T cell repertoire.

Exposure to naturally occurring variants of herpesviruses in clinical settings can have a dramatic impact on anti-viral immunity. Here we have evaluated the molecular imprint of variant peptide-MHC complexes on the T-cell repertoire during human cytomegalovirus (CMV) infection and demonstrate that primary co-infection with genetic variants of CMV was coincident with development of strain-specific T-cell immunity followed by emergence of cross-reactive virus-specific T-cells. Cross-reactive CMV-specific T cells exhibited a highly conserved public T cell repertoire, while T cells directed towards specific genetic variants displayed oligoclonal repertoires, unique to each individual. T cell recognition foot-print and pMHC-I structural analyses revealed that the cross-reactive T cells accommodate alterations in the pMHC complex with a broader foot-print focussing on the core of the peptide epitope. These findings provide novel molecular insight into how infection with naturally occurring genetic variants of persistent human herpesviruses imprints on the evolution of the anti-viral T-cell repertoire.

Multivariate Analysis Using High Definition Flow Cytometry Reveals Distinct T Cell Repertoires between the Fetal-Maternal Interface and the Peripheral Blood.

The human T cell compartment is a complex system and while some information is known on repertoire composition and dynamics in the peripheral blood, little is known about repertoire composition at different anatomical sites. Here, we determine the T cell receptor beta variable (TRBV) repertoire at the decidua and compare it with the peripheral blood during normal pregnancy and pre-eclampsia. We found total T cell subset disparity of up to 58% between sites, including large signature TRBV expansions unique to the fetal-maternal interface. Defining the functional nature and specificity of compartment-specific T cells will be necessary if we are to understand localized immunity, tolerance, and pathogenesis.

An in-depth case examination of an exotic dancer's experience of melanotan.

BACKGROUND: Cultural values placed on tanned skin equating with perceived health and attractiveness in the Western world have stimulated the development, sale and use of synthetic tanning agents. These agents are synthetic analogues of the naturally occurring melanocyte-stimulating hormones (α-MSHs) which stimulate melanogenesis or pigmentation of the skin. There is a lack of research on prevalence of use, user experiences and outcomes, despite evident 'health marketability' and diffusion of use via the Internet. METHODS: We present a unique, intensive, holistic and exploratory single case study analysis of an active user's experiences of synthetic tanning product's labelled as melanotan, with rich description of the case's meanings and identities attached to being tanned, motives for use, injecting experiences and practices, sourcing routes, outcomes and future intentions to use. RESULTS: The case, an exotic dancer, had no prior drug injecting experience and did not identify as 'injecting drug user'. Introduction to injecting of synthetic tanning products occurred with peer assistance. She was conscious of safe injecting practices, which were described as not using needles twice, keeping the product refrigerated, disinfecting and rotating injecting sites, and using sterilised water to dissolve the product. She was aware of synthetic tanning products being unlicensed, unregulated and possibly contaminated. She appeared assured in the self-administration of double dosage and self-management of nausea with benzodiazepines and by injecting before sleep. Experiences of synthetic tanning were positive, with reported feelings of enhanced self-confidence and perceived attractiveness grounded in her confidence in the product's effectiveness to achieve a desired darkened skin tone. No long term or chronic negative outcomes were reported. Development of tolerance and awareness of dependence on synthetic tanning agents was described. CONCLUSION: We discuss her expert account as it relates to the synthetic tanning product outcomes, risk heuristics, sourcing routes and make recommendations for policy.

HLA peptide length preferences control CD8+ T cell responses.

Class I HLAs generally present peptides of 8-10 aa in length, although it is unclear whether peptide length preferences are affected by HLA polymorphism. In this study, we investigated the CD8(+) T cell response to the BZLF1 Ag of EBV, which includes overlapping sequences of different size that nevertheless conform to the binding motif of the large and abundant HLA-B*44 supertype. Whereas HLA-B*18:01(+) individuals responded strongly and exclusively to the octamer peptide (173)SELEIKRY(180), HLA-B*44:03(+) individuals responded to the atypically large dodecamer peptide (169)EECDSELEIKRY(180), which encompasses the octamer peptide. Moreover, the octamer peptide bound more stably to HLA-B*18:01 than did the dodecamer peptide, whereas, conversely, HLA-B*44:03 bound only the longer peptide. Furthermore, crystal structures of these viral peptide-HLA complexes showed that the Ag-binding cleft of HLA-B*18:01 was more ideally suited to bind shorter peptides, whereas HLA-B*44:03 exhibited characteristics that favored the presentation of longer peptides. Mass spectrometric identification of > 1000 naturally presented ligands revealed that HLA-B*18:01 was more biased toward presenting shorter peptides than was HLA-B*44:03. Collectively, these data highlight a mechanism through which polymorphism within an HLA class I supertype can diversify determinant selection and immune responses by varying peptide length preferences.

The impact of a large and frequent deletion in the human TCR ß locus on antiviral immunity.

The TCR plays a critical role in recognizing intracellular pathogens and initiating pathways leading to the destruction of infected cells by the immune system. Although genetic variability is known to greatly impact on the human immune system and the outcome of infection, the influence of sequence variation leading to the inactivation or deletion of TCR gene segments is unknown. To investigate this issue, we examined the CD8(+) T cell response to an HLA-B7-restricted epitope ((265)RPHERNGFTVL(275)) from the pp65 Ag of human CMV that was highly biased and frequently dominated by a public TCR ß-chain encoded by the variable gene segment TRBV4-3. Approximately 40% of humans lack T cells expressing TRBV4-3 because of a 21.5-kb insertion/deletion polymorphism, but these individuals remain responsive to this epitope, using a diverse T cell repertoire characterized by private TCR usage. Although most residues within the bulged 11-mer peptide were accessible for TCR contact, the public and private TCRs showed distinct patterns of sensitivity to amino acid substitution at different positions within the peptide, thereby suggesting that the repertoire diversity generated in the absence of the dominant public TRBV4-3(+) TCR could lead to better protection from viral escape mutation. Thus, variation in the size of the TRBV repertoire clearly contributes toward interindividual variability in immune responses and is presumably maintained in many ethnic groups to enhance the diversity of Ag-specific T cell responses.

'Heads held high': an exploratory study of legal highs in pre-legislation Ireland.

The research aimed to present a unique 'snapshot' of legal psychoactive drug use prior to legislative control in Ireland, in relation to the types of products used; sourcings; consumptive practices and particular social settings for use; gauging of dosage; licit and illicit drug transitions, individualisation of drug decision-making and experiences; and future intentions regarding drug switching post legislation. Semi-structured in depth interviews (n = 32) were conducted with adults aged 18-33 years who had used legal highs in the 6 months prior to fieldwork. The findings indicate some support for 'differentiated' displacement consumptive patterns between illegal and legal drugs, with user pathways grounded in 'legal high' availability; perceived user effect, safety, legality, quality and price. Mephedrone emerged as most popular drug of choice. Internet sales, stockpiling and diversion of previously 'legal highs' onto the illegal street drug market remain of concern, against a background of emerging new designer drugs in Ireland.

Antigen-driven patterns of TCR bias are shared across diverse outcomes of human hepatitis C virus infection.

Hepatitis C virus (HCV) infection causes significant morbidity and mortality worldwide. T cells play a central role in HCV clearance; however, there is currently little understanding of whether the disease outcome in HCV infection is influenced by the choice of TCR repertoire. TCR repertoires used against two immunodominant HCV determinants--the highly polymorphic, HLA-B*0801 restricted (1395)HSKKKCDEL(1403) (HSK) and the comparatively conserved, HLA-A*0101-restricted, (1435)ATDALMTGY(1443) (ATD)--were analyzed in clearly defined cohorts of HLA-matched, HCV-infected individuals with persistent infection and HCV clearance. In comparison with ATD, TCR repertoire selected against HSK was more narrowly focused, supporting reports of mutational escape in this epitope, in persistent HCV infection. Notwithstanding the Ag-driven divergence, T cell repertoire selection against either Ag was comparable in subjects with diverse disease outcomes. Biased T cell repertoires were observed early in infection and were evident not only in persistently infected individuals but also in subjects with HCV clearance, suggesting that these are not exclusively characteristic of viral persistence. Comprehensive clonal analysis of Ag-specific T cells revealed widespread use of public TCRs displaying a high degree of predictability in TRBV/TRBJ gene usage, CDR3 length, and amino acid composition. These public TCRs were observed against both ATD and HSK and were shared across diverse disease outcomes. Collectively, these observations indicate that repertoire diversity rather than particular Vß segments are better associated with HCV persistence/clearance in humans. Notably, many of the anti-HCV TCRs switched TRBV and TRBJ genes around a conserved, N nucleotide-encoded CDR3 core, revealing TCR sequence mosaicism as a potential host mechanism to combat this highly variant virus.

Allelic polymorphism in the T cell receptor and its impact on immune responses.

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability.

alphabeta T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementarity-determining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.

The peptide length specificity of some HLA class I alleles is very broad and includes peptides of up to 25 amino acids in length.

The major ligands presented by MHC class I molecules after natural antigen processing are peptides of eight to ten residues in length, and it is widely accepted that the binding preferences of MHC class I molecules play a dominant role in dictating this classic feature of antigen presentation. In this report, we have reassessed the peptide size specificity of class I human leukocyte antigens (HLAs). By lengthening previously defined T cell epitopes by central amino acid insertion, we demonstrate that the peptide length specificity of some common HLA class I alleles (HLA-B*3501, B*0702 and A*2402) is very broad, and includes peptides of up to 25 residues. These data suggest that the length limitation of naturally processed MHC class I-associated peptides is primarily controlled by peptide availability after antigen processing rather than the binding specificity of MHC class I molecules. Furthermore, the findings provide an explanation for recent reports highlighting that epitopes of >10 amino acids play a minor but significant role in virus-specific immune surveillance by CD8(+) T cells.

Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition.

Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR-HLA-B*4405(EENLLDFVRF) complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

Widespread sequence variation in Epstein-Barr virus nuclear antigen 1 influences the antiviral T cell response.

Epstein-Barr virus (EBV) nuclear antigen (EBNA) 1 is perhaps the most widely studied EBV protein, because of its critical role in maintaining the EBV episome and its expression in all EBV-associated malignancies. Much of this research has focused exclusively on the EBV wild-type (wt) strain (B95-8). Sequence analysis of the gene encoding for EBNA1 in EBV isolates from 43 Caucasians has now revealed considerable EBNA1 sequence divergence from the EBV wt strain in the majority of isolates from this population group. Importantly, T cell recognition of an endogenously processed HLA-B8 - binding EBNA1 epitope was greatly influenced by this sequence polymorphism.