Treatment interruptions and community connectedness among gbMSM living with HIV in Metro Vancouver, Canada.

HIV treatment interruptions are a major public health concern that demonstrate a lack of engagement in care and is detrimental to the health of people living with HIV. Community connectedness have demonstrated a protective effect for psychosocial health but are not well understood for HIV treatment outcomes. We explored associations between community connectedness and treatment interruptions among gay, bisexual and other men who have sex with men (gbMSM) living with HIV in Vancouver, British Columbia. We analyzed survey data from the Momentum Health Study and identified treatment interruptions through data linkages with the provincial HIV Drug Treatment Program as episodes lasting more than 60 days beyond an expected antiretroviral therapy refill date from February 2012 to July 2019. We built a mixed-effects logistic regression model, adjusting for confounders. Of 213 gbMSM living with HIV, 54 experienced treatment interruption (25.4%) over a median five-year follow-up. Multivariable results found the number gbMSM who spoken to in the past month (aOR = 0.995; 95% CI = 0.991, 1.000 (per 100-unit increase)) and attending a gay community meeting more than once per month (aOR = 0.32; 95% CI = 0.11, 0.89) were associated with lower odds of treatment interruptions. These results highlight the importance of social connections in facilitating effective HIV care.

Lipid Phase Separation in Vesicles Enhances TRAIL-Mediated Cytotoxicity.

Ligand spatial presentation and density play important roles in signaling pathways mediated by cell receptors and are critical parameters when designing protein-conjugated therapeutic nanoparticles. Here, we harness lipid phase separation to spatially control the protein presentation on lipid vesicles. We use this system to improve the cytotoxicity of TNF-related apoptosis inducing ligand (TRAIL), a therapeutic anticancer protein. Vesicles with phase-separated TRAIL presentation induce more cell death in Jurkat cancer cells than vesicles with uniformly presented TRAIL, and cytotoxicity is dependent on TRAIL density. We assess this relationship in other cancer cell lines and demonstrate that phase-separated vesicles with TRAIL only enhance cytotoxicity through one TRAIL receptor, DR5, while another TRAIL receptor, DR4, is less sensitive to TRAIL density. This work demonstrates a rapid and accessible method to control protein conjugation and density on vesicles that can be adopted to other nanoparticle systems to improve receptor signaling by nanoparticles.

Programming "Atomic Substitution" in Alloy Colloidal Crystals Using DNA.

Although examples of colloidal crystal analogues to metal alloys have been reported, general routes for preparing 3D analogues to random substitutional alloys do not exist. Here, we use the programmability of DNA (length and sequence) to match nanoparticle component sizes, define parent lattice symmetry and substitutional order, and achieve faceted crystal habits. We synthesized substitutional alloy colloidal crystals with either ordered or random arrangements of two components (Au and Fe3O4 nanoparticles) within an otherwise identical parent lattice and crystal habit, confirmed via scanning electron microscopy and small-angle X-ray scattering. Energy dispersive X-ray spectroscopy reveals information regarding composition and local order, while the magnetic properties of Fe3O4 nanoparticles can direct different structural outcomes for different alloys in an applied magnetic field. This work constitutes a platform for independently defining substitution within multicomponent colloidal crystals, a capability that will expand the scope of functional materials that can be realized through programmable assembly.

Trends and risk factors for readmissions following press-fit total knee arthroplasty for the treatment of end-stage osteoarthritis of the knee: a five-year analysis.

INTRODUCTION: The development of new prostheses with improved osseointegration, bone preservation, and reduced cost has renewed interest in uncemented total knee arthroplasty (UCTKA). In the current study, we aimed to: (1) assess demographic data of patients who were and were not readmitted and (2) identify patient-specific risk factors associated with readmission. METHODS: A retrospective query from the PearlDiver database was performed from January 1, 2015, to October 31, 2020. International Classification of Disease, Ninth Revision (ICD-9), ICD-10, or Current Procedural Terminology (CPT) coding was used to distinguish cohorts of patients who had osteoarthritis of the knee and underwent UCTKA. Patients readmitted within 90 days were classified as the study population, while those who were not readmitted were classified as control. A linear regression model was utilized to analyze readmission risk factors. RESULTS: The query yielded 14,575 patients, with 986 (6.8%) being readmitted. Patient demographics such as age (P < 0.0001), sex (P < 0.009), and comorbidity (P < 0.0001) were associated with annual 90-day readmission. Patient-specific risk factors associated with 90-day readmission following press-fit total knee arthroplasty were: arrhythmia (OR: 1.29, 95% CI: 1.11-1.49, P < 0.0005), coagulopathy (OR: 1.36, 95% CI: 1.13-1.63, P < 0.0007), fluid and electrolyte abnormalities (OR: 1.59, 95% CI: 1.38-1.84, P < 0.0001), iron deficiency anemia (OR: 1.49, 95% CI: 1.27-1.73, P < 0.0001), and obesity (OR: 1.37, 95% CI: 1.18-1.60, P < 0.0001). DISCUSSION: This study demonstrates that patients with comorbidities, such as fluid and electrolyte problems, iron deficiency anemia, and obesity, were at an increased risk of readmission after having an uncemented total knee replacement. The risks of readmission following an uncemented total knee arthroplasty can be discussed with patients who have certain comorbidities by arthroplasty surgeons.

The influence of prior dental pathology on medical complications and peri-prosthetic joint infections following primary shoulder arthroplasty.

PURPOSE: Antibiotic prophylaxis before invasive dental procedures is a common practice in the USA. Consensus regarding the influence of prior dental pathology (DP) on postoperative complications is lacking. The objectives are to determine the association of DP prior to shoulder arthroplasty (SA) on: (1) lengths of stay (LOS), (2) medical complications, (3) readmissions, (4) implant-related complications including peri-prosthetic joint infections (PJIs) and (5) healthcare expenditures. METHODS: The PearlDiver database was queried for primary shoulder arthroplasty from 2010 to 2020. Patients with history of dental caries or dental implant placement before SA represented the study group (n = 1419). Patients without prior DP represented controls (n = 7062). Study group patients were 1:5 ratio matched to controls by age, sex, and comorbidities. Outcomes included LOS, 90-day complications, readmissions, 2-year implant-related complications, and healthcare reimbursements. Logistic regression was used to calculate odds ratios (OR) of complications and readmissions. T tests compared LOS and costs. P values < 0.003 were significant. RESULTS: LOS (2.17 vs. 2.07 days; p = 0.071) were similar between groups. Patients with DP had higher 90-day medical complications compared to controls (OR: 1.74, p < 0.0001), including myocardial infarctions (2.2% vs. 0.8%; OR: 2.79, p < 0.0001), acute kidney injuries (8.3% vs. 4.6%; OR: 1.92, p < 0.0001), and pneumonias (8.7% vs. 5.3%; OR: 1.72, p < 0.0001). Readmission rates (1.97% vs. 1.54%; p = 0.248) were similar. Two-year implant complications were higher in patients with DP compared to controls (16.1% vs. 11.5%; OR: 1.38, p = 0.0003), including dislocations (6.4% vs. 4.5%; OR: 1.45, p = 0.002) and mechanical loosenings (4.0% vs. 2.4%; OR: 1.67, p = 0.001); however, PJIs were similar (2.2% vs. 1.9%; OR: 1.12, p = 0.583). Healthcare expenditures between groups were similar ($12,611 vs. $12,059; p = 0.075). CONCLUSION: Patients with prior DP have higher 90-day medical complications and 2-year implant-related complications. Two-year incidence of PJIs were similar between groups. These findings can help shoulder surgeons counsel patients with a pertinent dental history. LEVEL OF EVIDENCE III: Retrospective comparative study.

Longitudinal uptake of the human papillomavirus vaccine among gay, bisexual and other men who have sex with men in British Columbia, Canada 2012-2019.

OBJECTIVES: In 2015, a publicly funded human papillomavirus (HPV) vaccination programme was implemented for gay, bisexual and other men who have sex with men (gbMSM) up to age 26 years in British Columbia, Canada. We assessed trends and correlates of HPV vaccine uptake from 2012 to 2019 in a cohort of gbMSM in Vancouver. METHODS: We recruited sexually active gbMSM aged ≥16 years using respondent-driven sampling from February 2012 to February 2015 and followed them until July 2019. We evaluated self-reported HPV vaccine trends using mixed-effects logistic regression and identified factors associated with uptake using multivariable mixed-effects Poisson regression. RESULTS: A total of 719 participants were recruited and completed the baseline visit, of whom 549 were unvaccinated with at least one follow-up visit. The median age was 33 years and 23% were living with HIV. HPV vaccination increased from 4% in 2012 to 28% in 2019 (p<0.001) among gbMSM >26 years, and from 9% in 2012 to 20% in 2017 (p<0.001) among gbMSM ≤26 years. Vaccination uptake increased after September 2015, following vaccination policy expansion (adjusted rate ratio (aRR)=1.82, 95% CI 1.06 to 3.12). In multivariable models, increased vaccination was associated with age ≤26 years vs ≥45 years (aRR=3.90; 95% CI 1.75 to 8.70), age 27-44 vs ≥45 years (aRR=2.86; 95% CI 1.46 to 5.62), involvement in gay community sports teams (aRR=2.31; 95% CI 1.15 to 4.64) and other groups (aRR=1.71; 95% CI 1.04 to 2.79), awareness of HIV-postexposure prophylaxis (aRR=5.50; 95% CI 1.31 to 23.09), recent sexually transmitted infection testing (aRR=2.72; 95% CI 1.60 to 4.60) and recent sex-work (aRR=2.59; 95% CI 1.08 to 6.19). CONCLUSIONS: Although we observed increases in HPV vaccination uptake from 2012, by 2019 HPV vaccination still remained below 30% among gbMSM in Vancouver, BC. Additional interventions are needed to increase vaccine uptake.

Family still matters: Human social motivation across 42 countries during a global pandemic.

The COVID-19 pandemic caused drastic social changes for many people, including separation from friends and coworkers, enforced close contact with family, and reductions in mobility. Here we assess the extent to which people's evolutionarily-relevant basic motivations and goals-fundamental social motives such as Affiliation and Kin Care-might have been affected. To address this question, we gathered data on fundamental social motives in 42 countries (N = 15,915) across two waves, including 19 countries (N = 10,907) for which data were gathered both before and during the pandemic (pre-pandemic wave: 32 countries, N = 8998; 3302 male, 5585 female; M age  = 24.43, SD = 7.91; mid-pandemic wave: 29 countries, N = 6917; 2249 male, 4218 female; M age  = 28.59, SD = 11.31). Samples include data collected online (e.g., Prolific, MTurk), at universities, and via community sampling. We found that Disease Avoidance motivation was substantially higher during the pandemic, and that most of the other fundamental social motives showed small, yet significant, differences across waves. Most sensibly, concern with caring for one's children was higher during the pandemic, and concerns with Mate Seeking and Status were lower. Earlier findings showing the prioritization of family motives over mating motives (and even over Disease Avoidance motives) were replicated during the pandemic. Finally, well-being remained positively associated with family-related motives and negatively associated with mating motives during the pandemic, as in the pre-pandemic samples. Our results provide further evidence for the robust primacy of family-related motivations even during this unique disruption of social life.

Dual-Responsive Glycopolymers for Intracellular Codelivery of Antigen and Lipophilic Adjuvants.

Traditional approaches to vaccines use whole organisms to trigger an immune response, but they do not typically generate robust cellular-mediated immunity and have various safety risks. Subunit vaccines composed of proteins and/or peptides represent an attractive and safe alternative to whole organism vaccines, but they are poorly immunogenic. Though there are biological reasons for the poor immunogenicity of proteins and peptides, one other key to their relative lack of immunogenicity could be attributed to the poor pharmacokinetic properties of exogenously delivered proteins and peptides. For instance, peptides often aggregate at the site of injection and are not stable in biological fluids, proteins and peptides are rapidly cleared from circulation, and both have poor cellular internalization and endosomal escape. Herein, we developed a delivery system to address the lack of protein immunogenicity by overcoming delivery barriers as well as codelivering immune-stimulating adjuvants. The glycopolymeric nanoparticles (glycoNPs) are composed of a dual-stimuli-responsive block glycopolymer, poly[2-(diisopropylamino)ethyl methacrylate]-b-poly[(pyridyl disulfide ethyl methacrylate)-co-(methacrylamidoglucopyranose)] (p[DPA-b-(PDSMA-co-MAG)]). This polymer facilitates protein conjugation and cytosolic release, the pH-responsive release of lipophilic adjuvants, and pH-dependent membrane disruption to ensure cytosolic delivery of antigens. We synthesized p[DPA-b-(PDSMA-co-MAG)] by reversible addition-fragmentation chain transfer (RAFT) polymerization, followed by the formation and physicochemical characterization of glycoNPs using the p[DPA-b-(PDSMA-co-MAG)] building blocks. These glycoNPs conjugated the model antigen ovalbumin (OVA) and released OVA in response to elevated glutathione levels. Moreover, the glycoNPs displayed pH-dependent drug release of the model hydrophobic drug Nile Red while also exhibiting pH-responsive endosomolytic behavior as indicated by a red blood cell hemolysis assay. GlycoNPs coloaded with OVA and the toll-like receptor 7/8 (TLR-7/8) agonist Resiquimod (R848) activated DC 2.4 dendritic cells (DCs) significantly more than free OVA and R848 and led to robust antigen presentation of the OVA epitope SIINFEKL on major histocompatibility complex I (MHC-I). In sum, the dual-stimuli-responsive glycopolymer introduced here overcomes major protein and peptide delivery barriers and could vastly improve the immunogenicity of protein-based vaccines.

Factors associated with transactional sex among a cohort of gay, bisexual, and other men who have sex with men in Vancouver, Canada.

Background Gay, bisexual, and other men who have sex with men (GBM) who engage in transactional sex (sex in exchange for drugs, money, or goods) experience increased risk of sexually transmitted infections (STI), including HIV. This study explored additional psychosocial and health-related factors associated with transactional sex among GBM. Methods Respondent-driven sampling was used to recruit GBM in Vancouver, Canada, from 2012 to 2015, with follow up every 6months until July2019. We examined factors associated with transactional sex using multivariable three-level mixed-effects modelling. Results Among 698 GBM, 22.1% reported ever receiving drugs, money, or goods for sex. Transactional sex was more likely to be reported by GBM who were younger (<30years) and who had lower incomes, less education, and insecure housing. GBM reporting transactional sex were more likely to report substance use (i.e. crystal methamphetamine, poppers, GHB, and non-steroid injection drugs) and higher risk sexual behaviours (i.e. more sex partners, sex party attendance, and condomless anal sex with serodifferent or unknown HIV status partners); however, they were no more likely to be living with HIV or to report a recent bacterial STI diagnosis. GBM who reported higher loneliness, anxiety, and cognitive escape were also more likely to report transactional sex. Conclusions More than one-fifth of GBM in Vancouver reported transactional sex and those who did were more likely to also experience psychosocial stressors, increased substance use, and higher risk sexual behaviours. Programs which consider the interconnections of personal, social, and structural challenges faced by GBM engaging in transactional sex are necessary to support improved mental, physical, and sexual health for these men.

Making the Most of your Electrons: Challenges and Opportunities in Characterizing Hybrid Interfaces with STEM.

Inspired by the unique architectures composed of hard and soft materials in natural and biological systems, synthetic hybrid structures and associated soft-hard interfaces have recently evoked significant interest. Soft matter is typically dominated by fluctuations even at room temperature, while hard matter (which often serves as the substrate or anchor for the soft component) is governed by rigid mechanical behavior. This dichotomy offers considerable opportunities to leverage the disparate properties offered by these components across a wide spectrum spanning from basic science to engineering insights with significant technological overtones. Such hybrid structures, which include polymer nanocomposites, DNA functionalized nanoparticle superlattices and metal organic frameworks to name a few, have delivered promising insights into the areas of catalysis, environmental remediation, optoelectronics, medicine, and beyond. The interfacial structure between these hard and soft phases exists across a variety of length scales and often strongly influence the functionality of hybrid systems. While scanning/transmission electron microscopy (S/TEM) has proven to be a valuable tool for acquiring intricate molecular and nanoscale details of these interfaces, the unusual nature of hybrid composites presents a suite of challenges that make assessing or establishing the classical structure-property relationships especially difficult. These include challenges associated with preparing electron-transparent samples and obtaining sufficient contrast to resolve the interface between dissimilar materials given the dose sensitivity of soft materials. We discuss each of these challenges and supplement a review of recent developments in the field with additional experimental investigations and simulations to present solutions for attaining a nano or atomic-level understanding of these interfaces. These solutions present a host of opportunities for investigating and understanding the role interfaces play in this unique class of functional materials.

Acetaminophen Interactions with Phospholipid Vesicles Induced Changes in Morphology and Lipid Dynamics.

Acetaminophen (APAP) or paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used 1,2-di-(octadecenoyl)-sn-glycero-3-phosphocholine (DOPC), a commonly found phospholipid in mammalian cell membranes, to synthesize large unilamellar vesicles to investigate how the incorporation of APAP changes the pure lipid vesicle structure, morphology, and fluidity at different concentrations. We used a combination of dynamic light scattering, small-angle neutron and X-ray scattering (SANS, SAXS), and cryo-TEM for structural characterization, and neutron spin-echo (NSE) spectroscopy to investigate the dynamics. We showed that the incorporation of APAP in the lipid bilayer significantly impacts the spherical phospholipid self-assembly in terms of its morphology and influences the lipid content in the bilayer, causing a decrease in bending rigidity. We observe a decrease in the number of lipids per vesicle by almost 28% (0.06 wt % APAP) and 19% (0.12 wt % APAP) compared to the pure DOPC (0 wt % APAP). Our results showed that the incorporation of APAP reduces the membrane rigidity by almost 50% and changes the spherical unilamellar vesicles into much more irregularly shaped vesicles. Although the bilayer structure did not show much change when observed by SAXS, NSE and cryo-TEM results showed the lipid dynamics change with the addition of APAP in the bilayer, which causes the overall decreased membrane rigidity. A strong effect on the lipid tail motion showed that the space explored by the lipid tails increases by a factor of 1.45 (for 0.06 wt % APAP) and 1.75 (for 0.12 wt % APAP) compared to DOPC without the drug.

Undetectable or Unknown? A Longitudinal Event-Level Analysis of Disclosure of HIV Serostatus and Undetectability Among Gay, Bisexual, and Other Men Who have Sex with Men (gbMSM) in Metro Vancouver.

We examined temporal trends and factors associated with reporting partner's serostatus and viral load among a sample of gay, bisexual and other men who have sex with men (gbMSM) in Vancouver, Canada. Participants were recruited using respondent-driven sampling and we collected prospective cohort data from 09/2014 to 02/2017 using a computer-assisted questionnaire and nurse-administered STI/HIV testing. Our study included 481 participants reporting on 3780 sexual events. Among HIV-negative/unknown gbMSM we found a trend towards decreased proportions of sexual events reporting an unknown HIV-status partner (42-19%; p = < 0.001) and found increased proportions among gbMSM living with HIV (11-27%; p = 0.043). More participants living with HIV reported sex with undetectable partners, compared to HIV-negative/unknown participants (14.8% versus 5%). Our multivariable model found that compared with unknown status partners, undetectable partners were older, were from longer sexual relationships and were more likely to engage in condomless anal sex. Findings indicate that HIV-negative gbMSM seem more aware of the serostatus of their partners over time, but knowledge of partners' viral load over time was not significant. Further research should assess the degree to which new campaigns such as Undetectable = Untransmittable (U = U) are associated with discussions about HIV disclosure and viral load status.

Variations in Sexual Behaviors by Use of Specific Substances Among Vancouver Gay, Bisexual, and Other Men Who Have Sex with Men: An Event-Level Analysis.

Event-level studies measure substance use and sexual behaviors happening during a specific sexual encounter, ensuring that both variables are temporally paired. This study explored the event-level associations between a range of sexual behaviors (masturbation, anal sex, oral sex, rimming, fisting, sex toys, and group sex) and five sexualized substances (poppers, methamphetamine, GHB, ecstasy/MDMA, and ketamine) used during 11,582 sexual events reported by 762 gay, bisexual, and other men who have sex with men (GBMSM) in Vancouver, Canada. Data were obtained from a prospective cohort of GBMSM who self-reported their behaviors via computer-based questionnaires on their last sexual encounter with up to five of their most recent partners in the past six months. These clustered data were analyzed with multivariable generalized linear mixed models. Participants reported popper use in 16.1% of sexual encounters, methamphetamine in 8.6%, gamma-hydroxybutyrate (GHB) in 4.1%, ecstasy/3,4-methylenedioxymethamphetamine (MDMA) in 3.3%, and ketamine in 1.5%. Condomless receptive anal sex (25.0% of events) was associated with increased odds of using poppers, methamphetamine, GHB, and ecstasy/MDMA. Group sex (13.1% of events) and sharing sex toys (2.0% of events) were more likely with the use of all five substances. Receiving money/drugs/goods in exchange for sex (2.5% of events) was associated with increased odds of poppers, methamphetamine, GHB, and ecstasy/MDMA use. GBMSM living with HIV (29.9% of participants) had higher odds of using poppers, methamphetamine, and GHB, but lower odds of using ecstasy/MDMA. In conclusion, these event-level results suggest public health strategies are needed to address the possible negative impacts of sexualized substance use among GBMSM.

Longitudinal Analysis of HIV Risk and Substance Use Patterns for Men Who Have Sex with Men and Women and Men Who Have Sex with Men Only.

Men Who Have Sex with Men and Women (MSMW) experience discrimination from same-sex and heterosexual communities partially because of perceptions they feature high-risk sexual behavior, elevated polysubstance use levels, and constitute an HIV bridge population. We used a longitudinal multivariate generalized linear mixed model comparing sexual risk and substance use patterns for Men Who Have Sex with Men Only (MSMO) with MSMW in the same cohort study. Data consisted of 771 men reporting 3,705 sexual partnerships from 2012-2017. For high-risk sexual behavior multivariate results showed non-significant (p>0.05) differences for partner number and commercial sex work, and significantly less (p<0.05) HIV prevalence and condomless anal sex. However, MSMW had significantly higher levels of hallucinogen and prescription opioid use, and substance treatment histories. Only one HIV-positive MSMW had a transmittable viral load, negating the concept of an HIV bridge population. Results indicate the need for additional longitudinal studies comparing MSMO and MSMW.

Escape expectancies and sexualized substance use among gay, bisexual, and other men who have sex with men.

McKirnan's Cognitive Escape Theory (1996) is often characterized by the hypothesis that drugs are used during sex by gay, bisexual, and other men who have sex with men (gbMSM) to relieve internal cognitive conflict over safe-sex norms and sexual desire. We examined how McKirnan's Cognitive Escape Scale (CES) is related to other widely used constructs relevant to sexualized substance use with hopes of better situating the theory within the evolving landscape of HIV-prevention. Associations between CES and trait anxiety, depression, treatment optimism, sexual altruism, sexual sensation seeking, and self-perceived risk for HIV transmission/acquisition were tested. Mediation analyses tested whether associated psychological measures mediated the effect of CES on the proportion of events in which participants reported co-occurrent substance use and condomless anal sex. Results indicated that CES is associated with higher sexual sensation seeking, treatment optimism, trait anxiety, and perceived likelihood of HIV transmission/acquisition. Mediation analyses suggest that CES is related to but operates independently of treatment optimism, sensation seeking, and trait anxiety. Nevertheless, the intersection of HIV-related worries and substance use expectancies are clearly more nuanced than is widely reported is discussions on cognitive escape.

Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse.

The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs.

Crystal Methamphetamine Use and Initiation among Gay, Bisexual, and Other Men Who Have Sex with Men Living with HIV in a Treatment as Prevention Environment.

BACKGROUND: Risk compensation in an HIV Treatment as Prevention (TasP) environment may increase high-risk sexual and substance use behaviors among people living with HIV. Objective: To examine recent crystal methamphetamine (CM) use/initiation in a longitudinal cohort of gay, bisexual, and other men who have sex with men (GBMSM) living with HIV in Metro Vancouver, Canada. Methods: Eligible participants were GBMSM aged >15 years who reported sex with another man in the past six months. Participants were recruited using respondent-driven sampling and self-completed a computer questionnaire every six months. We used multi-level generalized mixed-effect models to evaluate trends in recent CM use (past six months), multivariable logistic regression to identify covariates of recent CM use, and multivariable survival analysis to identify predictors of CM initiation. Results: Of 207 GBMSM living with HIV at enrollment, 44.3% reported recent CM use; there was a statistically non-significant decrease over the study period (41% in first period to 25% in final period, p = 0.087). HIV treatment optimism was not associated with CM use/initiation. CM use was positively associated with depressive symptomology, sexual escape motivation, transactional sex, number of anal sex partners, condomless anal sex with seroconcordant partners, STIs, and other substance use. Recent CM use was negatively associated with viral load sorting. CM initiation was predicted by escape motivation, transactional sex, and group sex participation. Conclusion: Results suggest that CM use among GBMSM living with HIV is prevalent and increased CM use/initiation is not a consequence of TasP public policy.

Factors Associated with Cessation or Reduction of Methamphetamine Use among Gay, Bisexual, and Other Men Who Have Sex with Men (gbMSM) in Vancouver Canada.

Background: Methamphetamine (MA) use among gay, bisexual, and other men who have sex with men (gbMSM) is a pervasive issue, associated with detrimental health outcomes. We identified factors associated with discontinuation or reduction in MA among a subset of gbMSM reporting frequent (at least weekly) use, with a specific focus on symptoms of anxiety and depression. Methods: We recruited sexually-active gbMSM aged ≥16 years in Vancouver, Canada into a prospective-cohort study using respondent-driven sampling. Participants completed study visits once every six months. We used generalized linear mixed models to identify factors associated with reductions in MA use following a visit where participants previously reported using MA at least weekly. Results: Of 584 cohort participants with at least one follow-up visit, 67 (11.5%) reported frequent MA use at baseline or in follow-up visits. Of these, 46 (68.7%) had at least one subsequent study visit where they transitioned to less frequent (monthly or less) or no MA use. In multivariable models, reduced MA use was less likely for those who spent >50% of social time with other gbMSM (aRR = 0.49, 95%CI:0.28-0.85), gave or received drugs in exchange for sex (aRR = 0.34, 95%CI:0.13-0.87), injected drugs (aRR = 0.35, 95%CI:0.18-0.68), or used gamma-hydroxybutyrate (GHB) (aRR = 0.41, 95%CI:0.21-0.78). Symptoms of anxiety or depression were not associated with reductions in MA use. Conclusions: Social connection and drug-related factors surrounding MA use were associated with reductions, but anxiety and depressive symptomatology were not. Incorporating socialization and polysubstance-related components with MA reduction may help in developing efficacious interventions toward reducing MA use for gbMSM.

Colloidal Crystal "Alloys".

Colloidal crystal engineering with DNA has emerged as a powerful tool for precisely controlling the arrangement of nanoscale building blocks in three-dimensional superlattices, where nanoparticles densely modified with DNA can be viewed as "programmable atom equivalents" (PAEs). Although a wide variety of complementary DNA-modified nanoparticles, differentiated by size, shape, and composition, have been assembled into many "ionic" phases, the predictable formation of "alloy" phases remains elusive. Here, we describe the design of "colloidal crystal alloys" by combining gold PAEs of two different sizes (core diameters ranging from 5 to 40 nm) with complementary DNA-modified 2 nm gold nanoparticles (∼15 DNA strands/particle) that act as electron equivalents (EEs). Electron microscopy and small-angle X-ray scattering (SAXS) experiments reveal the formation of four classes of colloidal alloy equivalents: interstitial, substitutional, phase-separated, and intermetallic alloys. In these colloidal alloy phases, PAEs occupy lattice positions, while EEs stabilize the PAE lattice but do not occupy specific lattice sites. A set of chemical design guidelines emerge from this study, analogous to that of the Hume-Rothery rules, allowing for programmed synthesis of different alloy phases depending on PAE particle size ratio, DNA surface coverage, stoichiometric ratio, and thermal annealing pathways. Furthermore, we study the phase separation process via in situ SAXS experiments as well as ex situ electron microscopy, revealing the critical role of kinetics on the phase behavior in these systems.

HIV Testing Among a Representative Community Sample of Gay, Bisexual, and Other Men Who Have Sex with Men in Vancouver, Canada.

Earlier HIV diagnosis allows for improved treatment outcomes and secondary prevention. It is recommended that all individuals know their HIV status and that those at higher risk test more frequently. Using a representative community sample of gay, bisexual, and other men who have sex with men (GBMSM), we aimed to: (1) determine the proportion of GBMSM who have tested in the past 2 years, (2) determine reasons for testing and never having tested, and (3) explore correlates of testing. Of 535 eligible participants, 80.0% reported having had an HIV test in the past 2 years, most commonly as part of a regular testing schedule. The most common reason for not testing was low perceived HIV risk. Bisexual and older GBMSM, as well as those who lived outside of Vancouver, were less likely to have tested in the past 2 years. Rapid point-of-care testing may help improve testing rates and was shown to effectively engage some hard-to-reach GBMSM (e.g., those who had not tested for other STIs) in this sample.