Risk Factors for Suboptimal Adherence Identified by Patient-Reported Outcomes Assessments in Routine HIV Care at 2 North American Clinics.

Purpose: Use of patient-reported outcomes assessments (PROs) can improve patient-provider communication and focus provider attention on current health issues. This analysis examines the association between suboptimal antiretroviral therapy (ART) adherence and factors obtained through PROs among people with HIV (PWH) at 2 North American outpatient clinics. Patients and Methods: Immediately before a clinic visit, PWH completed self-administered PROs. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from logistic regression models to identify sociodemographic and health-related factors (satisfaction with ART, difficulty meeting housing costs, depression, intimate partner violence, risk of malnutrition, smoking status, alcohol use, and substance use) associated with suboptimal adherence (defined as self-reporting <95% or <80% adherence). Multiple imputation was performed to account for missing data in the multivariate analyses. Results: Of 1632 PWH, 1239 (76%) responded to the adherence assessment; of these, 268 (22%) and 106 (9%) reported <95% and <80% adherence, respectively. Of 1580 PWH who responded, 354 (22%) were dissatisfied with their HIV medication. Of responding PWH, 19% reported moderate-to-severe depression, 23% indicated they were at risk of malnutrition, 34% were current smokers, and 62% reported substance use in the past 3 months. Dissatisfaction with ART was significantly associated with <95% and <80% adherence in the unadjusted analysis (unadjusted OR [95% CI], 3.38 [2.51-4.56] and 4.26 [2.82-6.42], respectively) and adjusted analysis (adjusted OR [95% CI], 2.76 [1.91-4.00] and 3.28 [1.95-5.52], respectively); significance remained after multiple imputation. In adjusted analyses, no risk of malnutrition was significantly associated with reduced odds of <95% adherence after multiple imputation (adjusted OR [95% CI], 0.714 [0.511-0.997]); no other factors were associated with <95% or <80% adherence. Conclusion: These results suggest that implementation of PROs evaluating treatment satisfaction may provide value to adherence management in routine HIV care.

Relationship Between Polypharmacy and Quality of Life Among People in 24 Countries Living With HIV.

INTRODUCTION: People living with HIV (PLHIV) have greater risk of having multiple health conditions. We measured the relationship between increased medication and overall quality of life among PLHIV from 24 countries. METHODS: We analyzed data for 2,112 adult PLHIV on antiretroviral therapy (ART) in 24 countries who completed the 2019 Positive Perspectives survey. Polypharmacy was defined as taking 5 or more pills a day or currently taking medications for 5 or more conditions. Outcomes were self-rated overall health, treatment satisfaction, and self-reported virologic control. New treatment concerns were issues not prioritized at ART initiation but now deemed paramount. Data were analyzed with descriptive and multivariable statistics. RESULTS: Overall prevalence of polypharmacy was 42.1%. People reporting polypharmacy had significantly poorer health outcomes independent of existing comorbidities; their odds of treatment satisfaction, optimal overall health, and virologic control were lower by 27.0% (adjusted odds ratio [AOR] = 0.73; 95% CI, 0.59-0.91), 36.0% (AOR = 0.64; 95% CI, 0.53-0.78), and 46.0% (AOR = 0.54, 95% CI, 0.42-0.70), respectively, compared with those without polypharmacy (all P < .05). Most PLHIV (56.6%) were concerned about taking more medicines as they age, and 73.1% were interested in ARTs with fewer medicines. Top reasons for switching ART among those who had ever switched (n = 1,550) were to reduce severity and frequency of side effects (45.3%), number of pills (35.0%), or number of medicines (26.8%). People reporting polypharmacy had significantly higher odds of having new concerns relative to when they initiated ART, regarding risks of drug-drug interactions (AOR = 1.32; 95% CI, 1.02-1.71) and side effects (AOR = 1.31; 95% CI, 1.02-1.68). CONCLUSION: Polypharmacy was associated with poorer health-related outcomes among PLHIV. Many PLHIV expressed concerns about side effects of ART. Clinicians should carefully consider patient preferences, comorbidities, and drug profiles when prescribing ART.

Network generation enhances interpretation of proteomic data from induced apoptosis.

Thirteen proteins (identified with 2-D gels and MALDI-TOF MS) are significantly altered during staurosporine-induced apoptosis in SH-SY5Y cells. To gain further insight into the integrated cellular response to apoptosis, we have investigated whether a network can be generated of direct and indirect interactions between these 13 proteins. A network that contains 12 out of the 13 proteins was generated using Ingenuity Pathway Analysis (IPA) and this network is dominated (89%) by direct protein-protein interactions. This network scored 34 with IPA. Bootstrapping 1000 random lists of 13 proteins suggested that the frequency of this score occurring by chance was 1 in 500. We examined whether subsets of proteins such as HSPs, which were elevated after staurosporine, had a disproportionate impact on the network generated. There was no evidence that any subset of 8 from the 13 proteins contributed disproportionately to the network. Network generation, using IPA, identified common features (such as endoplasmic reticular stress protein interactions) in apoptotic studies from different laboratories. The generation of protein interaction networks clearly enhances the interpretation of proteomic data, but only when interpreted cautiously, particularly in respect of statistical analyses.

The utility of functional interaction and cluster analysis in CNS proteomics.

Proteomic studies offer enormous potential for gaining insight into cellular dynamics and disease processes. An immediate challenge for enhancing the utility of proteomics in translational research lies in methods of handling and interpreting the large datasets generated. Publications rarely extend beyond lists of proteins, putatively altered derived from basic statistics. Here we describe two additional distinct approaches (with particular strengths and limitations) that will enhance the analysis of proteomic datasets. Arithmetic and functional cluster analyses have been performed on proteins found differentially regulated in human glioma. These two approaches highlight (i) subgroups of proteins that may be co-regulated and play a role in glioma pathophysiology, and (ii) functional protein interactions that may improve comprehension of the biological mechanisms involved. A coherent proteomic strategy which involves both arithmetic and functional clustering, (together with careful consideration of conceptual limitations), is imperative for quantitative proteomics to deliver and advance the biological understanding of disease of the CNS. A strategy which combines arithmetic analysis and bioinformatics of protein-protein interactions is both generally applicable and will facilitate the interpretation of proteomic data.

Apoptosis induced by staurosporine alters chaperone and endoplasmic reticulum proteins: Identification by quantitative proteomics.

Apoptosis contributes to cell death after cerebral ischaemia. A quantitative proteomics approach has been employed to define alterations in protein levels in apoptosis induced with staurosporine (STS). Human neuroblastoma derived SH-SY5Y cells were treated with STS (500 nM for 6 h) to induce apoptosis. Quantitative 2-DE was used to determine the changing protein levels with MALDI-TOF MS identification of proteins. Of the 154 proteins analysed, 13 proteins were significantly altered as a result of the apoptotic stimulus; ten of the proteins showed an increase in level with STS and were identified as heat shock cognate 71 (Hsc71), two isoforms of heat shock protein 70 (Hsp70), glucose regulated protein 78 (GRP78), F-actin capping protein, stress-induced phosphoprotein 1, chromatin assembly factor 1 (CAF-1), protein disulphide isomerase A3 (PDI A3) precursor, transitional ER ATPase and actin interacting protein 1 (AIP 1). Three proteins which displayed significant decrease in levels with STS were identified as tubulin, vimentin and glucose regulated protein 94 (GRP94). The functional roles and subcellular locations of these proteins collectively indicate that STS-induced apoptosis provokes induces an unfolded protein response involving molecular chaperones, cochaperones and structural proteins indicative of ER stress.

Changes in protein expression in the rat medial vestibular nuclei during vestibular compensation.

The molecular mechanisms of neural and synaptic plasticity in the vestibular nuclei during 'vestibular compensation', the behavioural recovery that follows deafferentation of one inner ear, are largely unknown. In this study we have used differential proteomics techniques to determine changes in protein expression in ipsi-lesional and contra-lesional medial vestibular nuclei (MVN) of rats, 1 week after either sham surgery or unilateral labyrinthectomy (UL). A systematic comparison of 634 protein spots in two-dimensional electrophoresis gels across five experimental conditions revealed 54 spots, containing 26 proteins whose level was significantly altered 1 week post-UL. The axon-guidance-associated proteins neuropilin-2 and dehydropyriminidase-related protein-2 were upregulated in the MVN after UL. Changes in levels of further specific proteins indicate a coordinated upregulation of mitochondrial function, ATP biosynthesis and phosphate metabolism in the vestibular nuclei 1 week post-UL. These may reflect the metabolic energy demands of processes such as gliosis, neuronal outgrowth and synaptic remodelling that occur after UL. Our findings suggest novel roles for axon elaboration and guidance molecules, as well as mitochondrial and metabolic regulatory proteins, in the post-lesional physiology of the MVN during vestibular system plasticity.

Metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, in mouse liver by alcohol dehydrogenase Adh1 and aldehyde reductase AKR1A4.

The reductive metabolism of trans, trans-muconaldehyde, a cytotoxic metabolite of benzene, was studied in mouse liver. Using an HPLC-based stopped assay, the primary reduced metabolite was identified as 6-hydroxy-trans, trans-2,4-hexadienal (OH/CHO) and the secondary metabolite as 1,6-dihydroxy-trans, trans-2,4-hexadiene (OH/OH). The main enzymes responsible for the highest levels of reductase activity towards trans, trans-muconaldehyde were purified from mouse liver soluble fraction first by Q-sepharose chromatography followed by either blue or red dye affinity chromatography. In mouse liver, trans, trans-muconaldehyde is predominantly reduced by an NADH-dependent enzyme, which was identified as alcohol dehydrogenase (Adh1). Kinetic constants obtained for trans, trans-muconaldehyde with the native Adh1 enzyme showed a Vmax of 2141+/-500 nmol/min/mg and a Km of 11+/-4 microM. This enzyme was inhibited by pyrazole with a KI of 3.1+/-0.57 microM. Other fractions were found to contain muconaldehyde reductase activity independent of Adh1, and one enzyme was identified as the NADPH-dependent aldehyde reductase AKR1A4. This showed a Vmax of 115 nmol/min/mg and a Km of 15+/-2 microM and was not inhibited by pyrazole.

The development and evaluation of a computerised decision support system for primary care based upon 'patient profile decision analysis'.

OBJECTIVE: To develop and evaluate in primary care a computerised decision support system for the management of stroke patients based upon 'patient profile decision analysis'. DESIGN: The decision support system incorporated the findings of 960 Markov models examining the decision to prescribe aspirin in the secondary prevention of stroke. The models reflected each combination of nine risk factors that determined a patient's profile. The evaluation comprised a qualitative interview and a questionnaire administered before and after the general practitioners (GPs) were given access to the support system. SETTING: Primary care. PARTICIPANTS: 15 GPs from the West Midlands. MAIN OUTCOME MEASURES: Decision certainty scoring of hypothetical patient vignettes. Qualitative perceptions of the applicability and acceptability of the system for primary care. RESULTS: After using the system, GPs were more certain of their decision making and made decisions more in line with national guidelines. Quantitative results further suggested that the system made decision making easier, improved feelings of being supported, improved the quality of decision making and increased satisfaction. Qualitative themes included that GPs thought the system could clarify their own decision making and improve GP-patient dialogue. CONCLUSIONS: The feasibility of individualised decision analysis for general practice has been questioned. Patient profile decision analysis, however, may be a valuable means of harnessing some of the advantages of the methodology to produce more patient-specific guidelines for primary care.