Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs.

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.

A Novel UHPLC-MS/MS Method for the Quantification of Seven Opioids in Different Human Tissues.

BACKGROUND: Opioids are considered the cornerstone of pain management: they show good efficacy as a first-line therapy for moderate to severe cancer pain. Since pharmacokinetic/pharmacodynamic information about the tissue-specific effect and toxicity of opioids is still scarce, their quantification in post-mortem autoptic specimens could give interesting insights. METHODS: We describe an ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method for the simultaneous quantification of methadone, morphine, oxycodone, hydrocodone, oxymorphone, hydromorphone and fentanyl in several tissues: liver, brain, kidney, abdominal adipose tissue, lung and blood plasma. The presented method has been applied on 28 autoptic samples from different organs obtained from four deceased PLWH who used opioids for palliative care during terminal disease. RESULTS: Sample preparation was based on tissue weighing, disruption, sonication with drug extraction medium and a protein precipitation protocol. The extracts were then dried, reconstituted and injected onto the LX50 QSight 220 (Perkin Elmer, Milan, Italy) system. Separation was obtained by a 7 min gradient run at 40 °C with a Kinetex Biphenyl 2.6 µm, 2.1 × 100 mm. Concerning the analyzed samples, higher opioids concentrations were observed in tissues than in plasma. Particularly, O-MOR and O-COD showed higher concentrations in kidney and liver than other tissues (>15-20 times greater) and blood plasma (>100 times greater). CONCLUSIONS: Results in terms of linearity, accuracy, precision, recovery and matrix effect fitted the recommendations of FDA and EMA guidelines, and the sensitivity was high enough to allow successful application on human autoptic specimens from an ethically approved clinical study, confirming its eligibility for post-mortem pharmacological/toxicological studies.

A Time-Kill Assay Study on the Synergistic Bactericidal Activity of Pomegranate Rind Extract and Zn (II) against Methicillin-Resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa.

There is a need for new antimicrobial systems due to increased global resistance to current antimicrobials. Pomegranate rind extract (PRE) and Zn (II) ions both possess a level of antimicrobial activity and work has previously shown that PRE/Zn (II) in combination possesses synergistic activity against Herpes simplex virus and Micrococcus luteus. Here, we determined whether such synergistic activity extended to other, more pathogenic, bacteria. Reference strains of methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa were cultured and subjected to challenge by PRE, Zn (II), or PRE + Zn (II), in time-kill assays. Data were obtained independently by two researchers using different PRE preparations. Statistically significant synergistic activity for PRE + Zn (II) was shown for all four bacterial strains tested compared to untreated controls, although the extent of efficacy and timescales varied. Zn (II) exerted activity and at 1 h, it was not possible to distinguish with PRE + Zn (II) combination treatment in all cases. PRE alone showed low activity against all four bacteria. Reproducible synergistic bactericidal activity involving PRE and Zn (II) has been confirmed. Potential mechanisms are discussed. The development of a therapeutic system that possesses demonstrable antimicrobial activity is supported which lends itself particularly to topical delivery applications, for example MRSA infections.

Social support, social participation, and cardiovascular reactivity to stress in the Midlife in the United States (MIDUS) study.

This study tested two hypotheses of associations between dimensions of social connectedness and cardiovascular reactivity to acute stress: (1) high social support predicts diminished cardiovascular responses to stress (i.e., the stress-buffering model of social support), and (2) diminished cardiovascular responses predict lower social participation, a form of motivated behaviour. Participants (N = 606) in the main Midlife in the United States study completed measures of social support and social participation and underwent psychophysiological stress testing. In unadjusted analyses, social support was positively, rather than inversely, associated with reactivity. Results withstood adjustment for several control variables, but not for depressive symptoms, which was associated with diminished reactivity. Further, diminished reactivity was associated with lower social participation, but not in fully adjusted models. No robust evidence was observed for either the stress-buffering model, or for an association between diminished reactivity and lower social participation. The implications for our understanding of links between social connectedness and cardiovascular reactivity are discussed.

Work Outcomes in Patients Who Stay at Work Despite Musculoskeletal Pain.

Purpose To assess self-reported work impacts and associations between psychosocial risk factors and work impairment amongst workers seeking care for musculoskeletal pain while continuing to work. Methods Patients were recruited from Musculoskeletal Assessment Clinics at 5 hospitals across Ireland. Participants completed questionnaires including assessments of work impairment (Work Productivity and Activity Impairment Questionnaire), work ability (single item from the Work Ability Index) and work performance (Work Role Functioning Questionnaire; WRFQ). Logistic and hierarchical regressions were conducted to analyse the relation between psychosocial variables and work outcomes. Results 155 participants (53.5% female; mean age = 46.50 years) who were working at the time of assessment completed the questionnaires. Absenteeism was low, yet 62.6% were classified as functioning poorly according to the WRFQ; 52.3% reported having poor work ability. Logistic regression analyses indicated that higher work role functioning was associated with higher pain self-efficacy (OR 1.51); better work ability was associated with older age (OR 1.063) and lower functional restriction (OR 0.93); greater absenteeism was associated with lower pain self-efficacy (OR 0.65) and poorer work expectancy (OR 1.18). Multiple regression analysis indicated that greater presenteeism was associated with higher pain intensity (ß = 0.259) and lower pain self-efficacy (ß = - 0.385). Conclusions While individuals continue to work with musculoskeletal pain, their work performance can be adversely affected. Interventions that target mutable factors, such as pain self-efficacy, may help reduce the likelihood of work impairment.

Early interventions to promote work participation in people with regional musculoskeletal pain: a systematic review and meta-analysis.

OBJECTIVES: To determine the effectiveness of early multidisciplinary interventions in promoting work participation and reducing work absence in adults with regional musculoskeletal pain. DATA SOURCES: Seven databases (CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, OT Seeker, PEDro; 1990 to December 2016) were searched for eligible studies. REVIEW METHODS: Trials were included if they reported on work-based outcomes for participants experiencing difficulties at work or ≤ three months' sick leave. Interventions had to include two or more elements of the biopsychosocial model delivered as a coordinated programme. Quality was assessed using the GRADE criteria. Results were analysed by hazard ratios for return to work data; continuous outcomes were analysed as standardised mean difference with 95% confidence intervals. RESULTS: A total of 20 randomized controlled trials, with 16,319 participants were included; the interventions were grouped according to their main components for meta-analyses. At 12-months follow-up, moderate quality evidence suggests that programmes involving a stepped care approach (four studies) were more effective than the comparisons in promoting return to work (hazard ratio (HR) 1.29 (95% confidence interval (CI) 1.03 to 1.61), p = 0.03), whereas case management (two studies) was not (HR 0.92 (95% CI 0.69 to 1.24), p = 0.59). Analyses suggested limited effectiveness in reducing sickness absences, in pain reduction or functional improvement across the intervention categories. CONCLUSION: There is uncertainty as to the effectiveness of early multicomponent interventions owing to the clinical heterogeneity and varying health and social insurance systems across the trials.

Functional Connectivity Anomalies in Adolescents with Psychotic Symptoms.

BACKGROUND: Previous magnetic resonance imaging (MRI) research suggests that, prior to the onset of psychosis, high risk youths already exhibit brain abnormalities similar to those present in patients with schizophrenia. OBJECTIVES: The goal of the present study was to describe the functional organization of endogenous activation in young adolescents who report auditory verbal hallucinations (AVH) in view of the "distributed network" hypothesis of psychosis. We recruited 20 young people aged 13-16 years who reported AVHs and 20 healthy controls matched for age, gender and handedness from local schools. METHODS: Each participant underwent a semi-structured clinical interview and a resting state (RS) neuroimaging protocol. We explored functional connectivity (FC) involving three different networks: 1) default mode network (DMN) 2) salience network (SN) and 3) central executive network (CEN). In line with previous findings on the role of the auditory cortex in AVHs as reported by young adolescents, we also investigated FC anomalies involving both the primary and secondary auditory cortices (A1 and A2, respectively). Further, we explored between-group inter-hemispheric FC differences (laterality) for both A1 and A2. Compared to the healthy control group, the AVH group exhibited FC differences in all three networks investigated. Moreover, FC anomalies were found in a neural network including both A1 and A2. The laterality analysis revealed no between-group, inter-hemispheric differences. CONCLUSIONS: The present study suggests that young adolescents with subclinical psychotic symptoms exhibit functional connectivity anomalies directly and indirectly involving the DMN, SN, CEN and also a neural network including both primary and secondary auditory cortical regions.

Psychotic experiences in the population: Association with functioning and mental distress.

Psychotic experiences are far more common in the population than psychotic disorder. They are associated with a number of adverse outcomes but there has been little research on associations with functioning and distress. We wished to investigate functioning and distress in a community sample of adolescents with psychotic experiences. Two hundred and twelve school-going adolescents were assessed for psychotic experiences, mental distress associated with these experiences, global (social/occupational) functioning on the Children's Global Assessment Scale, and a number of candidate mediator variables, including psychopathology, suicidality, trauma (physical and sexual abuse and exposure to domestic violence) and neurocognitive functioning. Seventy five percent of participants who reported psychotic experiences reported that they found these experiences distressing (mean score for severity of distress was 6.9 out of maximum 10). Participants who reported psychotic experiences had poorer functioning than participants who did not report psychotic experiences (respective means: 68.6, 81.9; OR=0.25, 95% CI=0.14-0.44). Similarly, participants with an Axis-1 psychiatric disorder who reported psychotic experiences had poorer functioning than participants with a disorder who did not report psychotic experiences (respective means: 61.8, 74.5; OR=0.28, 95% CI=0.12-0.63). Candidate mediator variables explained some but not all of the relationship between psychotic experiences and functioning (OR=0.48, 95% CI=0.22-1.05, P<0.07). Young people with psychotic experiences have poorer global functioning than those who do not, even when compared with other young people with psychopathology (but who do not report psychotic experiences). A disclosure of psychotic experiences should alert treating clinicians that the individual may have significantly more functional disability than suggested by the psychopathological diagnosis alone.

The carboxy-terminal segment of the human LINE-1 ORF2 protein is involved in RNA binding.

The human LINE-1/L1 ORF2 protein is a multifunctional enzyme which plays a vital role in the life cycle of the human L1 retrotransposon. The protein consists of an endonuclease domain, followed by a central reverse transcriptase domain and a carboxy-terminal C-domain with unknown function. Here, we explore the nucleic acid binding properties of the 180-amino acid carboxy-terminal segment (CTS) of the human L1 ORF2p in vitro. In a series of experiments involving gel shift assay, we demonstrate that the CTS of L1 ORF2p binds RNA in non-sequence-specific manner. Finally, we report that mutations destroying the putative Zn-knuckle structure of the protein do not significantly affect the level of RNA binding and discuss the possible functional role of the CTS in L1 retrotransposition.

Negligible effect of tenofovir on atazanavir trough concentrations and genotypic inhibitory quotients in the presence and absence of ritonavir.

BACKGROUND: It is recommended to boost atazanavir with ritonavir (ATV/r) when it is combined with tenofovir disoproxil fumarate (TDF) because of drug interactions. For tolerability, unboosted atazanavir (ATV) is sometimes coadministered with TDF. The objective of this study was to evaluate the impact of this interaction on the proportion of patients achieving target ATV C troughs and genotypic inhibitory quotients (GIQ). MATERIALS AND METHODS: A therapeutic drug monitoring database was screened to evaluate ATV concentrations. Differences in C trough and GIQ values among 4 antiretroviral drug combinations were evaluated. RESULTS: Three hundred eight C troughs, 91 GIQs, and 92 viral loads were evaluated for 238, 68, and 69 patients, respectively. Patients receiving ATV/r and TDF compared with ATV and TDF were more likely to have a therapeutic C trough (odds ratio, 2.27; 95% confidence interval: 1.46-3.52; P < 0.001). Among patients on unboosted ATV, the odds of having a therapeutic ATV C trough did not differ between groups with TDF versus without TDF. Although ritonavir increased the GIQ in patients receiving TDF (odds ratio, 3.38; 95% confidence interval: 1.30-8.81; P = 0.013), a similar proportion of patients on TDF and either ATV/r or ATV achieved a therapeutic GIQ. CONCLUSIONS: In patients receiving TDF, ritonavir increased the ATV C trough and GIQ and patients on ATV/r were more likely to have therapeutic C troughs. However, among subjects without ritonavir boosting, TDF compared with other nucleosides did not influence the odds of achieving a therapeutic ATV C trough. These data suggest that ritonavir boosting of ATV is prudent, particularly in patients with resistance mutations.

Canadian allergists' and nonallergists' perception of epinephrine use and vaccination of persons with egg allergy.

BACKGROUND: Studies suggest knowledge gaps about epinephrine use and vaccination of persons with egg allergy. OBJECTIVE: We compared the perception of Canadian allergists and nonallergists on issues related to epinephrine use and vaccination of persons with egg allergy. METHODS: Canadian allergists, pediatricians, general practitioners/family physicians and emergency room physicians were recruited through medical associations and surveyed on these issues. Multivariate logistic regression models were used to identify determinants of specific responses. RESULTS: One-hundred fourteen allergists and 613 nonallergists participated. For most issues with accepted best practices, allergists were more likely to adhere to recommendations. Allergists versus nonallergists were more likely to recommend intramuscular epinephrine for anaphylaxis (odds ratio [OR] = 3.8; 95% CI, 1.43-10.11). Older physicians (OR = 0.98; 95% CI, 0.97-0.99), Canadian-Paediatric-Surveillance-Program participants (OR = 0.48; 95% CI, 0.24-0.96), family physicians (OR = 0.39; 95% CI, 0.16-0.96), and general practitioners (OR = 0.14; 95% CI, 0.04-0.52) were less likely to recommend intramuscular use. However, in severe anaphylaxis, >25% of both groups would not give epinephrine for patients presenting with breathing difficulties or hypotension. Use of epinephrine for severe anaphylaxis was less likely in older physicians (OR = 0.97; 95% CI, 0.95-0.99), female physicians (OR = 0.60; 95% CI, 0.39-0.89), and those practicing in Ontario (OR = 0.56; 95% CI, 0.36-0.86), Manitoba (OR = 0.42; 95% CI, 0.19-0.90), or Nova-Scotia (OR = 0.31; 95% CI, 0.12-0.78). Allergists (OR = 6.22; 95% CI, 3.60-10.72) and physicians treating mainly children (OR = 3.41; 95% CI, 1.87-6.25), or practicing in Quebec (OR = 1.68; 95% CI, 1.12-2.55) were more likely to recommend measles-mumps-rubella vaccination in a community facility. CONCLUSION: Knowledge gaps about mode and indications for epinephrine administration and vaccination policies need to be addressed in future education programs to ensure prompt epinephrine use and to avoid unnecessary restriction of vaccines.

Individual differences in the impact of attentional bias training on cardiovascular responses to stress in women.

Experimental studies show that training people to attend to negative stimuli makes them more likely to respond with greater anxiety to stress. The present study investigated this effect in students using measures of cardiovascular responses to stress and examined whether individual differences influence the impact of attention training on stress responses. Using a standard dot probe task, 30 participants underwent negative attentional bias training and 34 participants underwent anti-negative training before completing a stressful speech task. Results indicated that, overall, participants exhibited acclimatization to the procedures (indicated by a dip in blood pressure post-training) and normal stress responding (indicated by elevated blood pressure in response to stress; p<.001). However, consideration of participants' scores for neuroticism/emotional-stability revealed important differences in how the intervention impacted on cardiovascular profiles (p=.008). For participants with high neuroticism scores, the negative attentional bias intervention elicited more exaggerated stress responding than the anti-negative intervention. For those with low neuroticism scores (i.e., emotionally stable participants), the anti-negative intervention was associated with elevated post-intervention blood pressure and higher blood pressure reactivity to stress. These findings provide evidence of the impact of attentional bias manipulation on physiological stress reactivity and suggest the effect is highly contingent on individual temperaments.

Individual differences in adaptation of cardiovascular responses to stress.

Previous research has described patterns of adaptation of cardiovascular responses across prolonged or recurring stress. However, despite important implications for the study of reactivity, relatively little research has directly examined the antecedents or consequences of this adaptation. We present data showing that neuroticism, a personality trait associated with dispositional appraisals of stress, is associated with reductions in HR, CO, and TPR responses across stress exposures. Comparisons of reactivity curves suggest blunted initial stress responses among persons with high neuroticism, and higher initial responses followed by greater decreases among persons with low neuroticism. The data also suggest an association between adaptation of cardiovascular responses and myocardial hemodynamic responding. Such findings shed new light on previous studies detecting healthful correlates of short-term stress responding, and highlight the relevance of adaptation to future cardiovascular reactivity research.

Habituation-sensitization of cardiovascular reactivity to repeated stress in smokers and non-smokers: an anthropometrically matched trial.

Previous research has been equivocal as to the impact of smoking status on cardiovascular reactivity to challenge. In addition, little is known about patterns of cardiovascular response habituation-sensitization to repeated challenge, in either smokers or the general population as a whole. The present study sought to clarify whether smokers and non-smokers differ in cardiovascular reactivity to challenge, or in patterns of reactivity to repeated challenge. 28 smokers and 28 anthropometrically matched non-smokers underwent repeated cardiovascular reactivity assessment. Results suggest that smokers had higher diastolic blood pressure (DBP) than non-smokers, and that female non-smokers demonstrated DBP response sensitization. Findings highlight direct associations between smoking and cardiovascular reactivity of potential significance to the etiology of cardiovascular disease.

Abacavir hypersensitivity reaction: an update.

OBJECTIVE: To review the clinical features, risk factors, diagnosis, and management of abacavir hypersensitivity reaction (HSR). DATA SOURCES: A MEDLINE (1950-October 2007) and EMBASE (1980-October 2007) search using key words abacavir, HIV, human immunodeficiency virus, hypersensitivity reaction, HLA-B(*)5701, and patch tests was conducted. Conference abstracts and article bibliographies were reviewed to identify relevant studies. STUDY SELECTION AND DATA EXTRACTION: Studies that investigated the clinical and immunogenetic risk factors for abacavir hypersensitivity and the benefit of genetic screening, as well as articles that focused on the clinical presentation, assessment, and management of abacavir HSR, were considered for this review. DATA SYNTHESIS: Abacavir hypersensitivity is an immune-mediated reaction that typically occurs within the first 6 weeks of therapy. Signs and symptoms of abacavir HSR are nonspecific, which makes the diagnosis challenging, particularly in medically complex patients. Patch testing may improve the diagnosis and confirmation of abacavir HSR, but it remains experimental. Clinical management is aimed at supportive therapy and discontinuation of abacavir. Rechallenge with abacavir is contraindicated due to the risk of precipitating a life-threatening reaction. Appropriate patient education and a clear communication plan are essential for the safe use of this medication. Identification of patients at risk of developing abacavir hypersensitivity through routine genetic screening for human leukocyte antigen (HLA) HLA-B(*)5701 represents a significant advance in the field of pharmacogenomics, with an apparent 100% negative predictive value when used to screen for abacavir HSR. Preliminary data suggest that pharmacogenetic testing for HLA-B(*)5701 is cost effective. However, until routine testing is available, pharmacovigilance is necessary for the safe and effective use of abacavir. CONCLUSIONS: Serious adverse events associated with the use of abacavir can be avoided by appropriate recognition and management of the HSR. Screening patients for HLA-B(*)5701 prior to initiation of abacavir represents a tool to further decrease the risk of HSRs as well as unnecessary discontinuation of this drug.

Factors associated with altered pharmacokinetics in substance users and non-substance users receiving lopinavir and atazanavir.

Substance use is highly prevalent in HIV-infected individuals in the United States, and clinical management is complicated by the need for antiretroviral treatment, addiction therapy, variable medication adherence, and co-morbidities. The interrelation between HIV and substance use prompted our investigation to examine substance use and self-reported medication adherence in patients receiving the HIV-1 protease inhibitors, atazanavir (ATV) or lopinavir (LPV). ATV and LPV pharmacokinetics were determined by measuring plasma concentrations in subjects with active substance use (SU group) or with no active substance use (NSU group). No difference in adherence was observed between groups (p > 0.05). The mean SU ATV trough was 0.550+/-0.45 microg/mL; the mean NSU ATV trough was 0.780+/-0.590 microg/mL (p > 0.05). The mean SU LPV trough was 4.02+/-2.39 microg/mL; the mean NSU LPV trough was 6.67+/-0.910 microg/mL (p = 0.01). Co-factors found to be associated with variation in ATV and LPV concentrations included concurrent methadone use, cigarette smoking, and substance use status. These data indicate that chronic HIV treatment may be assisted with plasma concentration monitoring to identify those patients who may require dosage modification and/or regimen adjustment in order to optimize antiretroviral effects.