Drug Use Mediates the Relationship Between Depressive Symptoms and Adherence to ART Among Recently Incarcerated People Living with HIV.

Depression is a known risk factor for antiretroviral therapy (ART) non-adherence, but little is known about the mechanisms explaining this relationship. Identifying these mechanisms among people living with HIV (PLHIV) after release from prison is particularly important, as individuals during this critical period are at high risk for both depression and poor ART adherence. 347 PLHIV recently released from prison in North Carolina and Texas were included in analyses to assess mediation of the relationship between depressive symptoms at 2 weeks post-release and ART adherence (assessed by unannounced telephone pill counts) at weeks 9-21 post-release by the hypothesized explanatory mechanisms of alcohol use, drug use, adherence self-efficacy, and adherence motivation (measured at weeks 6 and 14 post-release). Indirect effects were estimated using structural equation models with maximum likelihood estimation and bootstrapped confidence intervals. On average, participants achieved 79% ART adherence. The indirect effect of depression on adherence through drug use was statistically significant; greater symptoms of depression were associated with greater drug use, which was in turn associated with lower adherence. Lower adherence self-efficacy was associated with depressive symptoms, but not with adherence. Depression screening and targeted mental health and substance use services for depressed individuals at risk of substance use constitute important steps to promote adherence to ART after prison release.

Antiretroviral Adherence Following Prison Release in a Randomized Trial of the imPACT Intervention to Maintain Suppression of HIV Viremia.

Many people living with HIV (PLWH) pass through correctional facilities each year, a large proportion of whom do not maintain viral suppression following release. We examined the effects of imPACT, an intervention designed to promote post-release viral suppression, on antiretroviral therapy (ART) adherence. PLWH awaiting release from prisons in two southern states were randomized to imPACT (consisting of motivational interviewing, care linkage coordination, and text message medication reminders) versus standard care (SC). ART adherence, measured by unannounced monthly telephone pill counts, was compared between study arms over 6 months post-release. Of 381 participants eligible for post-release follow-up, 302 (79%) completed ≥ 1 of 6 possible pill counts (median: 4; IQR 1-6). Average adherence over follow-up was 80.3% (95% CI 77.5, 83.1) and 81.0% (78.3, 83.6) of expected doses taken in the imPACT and SC arms, respectively. There was no difference between arms when accounting for missing data using multiple imputation (mean difference = - 0.2 percentage points [- 3.7, 3.3]), controlling for study site and week of follow-up. Of the 936 (40.9%) pill counts that were missed, 212 (22.7%) were due to re-incarceration. Those who missed pill counts for any reason were more likely to be unsuppressed, suggesting that they had lower adherence. However, missingness was balanced between arms. Among PLWH released from prison, ART adherence averaged > 80% in both study arms over 6 months-a level higher than seen with most other chronic diseases. However, missing data may have led to an overestimate of adherence. Factors independent of the intervention influence ART adherence in this population and should be identified to inform future targeted interventions.

Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress.

The dynamic post-translational modification O-linked ß-N-acetylglucosamine (O-GlcNAc) regulates thousands of nuclear, cytoplasmic, and mitochondrial proteins. Cellular stress, including oxidative stress, results in increased O-GlcNAcylation of numerous proteins, and this increase is thought to promote cell survival. The mechanisms by which the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA), the enzymes that add and remove O-GlcNAc, respectively, are regulated during oxidative stress to alter O-GlcNAcylation are not fully characterized. Here, we demonstrate that oxidative stress leads to elevated O-GlcNAc levels in U2OS cells but has little impact on the activity of OGT. In contrast, the expression and activity of OGA are enhanced. We hypothesized that this seeming paradox could be explained by proteins that bind to and control the local activity or substrate targeting of OGA, thereby resulting in the observed stress-induced elevations of O-GlcNAc. To identify potential protein partners, we utilized BioID proximity biotinylation in combination with stable isotopic labeling of amino acids in cell culture (SILAC). This analysis revealed 90 OGA-interacting partners, many of which exhibited increased binding to OGA upon stress. The associations of OGA with fatty acid synthase (FAS), filamin-A, heat shock cognate 70-kDa protein, and OGT were confirmed by co-immunoprecipitation. The pool of OGA bound to FAS demonstrated a substantial (∼85%) reduction in specific activity, suggesting that FAS inhibits OGA. Consistent with this observation, FAS overexpression augmented stress-induced O-GlcNAcylation. Although the mechanism by which FAS sequesters OGA remains unknown, these data suggest that FAS fine-tunes the cell's response to stress and injury by remodeling cellular O-GlcNAcylation.

Characterization of tools to detect and enrich human and mouse O-GlcNAcase.

O-linked ß-N-acetylglucosamine (O-GlcNAc) is an essential regulatory post-translational modification of thousands of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc is dynamically added and removed from proteins by the O-GlcNAc transferase and the O-GlcNAcase (OGA), respectively. Dysregulation of O-GlcNAc-cycling is implicated in the etiology of numerous diseases including tumorigenesis, metabolic dysfunction, and neurodegeneration. To facilitate studies focused on the role of O-GlcNAc and OGA in disease, we sought to identify commercially available antibodies that enable the enrichment of full-length OGA from lysates of mouse and human origin. Here, we report that antibodies from Abcam and Bethyl Laboratories can be used to immunoprecipitate OGA to near-saturation from human and mouse cell lysates. However, Western blotting analysis indicates that both antibodies, as well as three non-commercially available antibodies (345, 346, 352), detect full-length OGA and numerous cross-reacting proteins. These non-specific signals migrate similarly to full-length OGA and are detected robustly, suggesting that the use of appropriate controls is essential to avoid the misidentification of OGA.

Mind the Gap: Hospitalizations from Multiple Sources in a Longitudinal Study.

BACKGROUND: Medicare claims and prospective studies with self-reported utilization are important sources of hospitalization data for epidemiologic and outcomes research. OBJECTIVES: To assess the concordance of Medicare claims merged with interview-based surveillance data to determine factors associated with source completeness. METHODS: The Atherosclerosis Risk in Communities (ARIC) study recruited 15,792 cohort participants aged 45 to 64 years in the period 1987 to 1989 from four communities. Hospitalization records obtained through cohort report and hospital record abstraction were matched to Medicare inpatient records (MedPAR) from 2006 to 2011. Factors associated with concordance were assessed graphically and using multinomial logit regression. RESULTS: Among fee-for-service enrollees, MedPAR and ARIC hospitalizations matched approximately 67% of the time. For Medicare Advantage enrollees, completeness increased after initiation of hospital financial incentives in 2008 to submit shadow bills for Medicare Advantage enrollees. Concordance varied by geographic site, age, veteran status, proximity to death, study attrition, and whether hospitalizations were within ARIC catchment areas. CONCLUSIONS: ARIC and MedPAR records had good concordance among fee-for-service enrollees, but many hospitalizations were available from only one source. MedPAR hospital records may be missing for veterans or observation stays. Maintaining study participation increases stay completeness, but new sources such as electronic health records may be more efficient than surveillance for mobile elderly populations.

Individuals motivated to participate in adherence, care and treatment (imPACT): development of a multi-component intervention to help HIV-infected recently incarcerated individuals link and adhere to HIV care.

BACKGROUND: Policy-makers promote a seek, test, treat and retain (STTR) strategy to expand HIV testing, support linkage and engagement in care, and enhance the continuous use of antiretroviral therapy for those HIV-infected. This HIV prevention strategy is particularly appropriate in correctional settings where HIV screening and treatment are routinely available yet many HIV-infected individuals have difficulty sustaining sufficient linkage and engagement in care, disease management, and viral suppression after prison release. METHODS/DESIGN: Our research team developed Project imPACT (individuals motivated to Participate in Adherence, Care and Treatment), a multi-component approach for HIV-Infected recently incarcerated individuals that specifically targets their care linkage, retention, and medication adherence by addressing multiple barriers to care engagement after release. The ultimate goals of this intervention are to improve the health of HIV-infected individuals recently released from prison and reduce HIV transmission to their communities by maintaining viral suppression. This paper describes the intervention and technology development processes, based on best practices for intervention development and process evaluation. These processes included: 1) identifying the target population; 2) clarifying the theoretical basis for intervention design; 3) describing features of its foundational interventions; 4) conducting formative qualitative research; 5) integrating and adapting foundational interventions to create and refine intervention content based on target audience feedback. These stages along with the final intervention product are described in detail. The intervention is currently being evaluation and a two arm randomized, controlled trial in two US state prison systems. DISCUSSION: Based on a literature review, qualitative research, integration of proven interventions and behavioral theory, the final imPACT intervention focused on the transition period two to three months before and three months after prison release. It emphasized pre-release readiness, pre- and post-release supportive non-judgmental counseling, linking individuals to a HIV care clinic and technological supports through videos and text messages. This article provides a useful model for how researchers can develop, test, and refine multi-component interventions to address HIV care linkage, retention and adherence. CLINICAL TRIAL REGISTRATION: NCT01629316 , first registered 6-4-2012; last updated 6-9-2015.

Improving our understanding of the surgical oncology workforce.

OBJECTIVE: This study characterizes the surgical oncology workforce as a baseline for future workforce projections. BACKGROUND: Measuring the capacity of the surgical oncology workforce is difficult due to the wide variety of surgeons who contribute to surgical cancer care. We hypothesize that the bulk of surgical oncology care is provided by general surgeons. METHODS: Using Medicare claims data linked to the North Carolina Central Cancer Registry, all patients 65 years or older who had a diagnosis of incident cancer of the bladder, breast, colon/rectum, esophagus, gallbladder, kidney, liver, lung, skin (melanoma-only), ovary, pancreas, prostate, small bowel, stomach, or uterus in 2005 and who underwent an extirpative procedure for cancer were identified. The proportion of procedures performed by different types of providers was examined. RESULTS: A total of 7759 patients underwent 16,734 extirpative surgical procedures. Excluding procedures for gynecologic/urologic malignancies, the proportion of procedures performed by general surgeons and surgical oncologists was 48% and 12%, respectively. Patients treated by general surgeons were more likely to be older, female, minority, and from areas of high poverty. For each tumor type, travel distances were shorter for patients treated by general surgeons than those treated by specialists. CONCLUSIONS: Workforce projections must account for the significant overlap in the scope of services delivered by providers of different specialties and for the large contribution of general surgeons to cancer care. Efforts to improve the quality of cancer care need to move beyond centralization and focus on educating the surgeons who are providing the bulk of oncology care.

Longitudinal effects of SafeTalk, a motivational interviewing-based program to improve safer sex practices among people living with HIV/AIDS.

Programs to help people living with HIV/AIDS practice safer sex are needed to prevent transmission of HIV and other sexually transmitted infections. We sought to assess the impact of SafeTalk, a multicomponent motivational interviewing-based safer sex program, on HIV-infected patients' risky sexual behavior. We enrolled sexually active adult HIV-infected patients from one of three clinical sites in North Carolina and randomized them to receive the 4-session SafeTalk intervention versus a hearthealthy attention-control. There was no significant difference in the proportion of people having unprotected sex between the two arms at enrollment. SafeTalk significantly reduced the number of unprotected sex acts with at-risk partners from baseline, while in controls the number of unprotected sex acts increased. Motivational interviewing can provide an effective, flexible prevention intervention for a heterogeneous group of people living with HIV.

Identification of Novel Binding Partners for Transcription Factor Emx2.

The mammalian homolog of Drosophila empty spiracles 2 (Emx2) is a homeobox transcription factor that plays central roles in early development of the inner ear, pelvic and shoulder girdles, cerebral cortex, and urogenital organs. The role for Emx2 is best understood within the context of the development of the neocortical region of the cortex, where Emx2 is expressed in a high posterior-medial to low anterior-lateral gradient that regulates the partitioning of the neocortex into different functional fields that perform discrete computational tasks. Despite several lines of evidence demonstrating an Emx2 concentration-dependent mechanism for establishing functional areas within the developing neocortex, little is known about how Emx2 physically carries out this role. Although several binding partners for Emx2 have been identified (including Sp8, eIF4E, and Pbx1), no screens have been used to identify potential protein binding partners for this protein. We utilized a yeast two-hybrid screen using a library constructed from embryonic mouse cDNA in an attempt to identify novel binding partners for Emx2. This initial screen isolated two potential Emx2-binding partner proteins, Cnot6l and QkI-7. These novel Emx2-binding proteins are involved in multiple levels of mRNA metabolism that including splicing, mRNA export, translation, and destruction, thus making them interesting targets for further study.

O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis.

Mutant KRAS drives glycolytic flux in lung cancer, potentially impacting aberrant protein glycosylation. Recent evidence suggests aberrant KRAS drives flux of glucose into the hexosamine biosynthetic pathway (HBP). HBP is required for various glycosylation processes, such as protein N- or O-glycosylation and glycolipid synthesis. However, its function during tumorigenesis is poorly understood. One contributor and proposed target of KRAS-driven cancers is a developmentally conserved epithelial plasticity program called epithelial-mesenchymal transition (EMT). Here we showed in novel autochthonous mouse models that EMT accelerated KrasG12D lung tumorigenesis by upregulating expression of key enzymes of the HBP pathway. We demonstrated that HBP was required for suppressing KrasG12D-induced senescence, and targeting HBP significantly delayed KrasG12D lung tumorigenesis. To explore the mechanism, we investigated protein glycosylation downstream of HBP and found elevated levels of O-linked ß-N-acetylglucosamine (O-GlcNAcylation) posttranslational modification on intracellular proteins. O-GlcNAcylation suppressed KrasG12D oncogene-induced senescence (OIS) and accelerated lung tumorigenesis. Conversely, loss of O-GlcNAcylation delayed lung tumorigenesis. O-GlcNAcylation of proteins SNAI1 and c-MYC correlated with the EMT-HBP axis and accelerated lung tumorigenesis. Our results demonstrated that O-GlcNAcylation was sufficient and required to accelerate KrasG12D lung tumorigenesis in vivo, which was reinforced by epithelial plasticity programs.

Does the quality of safetalk motivational interviewing counseling predict sexual behavior outcomes among people living with HIV?

OBJECTIVE: Although past research has demonstrated a link between the quality of motivational interviewing (MI) counseling and client behavior change, this relationship has not been examined in the context of sexual risk behavior among people living with HIV/AIDS. We studied MI quality and unprotected anal/vaginal intercourse (UAVI) in the context of SafeTalk, an evidence-based secondary HIV prevention intervention. METHODS: We used a structured instrument (the MISC 2.0 coding system) as well as a client-reported instrument to rate intervention sessions on aspects of MI quality. Then we correlated client-reported UAVI with specific counseling behaviors and the proportion of interactions that achieved MI quality benchmarks. RESULTS/CONCLUSION: Higher MISC-2.0 global ratings and a higher ratio of reflections to questions both significantly predicted fewer UAVI acts at 8-month follow-up. Analysis of client ratings, which was more exploratory, showed that clients who rated their sessions higher in counselor acceptance, client disclosure, and relevance reported higher numbers of UAVIs, whereas clients who selected higher ratings for perceived benefit were more likely to have fewer UAVI episodes. PRACTICE IMPLICATIONS: Further research is needed to determine the best methods of translating information about MI quality into dissemination of effective MI interventions with people living with HIV.

Randomized Controlled Trial of an Intervention to Maintain Suppression of HIV Viremia After Prison Release: The imPACT Trial.

BACKGROUND: HIV-infected individuals transitioning from incarceration to the community are at risk for loss of viral suppression. We compared the effects of imPACT, a multidimensional intervention to promote care engagement after release, to standard care on sustaining viral suppression after community re-entry. METHODS: This trial randomized 405 HIV-infected inmates being released from prisons in Texas and North Carolina with HIV-1 RNA levels <400 copies/mL to imPACT versus standard care. The imPACT arm received motivational interviewing prerelease and postrelease, referral to care within 5 days of release, and a cellphone for medication text reminders. The standard care arm received routine discharge planning and a cellphone for study staff contact. The primary outcome was the difference between arms in week 24 postrelease viral suppression (HIV-1 RNA <50 copies/mL) using intention-to-treat analysis with multiple imputation of missing data. RESULTS: The proportion with 24-week HIV-1 RNA <50 copies/mL was 60% and 61% in the imPACT and standard care arms, respectively [odds ratio for suppression 0.95 (95% confidence interval: 0.59 to 1.53)]. By week 6 postrelease, 86% in the imPACT arm versus 75% in the standard care arm attended at least 1 nonemergency clinic visit (P = 0.02). At week 24, 62% in both arms reported not missing any antiretroviral doses in the past 30 days (P > 0.99). CONCLUSIONS: Higher rates of HIV suppression and medical care engagement than expected based on previous literature were observed among HIV-infected patients with suppressed viremia released from prison. Randomization to a comprehensive intervention to motivate and facilitate HIV care access after prison release did not prevent loss of viral suppression. A better understanding of the factors influencing prison releasees' linkage to community care, medication adherence, and maintenance of viral suppression is needed to inform policy and other strategic approaches to HIV prevention and treatment.

Locomotor adaptations for changes in the slope of the walking surface.

The goal of this study was to examine the transition of walking from a level surface onto different inclined surfaces. Kinematic data of limb and trunk segments were recorded from individuals as they approached and stepped onto four different ramped surfaces (slopes= 3 degrees , 6 degrees , 9 degrees , 12 degrees ). This transition introduced significant adaptations to the swing limb trajectory that were evident in even the lowest ramp condition and appear to be scaled to the ramp inclination although the nature of this scaling seemed to change between the 6 degrees and 9 degrees conditions. An increased forward pitch of the trunk orientation during all ramp conditions was initiated early on during the preceding stance phase on level ground. The swing limb modification essentially consisted of a two-stage response. The initial response of the limb trajectory changes was not specific to the degree of inclination but later changes were dependent on the ramp condition. The initial response is to ensure a safe toe clearance as the foot approaches the edge of the ramp and then later modifications provide the appropriate positioning of the limb to prepare for an elevated foot contact. Early changes were actively produced through an increased pull-off by the hip flexors and an elevation of the swing limb by the active muscle control of the stance limb. Ankle dorsiflexion also appears to have a supporting role increasing toe clearance. Absorption at the hip and knee during later swing contribute to control and position the limb in preparation for foot contact. These strategies were similar to those adopted for step changes in the level of the walking surface where there are similar demands of the quickly moving the limb forward and upward, however, the positioning of the limb for new angled landing surface requires further adaptations.

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis.

O-linked N-acetyl-ß-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-ß-glucosaminidase (O-GlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced O-GlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.