Nanoparticle Retinoic Acid-Inducible Gene I Agonist for Cancer Immunotherapy.

Pharmacological activation of the retinoic acid-inducible gene I (RIG-I) pathway holds promise for increasing tumor immunogenicity and improving the response to immune checkpoint inhibitors (ICIs). However, the potency and clinical efficacy of 5'-triphosphate RNA (3pRNA) agonists of RIG-I are hindered by multiple pharmacological barriers, including poor pharmacokinetics, nuclease degradation, and inefficient delivery to the cytosol where RIG-I is localized. Here, we address these challenges through the design and evaluation of ionizable lipid nanoparticles (LNPs) for the delivery of 3p-modified stem-loop RNAs (SLRs). Packaging of SLRs into LNPs (SLR-LNPs) yielded surface charge-neutral nanoparticles with a size of ∼100 nm that activated RIG-I signaling in vitro and in vivo. SLR-LNPs were safely administered to mice via both intratumoral and intravenous routes, resulting in RIG-I activation in the tumor microenvironment (TME) and the inhibition of tumor growth in mouse models of poorly immunogenic melanoma and breast cancer. Significantly, we found that systemic administration of SLR-LNPs reprogrammed the breast TME to enhance the infiltration of CD8+ and CD4+ T cells with antitumor function, resulting in enhanced response to αPD-1 ICI in an orthotopic EO771 model of triple-negative breast cancer. Therapeutic efficacy was further demonstrated in a metastatic B16.F10 melanoma model, with systemically administered SLR-LNPs significantly reducing lung metastatic burden compared to combined αPD-1 + αCTLA-4 ICI. Collectively, these studies have established SLR-LNPs as a translationally promising immunotherapeutic nanomedicine for potent and selective activation of RIG-I with the potential to enhance response to ICIs and other immunotherapeutic modalities.

A Cancer Nanovaccine for Co-Delivery of Peptide Neoantigens and Optimized Combinations of STING and TLR4 Agonists.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment and led to complete and durable responses, but only for a minority of patients. Resistance to ICB can largely be attributed to insufficient number and/or function of antitumor CD8+ T cells in the tumor microenvironment. Neoantigen targeted cancer vaccines can activate and expand the antitumor T cell repertoire, but historically, clinical responses have been poor because immunity against peptide antigens is typically weak, resulting in insufficient activation of CD8+ cytotoxic T cells. Herein, we describe a nanoparticle vaccine platform that can overcome these barriers in several ways. First, the vaccine can be reproducibly formulated using a scalable confined impingement jet mixing method to coload a variety of physicochemically diverse peptide antigens and multiple vaccine adjuvants into pH-responsive, vesicular nanoparticles that are monodisperse and less than 100 nm in diameter. Using this approach, we encapsulated synergistically acting adjuvants, cGAMP and monophosphoryl lipid A (MPLA), into the nanocarrier to induce a robust and tailored innate immune response that increased peptide antigen immunogenicity. We found that incorporating both adjuvants into the nanovaccine synergistically enhanced expression of dendritic cell costimulatory markers, pro-inflammatory cytokine secretion, and peptide antigen cross-presentation. Additionally, the nanoparticle delivery increased lymph node accumulation and uptake of peptide antigen by dendritic cells in the draining lymph node. Consequently, nanoparticle codelivery of peptide antigen, cGAMP, and MPLA enhanced the antigen-specific CD8+ T cell response and delayed tumor growth in several mouse models. Finally, the nanoparticle platform improved the efficacy of ICB immunotherapy in a murine colon carcinoma model. This work establishes a versatile nanoparticle vaccine platform for codelivery of peptide neoantigens and synergistic adjuvants to enhance responses to cancer vaccines.

Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing.

The clinical translation of many biomolecular therapeutics has been hindered by undesirable pharmacokinetic (PK) properties, inadequate membrane permeability, poor endosomal escape and cytosolic delivery, and/or susceptibility to degradation. Overcoming these challenges merits the development of nanoscale drug carriers (nanocarriers) to improve the delivery of therapeutic cargo. Herein, we implement a flash nanoprecipitation (FNP) approach to produce nanocarriers of diverse vesicular morphologies by using various molecular weight PEG-bl-DEAEMA-co-BMA (PEG-DB) polymers. We demonstrated that FNP can produce uniform (PDI < 0.1) particles after 5 impingements, and that by varying the copolymer hydrophilic mass fraction, FNP enables access to a diverse variety of nanoarchitectures including micelles, unilamellar vesicles (polymersomes), and multi-compartment vesicles (MCVs). We synthesized a library of 2 kDa PEG block copolymers, with DEAEMA-co-BMA second block molecular weights of 3, 6, 12, 15, 20, and 30 kDa. All formulations were both pH responsive, endosomolytic, and capable of loading and cytosolically delivering small negatively charged molecules - albeit to different degrees. Using a B16.F10 melanoma model, we showcased the therapeutic potential of a lead FNP formulated PEG-DB nanocarrier, encapsulating the cyclic dinucleotide (CDN) cGAMP to activate the stimulator of interferon genes (STING) pathway in a therapeutically relevant context. Collectively, these data demonstrate that an FNP process can be used to formulate pH-responsive nanocarriers of diverse morphologies using a PEG-DB polymer system. As FNP is an industrially scalable process, these data address the critical translational challenge of producing PEG-DB nanoparticles at scale. Furthermore, the diverse morphologies produced may specialize in the delivery of distinct biomolecular cargos for other therapeutic applications, implicating the therapeutic potential of this platform in an array of disease applications.

Kinetic Growth of Multicomponent Microcompartment Shells.

An important goal of systems and synthetic biology is to produce high value chemical species in large quantities. Microcompartments, which are protein nanoshells encapsulating catalytic enzyme cargo, could potentially function as tunable nanobioreactors inside and outside cells to generate these high value species. Modifying the morphology of microcompartments through genetic engineering of shell proteins is one viable strategy to tune cofactor and metabolite access to encapsulated enzymes. However, this is a difficult task without understanding how changing interactions between the many different types of shell proteins and enzymes affect microcompartment assembly and shape. Here, we use multiscale molecular dynamics and experimental data to describe assembly pathways available to microcompartments composed of multiple types of shell proteins with varied interactions. As the average interaction between the enzyme cargo and the multiple types of shell proteins is weakened, the shell assembly pathway transitions from (i) nucleating on the enzyme cargo to (ii) nucleating in the bulk and then binding the cargo as it grows to (iii) an empty shell. Atomistic simulations and experiments using the 1,2-propanediol utilization microcompartment system demonstrate that shell protein interactions are highly varied and consistent with our multicomponent, coarse-grained model. Furthermore, our results suggest that intrinsic bending angles control the size of these microcompartments. Overall, our simulations and experiments provide guidance to control microcomparmtent size and assembly by modulating the interactions between shell proteins.

Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei.

Topographical cues on cells can, through contact guidance, alter cellular plasticity and accelerate the regeneration of cultured tissue. Here we show how changes in the nuclear and cellular morphologies of human mesenchymal stromal cells induced by micropillar patterns via contact guidance influence the conformation of the cells' chromatin and their osteogenic differentiation in vitro and in vivo. The micropillars impacted nuclear architecture, lamin A/C multimerization and 3D chromatin conformation, and the ensuing transcriptional reprogramming enhanced the cells' responsiveness to osteogenic differentiation factors and decreased their plasticity and off-target differentiation. In mice with critical-size cranial defects, implants with micropillar patterns inducing nuclear constriction altered the cells' chromatin conformation and enhanced bone regeneration without the need for exogenous signalling molecules. Our findings suggest that medical device topographies could be designed to facilitate bone regeneration via chromatin reprogramming.

Psychosocial factors associated with the intention to get a COVID-19 booster vaccine: evidence from a low-income country.

Aim: To identify psychosocial predictors of the intention to get a booster COVID-19 vaccine in a low-income country, given that increasing booster vaccination rates against COVID-19 remains a global challenge, especially among low- and middle-income countries (LMIC). Subject and methods: We used an online survey to collect responses from a non-probabilistic sample of 720 Bolivians regarding vaccine uptake, motives, perceived confidence, information sources, attitudes favouring COVID-19 vaccines, biosafety behaviour, and sociodemographic characteristics. Descriptive, bivariate, and multivariate analyses were performed to identify significant associations and predictors. Results: We found that having already received the third dose, obtaining recommendations from family or friends, recommendation from the government, perceived confidence in the previously received dose, and higher attitudes in favour of COVID-19 vaccines significantly predicted the intention to get a booster dose. The associations were significant even when adjusting the model for sociodemographic variables. Conclusion: Including certain psychosocial factors could enhance the promotion of voluntary booster doses among residents of low- and middle-income countries such as Bolivia, where cultural, social, political, and contextual variables may influence health behaviour and increase health-associated risk factors. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-023-01937-x.

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 association of QTc prolongation with cardiovascular events in cancer patients taking tyrosine kinase inhibitors (TKIs).

OBJECTIVE: To investigate the association between stages of QTc prolongation and the risk of cardiac events among patients on TKIs. METHODS: This was a retrospective cohort study performed at an academic tertiary care center of cancer patients who were taking TKIs or not taking TKIs. Patients with two recorded ECGs between January 1, 2009, and December 31, 2019, were selected from an electronic database. The QTc duration > 450ms was determined as prolonged. The association between QTc prolongation progression and events of cardiovascular disease were compared. RESULTS: This study included a total of 451 patients with 41.2% of patients taking TKIs. During a median follow up period of 3.1 years, 49.5% subjects developed CVD and 5.4% subjects suffered cardiac death in patient using TKIs (n = 186); the corresponding rates are 64.2% and 1.2% for patients not on TKIs (n = 265), respectively. Among patient on TKIs, 4.8% of subjects developed stroke, 20.4% of subjects suffered from heart failure (HF) and 24.2% of subjects had myocardial infarction (MI); corresponding incidence are 6.8%, 26.8% and 30.6% in non-TKIs. When patients were regrouped to TKIs versus non-TKIs with and without diabetes, there was no significant difference in the incidence of cardiac events among all groups. Adjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). There is a significant increased risk of HF events (HR, 95% CI: 2.12, 1.36-3.32) and MI events (HR, 95% CI: 1.78, 1.16-2.73) during the 1st visit. There are also trends for an increased incidence of cardiac adverse events associated with QTc prolongation among patient with QTc > 450ms, however the difference is not statistically significant. Increased cardiac adverse events in patients with QTc prolongation were reproduced during the 2nd visit and the incidence of heart failure was significantly associated with QTc prolongation(HR, 95% CI: 2.94, 1.73-5.0). CONCLUSION: There is a significant increased QTc prolongation in patients taking TKIs. QTc prolongation caused by TKIs is associated with an increased risk of cardiac events.

Magnetically Powered Chitosan Milliwheels for Rapid Translation, Barrier Function Rescue, and Delivery of Therapeutic Proteins to the Inflamed Gut Epithelium.

Inflammatory bowel disease (IBD) is mediated by an overexpression of tumor necrosis factor-α (TNF) by mononuclear cells in the intestinal mucosa. Intravenous delivery of neutralizing anti-TNF antibodies can cause systemic immunosuppression, and up to one-third of people are non-responsive to treatment. Oral delivery of anti-TNF could reduce adverse effects; however, it is hampered by antibody degradation in the harsh gut environment during transit and poor bioavailability. To overcome these shortcomings, we demonstrate magnetically powered hydrogel particles that roll along mucosal surfaces, provide protection from degradation, and sustain the local release of anti-TNF. Iron oxide particles are embedded into a cross-linked chitosan hydrogel and sieved to produce 100-200 µm particles called milliwheels (m-wheels). Once loaded with anti-TNF, these m-wheels release 10 to 80% of their payload over 1 week at a rate that depends on the cross-linking density and pH. A rotating magnetic field induces a torque on the m-wheels that results in rolling velocities greater than 500 µm/s on glass and mucus-secreting cells. The permeability of the TNF-challenged gut epithelial cell monolayers was rescued in the presence of anti-TNF carrying m-wheels, which both neutralized the TNF and created an impermeable patch over leaky cell junctions. With the ability to translate over mucosal surfaces at high speed, provide sustained release directly to the inflamed epithelium, and provide barrier rescue, m-wheels demonstrate a potential strategy to deliver therapeutic proteins for the treatment of IBD.

A soil-inspired dynamically responsive chemical system for microbial modulation.

Interactions between the microbiota and their colonized environments mediate critical pathways from biogeochemical cycles to homeostasis in human health. Here we report a soil-inspired chemical system that consists of nanostructured minerals, starch granules and liquid metals. Fabricated via a bottom-up synthesis, the soil-inspired chemical system can enable chemical redistribution and modulation of microbial communities. We characterize the composite, confirming its structural similarity to the soil, with three-dimensional X-ray fluorescence and ptychographic tomography and electron microscopy imaging. We also demonstrate that post-synthetic modifications formed by laser irradiation led to chemical heterogeneities from the atomic to the macroscopic level. The soil-inspired material possesses chemical, optical and mechanical responsiveness to yield write-erase functions in electrical performance. The composite can also enhance microbial culture/biofilm growth and biofuel production in vitro. Finally, we show that the soil-inspired system enriches gut bacteria diversity, rectifies tetracycline-induced gut microbiome dysbiosis and ameliorates dextran sulfate sodium-induced rodent colitis symptoms within in vivo rodent models.

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.

Magic Mushroom Use: A Qualitative Interview Study of Post-Trip Impacts and Strategies for Optimizing Experiences.

The field of psychedelic research is undergoing a revival, yet research focused on non-clinical psychedelic use remains relatively limited. The current qualitative study sheds light on how people use magic mushrooms, what they perceive the effects of such use to be, and the meanings that users attach to their magic mushroom experiences. To be eligible to participate in the study, participants were required to be young adults who had used magic mushrooms within the past three months and residents of Victoria, Canada. Semi-structured, one-on-one in-person interviews regarding magic mushroom use habits, culture, knowledge and other factors were conducted with each participant and subsequently analyzed thematically. Participants associated magic mushroom use with lasting impacts on their lives including transformation and learning experiences. Additionally, participants described strategies to optimize their magic mushroom experiences, including engaging in research regarding magic mushrooms as well as making use of peer supports. Furthermore, aspects of magic mushroom experiences conceptualized as harmful in previous studies were described by participants as associated with learning experiences and few harms. Participants' perceived positive outcomes and relatively low risk profile warrants further research to inform how magic mushroom users can maximize potential positive outcomes and also minimize harms.

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.

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.

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.

Virological suppression among gay, bisexual, and other men who have sex with men living with HIV in Vancouver, Canada: A longitudinal cohort study from 2012-2017.

INTRODUCTION: In 2010, British Columbia (BC) implemented HIV Treatment as Prevention (TasP) as policy. We examined trends in virologic suppression and determinants of significant viremia among a prospective biobehavioural cohort of men who have sex with men (gbMSM) in Vancouver from 2012-2017. METHODS: Respondent-driven sampling was used to recruit sexually active gbMSM (≥16 years) who completed biannual study visits with a computer-assisted self-interview and clinical CD4 and viral load (VL) testing. We linked participant data with the BC HIV Drug Treatment Program to obtain antiretroviral dispensing and VL data. We conducted a trend analysis of VL suppression using univariable generalized estimating equation (GEE) multi-level modelling and multivariable GEE to identify factors associated with episodes of VL ≥200 copies/mL. RESULTS: Of 774 participants, 223 were living with HIV at baseline and 16 were diagnosed during follow-up (n = 239). We observed a significant trend towards reduced levels of unsuppressed VL (>200 copies/mL) from 22% (07/2012-12/2012) to 12% (07/2016-12/2016) (OR:0.87; 95%CI:0.83-0.91 for each 6-month period). Among those with at least one follow-up visit, (n = 178, median follow-up = 3.2 years, median age = 46.9 years), younger age (aOR:0.97; 95%CI:0.94-0.99, per year), ecstasy use (aOR:1.69; 95%CI:1.13-2.53), crystal methamphetamine use (aOR:1.71; 95%CI:1.18-2.48), seeking sex via websites (aOR:1.46; 95%CI:1.01-2.12), and lower HIV treatment optimism (aOR:0.94; 95%CI:0.90-0.97) were associated with episodes of elevated viremia. CONCLUSIONS: During a period when TasP policy was actively promoted, we observed a significant trend towards reduced levels of unsuppressed VL. Continued efforts should promote HIV treatment optimism and engagement, especially among younger gbMSM and those who use ecstasy and crystal methamphetamine.

ROS-Responsive Glycopolymeric Nanoparticles for Enhanced Drug Delivery to Macrophages.

Macrophages play a diverse, key role in many pathologies, including inflammatory diseases, cardiovascular diseases, and cancer. However, many therapeutic strategies targeting macrophages suffer from systemic off-target toxicity resulting in notoriously narrow therapeutic windows. To address this shortcoming, the development of poly(propylene sulfide)-b-poly(methacrylamidoglucopyranose) [PPS-b-PMAG] diblock copolymer-based nanoparticles (PMAG NPs) capable of targeting macrophages and releasing drug in the presence of reactive oxygen species (ROS) is reported. PMAG NPs have desirable physicochemical properties for systemic drug delivery, including slightly negative surface charge, ≈100 nm diameter, and hemo-compatibility. Additionally, due to the presence of PPS in the NP core, PMAG NPs release drug cargo preferentially in the presence of ROS. Importantly, PMAG NPs display high cytocompatibility and are taken up by macrophages in cell culture at a rate ≈18-fold higher than PEGMA NPs-NPs composed of PPS-b-poly(oligoethylene glycol methacrylate). Computational studies indicate that PMAG NPs likely bind with glucose transporters such as GLUT 1/3 on the macrophage cell surface to facilitate high levels of internalization. Collectively, this study introduces glycopolymeric NPs that are uniquely capable of both receptor-ligand targeting to macrophages and ROS-dependent drug release and that can be useful in many immunotherapeutic settings.

Electrostatic Control of Shape Selection and Nanoscale Structure in Chiral Molecular Assemblies.

How molecular chirality manifests at the nano- to macroscale has been a scientific puzzle since Louis Pasteur discovered biochirality. Chiral molecules assemble into meso-shapes such as twisted and helical ribbons, helicoidal scrolls (cochleates), or möbius strips (closed twisted ribbons). Here we analyze self-assembly for a series of amphiphiles, C n -K, consisting of an ionizable amino acid [lysine (K)] coupled to alkyl tails with n = 12, 14, or 16 carbons. This simple system allows us to probe the effects of electrostatic and van der Waals interactions in chiral assemblies. Small/wide-angle X-ray scattering (SAXS/WAXS) reveals that at low pH, where the headgroups are ionized (+1), C16-K forms high aspect ratio, planar crystalline bilayers. Molecular dynamics (MD) simulations reveal that tilted tails of the bilayer leaflets are interdigitated. SAXS shows that, with increasing salt concentration, C16-K molecules assemble into cochleates, whereas at elevated pH (reduced degree of ionization), helices are observed for all C n -K assemblies. The shape selection between helices and scrolls is explained by a membrane energetics model. The nano- to meso-scale structure of the chiral assemblies can be continuously controlled by solution ionic conditions. Overall, our study represents a step toward an electrostatics-based approach for shape selection and nanoscale structure control in chiral assemblies.