Structure of a fully assembled γδ T cell antigen receptor.

T cells in jawed vertebrates comprise two lineages, αß T cells and γδ T cells, defined by the antigen receptors they express-that is, αß and γδ T cell receptors (TCRs), respectively. The two lineages have different immunological roles, requiring that γδ TCRs recognize more structurally diverse ligands1. Nevertheless, the receptors use shared CD3 subunits to initiate signalling. Whereas the structural organization of αß TCRs is understood2,3, the architecture of γδ TCRs is unknown. Here, we used cryogenic electron microscopy to determine the structure of a fully assembled, MR1-reactive, human Vγ8Vδ3 TCR-CD3δγε2ζ2 complex bound by anti-CD3ε antibody Fab fragments4,5. The arrangement of CD3 subunits in γδ and αß TCRs is conserved and, although the transmembrane α-helices of the TCR-γδ and -αß subunits differ markedly in sequence, packing of the eight transmembrane-helix bundles is similar. However, in contrast to the apparently rigid αß TCR2,3,6, the γδ TCR exhibits considerable conformational heterogeneity owing to the ligand-binding TCR-γδ subunits being tethered to the CD3 subunits by their transmembrane regions only. Reducing this conformational heterogeneity by transfer of the Vγ8Vδ3 TCR variable domains to an αß TCR enhanced receptor signalling, suggesting that γδ TCR organization reflects a compromise between efficient signalling and the ability to engage structurally diverse ligands. Our findings reveal the marked structural plasticity of the TCR on evolutionary timescales, and recast it as a highly versatile receptor capable of initiating signalling as either a rigid or flexible structure.

Behavioral and Health Outcome Differences by Heroin or Methamphetamine Preference Among People in Rural US Communities Who Use Both Substances.

Background: The United States' (US) opioid overdose epidemic has evolved into a combined stimulant/opioid epidemic, a pattern driven in part by mitigating opioid overdose risk, variable substance availability, and personal preferences. This study aimed to investigate the association between self-reported substance preference (heroin or methamphetamine) and behavioral/health outcomes among individuals who used both heroin and methamphetamine in the rural US. Methods: The Rural Opioid Initiative is a consortium of 8 research cohorts from 10 states and 65 rural counties that recruited individuals reporting past 30-day injection of any substance or opioid substance use by any route from 1/2018 to 3/2020. Analyses were restricted to participants ⩾18 years, who self-reported either heroin or methamphetamine as their preferred substance and past 30-day use of both heroin and methamphetamine. We examined cross-sectional associations between preferred substance (heroin versus methamphetamine) and behavioral and health outcomes using random effects meta-analysis with adjusted regression models. Results: Among 1239 participants, 61% (n = 752) reported heroin as their preferred substance. Adjusting for age, sex, and race/ethnicity, methamphetamine preference was associated with lower prevalence ratios for current naloxone possession (adjusted prevalence ratio [aPR] = 0.68; 95% Confidence Interval [95% CI] = 0.59-0.78; P-value ⩽ .001), of ever being told they had the hepatitis C virus (HCV; aPR = 0.72; 95% CI: 0.61-0.85; P-value ⩽ .001) and a personal history of overdose (aPR = 0.81; 95% CI = 0.73-0.90; P-value ⩽ .001). Conclusion: In our study analyzing associations between preferred substance and various behavioral and health outcomes amongst people who use both heroin and methamphetamine, a majority of participants preferred heroin. Methamphetamine preference was associated with lower prevalence of naloxone possession, ever being told they had HCV, and prior history of an overdose. This study underscores the need for targeted harm reduction services for people who prefer methamphetamine in rural areas.

Strategies used to reduce harms associated with fentanyl exposure among rural people who use drugs: multi-site qualitative findings from the rural opioid initiative.

AIM: Illicitly manufactured fentanyl and its analogs are the primary drivers of opioid overdose deaths in the United States (U.S.). People who use drugs may be exposed to fentanyl or its analogs intentionally or unintentionally. This study sought to identify strategies used by rural people who use drugs to reduce harms associated with unintentional fentanyl exposure. METHODS: This analysis focused on 349 semi-structured qualitative interviews across 10 states and 58 rural counties in the U.S conducted between 2018 and 2020. Interview guides were collaboratively standardized across sites and included questions about drug use history (including drugs currently used, frequency of use, mode of administration) and questions specific to fentanyl. Deductive coding was used to code all data, then inductive coding of overdose and fentanyl codes was conducted by an interdisciplinary writing team. RESULTS: Participants described being concerned that fentanyl had saturated the drug market, in both stimulant and opioid supplies. Participants utilized strategies including: (1) avoiding drugs that were perceived to contain fentanyl, (2) buying drugs from trusted sources, (3) using fentanyl test strips, 4) using small doses and non-injection routes, (5) using with other people, (6) tasting, smelling, and looking at drugs before use, and (7) carrying and using naloxone. Most people who used drugs used a combination of these strategies as there was an overwhelming fear of fatal overdose. CONCLUSION: People who use drugs living in rural areas of the U.S. are aware that fentanyl is in their drug supply and use several strategies to prevent associated harms, including fatal overdose. Increasing access to harm reduction tools (e.g., fentanyl test strips, naloxone) and services (e.g., community drug checking, syringe services programs, overdose prevention centers) should be prioritized to address the polysubstance-involved overdose crisis. These efforts should target persons who use opioids and other drugs that may contain fentanyl.

Enhanced Solubility and Polarization of 13C-Fumarate with Meglumine Allows for In Vivo Detection of Gluconeogenic Metabolism in Kidneys.

Hyperpolarized 13C-labeled fumarate probes tissue necrosis via the production of 13C-malate. Despite its promises in detecting tumor necrosis and kidney injuries, its clinical translation has been limited, primarily due to the low solubility in conventional glassing solvents. In this study, we introduce a new formulation of fumarate for dissolution dynamic nuclear polarization (DNP) by using meglumine as a counterion, a nonmetabolizable derivative of sorbitol. We have found that meglumine fumarate vitrifies by itself with enhanced water solubility (4.8 M), which is expected to overcome the solubility-restricted maximum concentration of hyperpolarized fumarate after dissolution. The achievable liquid-state polarization level of meglumine-fumarate is more than doubled (29.4 ± 1.3%) as compared to conventional dimethyl sulfoxide (DMSO)-mixed fumarate (13.5 ± 2.4%). In vivo comparison of DMSO- and meglumine-prepared 50-mM hyperpolarized [1,4-13C2]fumarate shows that the signal sensitivity in rat kidneys increases by 10-fold. As a result, [1,4-13C2]aspartate and [13C]bicarbonate in addition to [1,4-13C2]malate can be detected in healthy rat kidneys in vivo using hyperpolarized meglumine [1,4-13C2]fumarate. In particular, the appearance of [13C]bicarbonate indicates that hyperpolarized meglumine [1,4-13C2]fumarate can be used to investigate phosphoenolpyruvate carboxykinase, a key regulatory enzyme in gluconeogenesis.

The molecular basis underlying T cell specificity towards citrullinated epitopes presented by HLA-DR4.

CD4+ T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit59-71 and α-enolase-15cit10-22 remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen ß-74cit69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6+ and human TRAV26-1+ TCR-HLA-DR4 complexes presenting vimentin-64cit59-71 and α-enolase-15cit10-22, respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes.

Accessibility of Naloxone in Pharmacies Registered Under the Illinois Standing Order.

Introduction: To expand access to naloxone, the state of Illinois implemented a standing order allowing registered pharmacies to dispense the drug without an individual prescription. To participate under the standing order, pharmacies were required to opt in through a formal registration process. In our study we aimed to evaluate the availability and price of naloxone at registered pharmacies. Methods: This was a prospective, de-identified, cross-sectional telephone survey. Trained interviewers posed as potential customers and used a standardized script to determine the availability of naloxone between February-December, 2019. The primary outcome was defined as a pharmacy indicating it carried naloxone, currently had naloxone in stock, and was able to dispense it without an individual prescription. Results: Of 948 registered pharmacies, 886 (93.5%) were successfully contacted. Of those, 792 (83.4%) carried naloxone, 659 (74.4%) had naloxone in stock, and 472 (53.3%) allowed purchase without a prescription. Naloxone nasal spray (86.4%) was the formulation most commonly stocked. Chain pharmacies were more likely to carry naloxone (adjusted odds ratio [aOR] 3.16, 95% confidence interval [CI] 1.97-5.01, P < 0.01) and have naloxone in stock (aOR 2.72, 95% CI 1.76-4.20, P < 0.01), but no more likely to dispense it without a prescription. Pharmacies in higher population areas (aOR 0.99, 95% CI 0.99-0.99, P < 0.05) and rural areas adjacent to metropolitan areas (aOR 0.5, 95% CI 025-0.98, P < 0.05) were less likely to have naloxone available without a prescription. Associations of naloxone availability based on other urbanicity designations, overdose count, and overdose rate were not significant. Conclusion: Among pharmacies in Illinois that formally registered to dispense naloxone without a prescription, the availability of naloxone remains limited. Additional interventions may be needed to maximize the potential impact of a statewide standing order.

Severity predictors for multisystemic inflammatory syndrome in children after SARS-CoV-2 infection in Vietnam.

Multisystemic inflammatory syndrome in children (MIS-C) might manifest in a broad spectrum of clinical scenarios, ranging from mild features to multi-organ dysfunction and mortality. However, this novel entity has a heterogenicity of data regarding prognostic factors associated with severe outcomes. The present study aimed to identify independent predictors for severity by using multivariate regression models. A total of 391 patients (255 boys and 136 girls) were admitted to Vietnam National Children's Hospital from January 2022 to June 2023. The median age was 85 (range: 2-188) months, and only 12 (3.1%) patients had comorbidities. 161 (41.2%) patients required PICU admission, and the median PICU LOS was 4 (2-7) days. We observed independent factors related to PICU admission, including CRP ≥ 50 (mg/L) (OR 2.52, 95% CI 1.39-4.56, p = 0.002), albumin ≤ 30 (g/L) (OR 3.18, 95% CI 1.63-6.02, p = 0.001), absolute lymphocyte count ≤ 2 (× 109/L) (OR 2.18, 95% CI 1.29-3.71, p = 0.004), ferritin ≥ 300 (ng/mL) (OR 2.35, 95% CI 1.38-4.01), p = 0.002), and LVEF < 60 (%) (OR 2.48, 95% CI 1.28-4.78, p = 0.007). Shock developed in 140 (35.8%) patients, especially for those decreased absolute lymphocyte ≤ 2 (× 109/L) (OR 2.48, 95% CI 1.10-5.61, p = 0.029), albumin ≤ 30 (g/L) (OR 2.53, 95% CI 1.22-5.24, p = 0.013), or LVEF < 60 (%) (OR 2.24, 95% CI 1.12-4.51, p = 0.022). In conclusion, our study emphasized that absolute lymphocyte count, serum albumin, CRP, and LVEF were independent predictors for MIS-C severity. Further well-designed investigations are required to validate their efficacy in predicting MIS-C severe cases, especially compared to other parameters. As MIS-C is a new entity and severe courses may progress aggressively, identifying high-risk patients optimizes clinicians' follow-up and management to improve disease outcomes.

A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8.

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4+ T cell clones not only respond to proinsulin C-peptide (PI40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI40-47-IAPP74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognize self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4+ T cell clones reactive to native PI40-54 epitope and multiple HIPs fused at the same N-terminus (PI40-54) to the degradation products of two highly expressed pancreatic islet proteins, neuropeptide Y (NPY68-74) and amyloid polypeptide (IAPP23-29 and IAPP74-80). We observed that five out of the seven selected SKW3 T cell lines expressing TCRs isolated from CD4+ T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI40-54 and HIP epitopes. Crystal structures of two TRAV26-1+-TRBV5-1+ T cell receptors (TCRs) in complex with PI40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI40-54 and HIPs determined that the P2, P7, and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8.

Hyperpolarized [2-13C, 3-2H3]Pyruvate Detects Hepatic Gluconeogenesis In Vivo.

The feasibility of hyperpolarized [2-13C, 3-2H3]pyruvate for probing gluconeogenesis in vivo was investigated in this study. Whereas hyperpolarized [1-13C]pyruvate has clear access to metabolic pathways that convert pyruvate to lactate, alanine, and bicarbonate, its utility for assessing pyruvate carboxylation and gluconeogenesis has been limited by technical challenges, including spectral overlap and an obscure enzymatic step that decarboxylates the labeled carbon. To achieve unambiguous detection of gluconeogenic products, the carbonyl carbon in pyruvate was labeled with 13C. To prolong the T1 relaxation time, [2-13C, 3-2H3]pyruvate was synthesized and dissolved with D2O after dynamic nuclear polarization. The T1 of [2-13C, 3-2H3]pyruvate in D2O could be improved by 76.9% (79.6 s at 1 T and 74.5 s at 3 T) as compared to [2-13C]pyruvate in water. Hyperpolarized [2-13C, 3-2H3]pyruvate with D2O dissolution was applied to rat livers in vivo under normal feeding and fasting conditions. A gluconeogenic product, [2-13C]phosphoenolpyruvate, was observed at 149.9 ppm from fasted rats only, highlighting the utility of [2-13C, 3-2H3]pyruvate in detecting key gluconeogenic enzyme activities such as pyruvate carboxylase and phosphoenolpyruvate carboxykinase in vivo.

Pembrolizumab-induced Stevens-Johnson syndrome/Toxic Epidermal Necrolysis in a Vietnamese patient with nonsmall-cell lung cancer.

Chemoimmunotherapy is an effective therapy for an individual with nonsmall-cell lung cancer (NSCLC) without anaplastic lymphoma kinase or epidermal growth factor receptor mutations. However, it can also be related to adverse cutaneous reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with high morbidities and mortality rates. We present a case of a 65-year-old male with NSCLC who underwent first-line chemotherapy with paclitaxel, carboplatin, and pembrolizumab, which was later followed by a second cycle of the same therapies. The patient developed a fever and rash 12 days after the second cycle. Pembrolizumab was strongly suspected as the culprit medication because cutaneous reactions to this drug have been frequently reported and threw other medications used as less likely candidates. This is the first case reported in Vietnam of SJS/TEN related to pembrolizumab and contributes to our knowledge of severe skin reactions associated with immune checkpoint inhibitors.

Barriers to Healthcare and Social Service Utilization Among Rural Older Adults Who Use Drugs.

The objective of this study was to understand barriers to healthcare and social service utilization among older adults residing in rural areas who use drugs. A cross-sectional survey of persons who use opioids or inject drugs in rural counties with high overdose rates across ten states was conducted. For this analysis, participants were restricted to only the 375 individuals aged 50 and older. They were asked about barriers to utilizing healthcare and social services. Multivariate analyses were conducted. The most common barriers were a lack of transportation and a fear of stigma. The average number of barriers was 2.53. Those who were either uninsured or homeless endorsed 37% more barriers. For every five-year increase in age, the number of barriers reduced by 15%. Efforts to reduce these barriers may include expanding eligibility for transportation and housing services and leveraging trusted community members to broker linkages to providers to overcome stigma.

Corrigendum to "Stigma towards persons who use methamphetamine: Results from a nationally representative survey of U.S. Adults" [Pre. Med. Rep. 36 (2023) 102496].

[This corrects the article DOI: 10.1016/j.pmedr.2023.102496.].

How do people who use opioids express their qualities and capacities? An assessment of attitudes, behaviors, and opportunities.

People who nonmedically use drugs (PWUD) face intricate social issues that suppress self-actualization, communal integration, and overall health and wellness. "Strengths-based" approaches, an under-used pedagogy and practice in addiction medicine, underscore the significance of identifying and recognizing the inherent and acquired skills, attributes, and capacities of PWUD. A strengths-based approach engenders client affirmation and improves their capacity to reduce drug use-related harms by leveraging existing capabilities. Exploring this paradigm, we conducted and analyzed interviews with 46 PWUD who were clients at syringe services programs in New York City and rural southern Illinois, two areas with elevated rates of opioid-related morbidity and mortality, to assess respondents' perceived strengths. We located two primary thematic modalities in which strengths-based ethos is expressed: individuals (1) being and advocate and resource for harm reduction knowledge and practices and (2) engaging in acts of continuous self-actualization. These dynamics demonstrate PWUD strengths populating and manifesting in complex ways that both affirm and challenge humanist and biomedical notions of individual agency, as PWUD refract enacted, anticipated, and perceived stigmas. In conclusion, programs that blend evidence-based, systems-level interventions on drug use stigma and disenfranchisement with meso and micro-level strengths-based interventions that affirm and leverage personal identity, decision-making capacity, and endemic knowledge may help disrupt health promotion cleavages among PWUD.

Opioid use, prescribing and fatal overdose patterns among racial/ethnic minorities in the United States: A scoping review and conceptual risk environment model.

ISSUES: To date, there has been no synthesis of research addressing the scale and nuances of the opioid epidemic in racial/ethnic minority populations in the United States that considers the independent and joint impacts of dynamics such as structural disadvantage, provider bias, health literacy, cultural norms and various other risk factors. APPROACH: Using the "risk environment" framework, we conducted a scoping review on PubMed, Embase and Google Scholar of peer-reviewed literature and governmental reports published between January 2000 and February 2024 on the nature and scale of opioid use, opioid prescribing patterns, and fatal overdoses among racial/ethnic minorities in the United States, while also examining macro, meso and individual-level risk factors. KEY FINDINGS: Results from this review illuminate a growing, but fragmented, literature lacking standardisation in racial/ethnic classification and case reporting, specifically in regards to Indigenous and Asian subpopulations. This literature broadly illustrates racial/ethnic minorities' increasing nonmedical use of opioids, heightened burdens of fatal overdoses, specifically in relation to polydrug use and synthetic opioids, with notable elevations among Black/Latino subgroups, in addition uneven opioid prescribing patterns. Moreover, the literature implicates a variety of unique risk environments corresponding to dynamics such as residential segregation, provider bias, overpolicing, acculturative stress, patient distrust, and limited access to mental health care services and drug treatment resources, including medications for opioid use disorder. IMPLICATIONS: There has been a lack of rigorous, targeted study on racial/ethnic minorities who use opioids, but evidence highlights burgeoning increases in usage, especially polydrug/synthetic opioid use, and disparities in prescriptions and fatal overdose risk-phenomena tied to multi-level forms of entrenched disenfranchisement. CONCLUSION: There is a need for further research on the complex, overlapping risk environments of racial/ethnic minorities who use opioids, including deeper inclusion of Indigenous and Asian individuals, and efforts to generate greater methodological synergies in population classification and reporting guidelines.

Influence of Socioeconomic Status on Functional Outcomes After Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: This review aimed to quantify the impact of socioeconomic status on functional outcomes from stroke and identify the socioeconomic status indicators that exhibit the highest magnitude of association. METHODS AND RESULTS: We performed a systematic literature search across Medline and Embase from inception to May 2022, to identify observational studies (n≥100, and in English). Risk of bias was assessed using the modified Newcastle Ottawa Scale. Random effects meta-analysis was used to pool data. We included 19 studies (157 715 patients, 47.7% women) reporting functional outcomes measured with modified Rankin Scale or Barthel index, with 10 assessed as low risk of bias. Measures of socioeconomic status reported were education (11 studies), income (8), occupation (4), health insurance status (3), and neighborhood socioeconomic deprivation (3). Pooled data suggested that low socioeconomic status was significantly associated with poor functional outcomes, including incomplete education or below high school level versus high school attainment and above (odds ratio [OR], 1.66 [95% CI, 1.40-1.95]), lowest income versus highest income (OR, 1.36 [95% CI, 1.02-1.83]), a manual job/being unemployed versus a nonmanual job/working (OR, 1.62 [95% CI, 1.29-2.02]), and living in the most disadvantaged socioeconomic neighborhood versus the least disadvantaged (OR, 1.55 [95% CI, 1.25-1.92]). Low health insurance status was also associated with an increased risk of poor functional outcomes (OR, 1.32 [95% CI, 0.95-1.84]), although this was association was not statistically significant. CONCLUSIONS: Despite great strides in stroke treatment in the past decades, social disadvantage remains a risk factor for poor functional outcome after an acute stroke. Further research is needed to better understand causal mechanisms and disparities.

Evaluation of respondent-driven sampling in seven studies of people who use drugs from rural populations: findings from the Rural Opioid Initiative.

BACKGROUND: Accurate prevalence estimates of drug use and its harms are important to characterize burden and develop interventions to reduce negative health outcomes and disparities. Lack of a sampling frame for marginalized/stigmatized populations, including persons who use drugs (PWUD) in rural settings, makes this challenging. Respondent-driven sampling (RDS) is frequently used to recruit PWUD. However, the validity of RDS-generated population-level prevalence estimates relies on assumptions that should be evaluated. METHODS: RDS was used to recruit PWUD across seven Rural Opioid Initiative studies between 2018-2020. To evaluate RDS assumptions, we computed recruitment homophily and design effects, generated convergence and bottleneck plots, and tested for recruitment and degree differences. We compared sample proportions with three RDS-adjusted estimators (two variations of RDS-I and RDS-II) for five variables of interest (past 30-day use of heroin, fentanyl, and methamphetamine; past 6-month homelessness; and being positive for hepatitis C virus (HCV) antibody) using linear regression with robust confidence intervals. We compared regression estimates for the associations between HCV positive antibody status and (a) heroin use, (b) fentanyl use, and (c) age using RDS-1 and RDS-II probability weights and no weights using logistic and modified Poisson regression and random-effects meta-analyses. RESULTS: Among 2,842 PWUD, median age was 34 years and 43% were female. Most participants (54%) reported opioids as their drug of choice, however regional differences were present (e.g., methamphetamine range: 4-52%). Many recruitment chains were not long enough to achieve sample equilibrium. Recruitment homophily was present for some variables. Differences with respect to recruitment and degree varied across studies. Prevalence estimates varied only slightly with different RDS weighting approaches, most confidence intervals overlapped. Variations in measures of association varied little based on weighting approach. CONCLUSIONS: RDS was a useful recruitment tool for PWUD in rural settings. However, several violations of key RDS assumptions were observed which slightly impacts estimation of proportion although not associations.

Conveying the pathogenesis of type 1 diabetes to the blind, low-vision and diverse needs communities through sensory stimulation.

To educate members of the blind, low-vision and diverse needs communities on the pathogenesis of the chronic autoimmune disease, type 1 diabetes, members of our team with research expertise in immune-mediated diseases, participated in the 2023 Monash Sensory Science (MSS) Exhibition. Using QR code linked audio commentary, participants were guided through tactile displays demonstrating normal insulin action in the regulation of blood glucose levels and its vital role in providing energy to tissues, followed by displays describing the various stages of the immune system's aberrant attack and the eventual complete destruction of the insulin producing beta-cells of the pancreatic islets in type 1 diabetes. These models conveyed to the participants the huge effect that this autoimmune-mediated disease has on the quality of life of affected individuals including the subsequent lifelong reliance on insulin injections to maintain glucose homeostasis. This MSS Exhibition provided a unique opportunity for our researchers to engage with under-represented members of the community and to raise awareness about such a debilitating and common autoimmune disease.

Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases.

Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.

The Million Veteran Program 1990-1991 Gulf War Era Survey: An Evaluation of Veteran Response, Characteristics, and Representativeness of the Gulf War Era Veteran Population.

To address gaps in understanding the pathophysiology of Gulf War Illness (GWI), the VA Million Veteran Program (MVP) developed and implemented a survey to MVP enrollees who served in the U.S. military during the 1990-1991 Persian Gulf War (GW). Eligible Veterans were invited via mail to complete a survey assessing health conditions as well as GW-specific deployment characteristics and exposures. We evaluated the representativeness of this GW-era cohort relative to the broader population by comparing demographic, military, and health characteristics between respondents and non-respondents, as well as with all GW-era Veterans who have used Veterans Health Administration (VHA) services and the full population of U.S. GW-deployed Veterans. A total of 109,976 MVP GW-era Veterans were invited to participate and 45,270 (41%) returned a completed survey. Respondents were 84% male, 72% White, 8% Hispanic, with a mean age of 61.6 years (SD = 8.5). Respondents were more likely to be older, White, married, better educated, slightly healthier, and have higher socioeconomic status than non-respondents, but reported similar medical conditions and comparable health status. Although generally similar to all GW-era Veterans using VHA services and the full population of U.S. GW Veterans, respondents included higher proportions of women and military officers, and were slightly older. In conclusion, sample characteristics of the MVP GW-era cohort can be considered generally representative of the broader GW-era Veteran population. The sample represents the largest research cohort of GW-era Veterans established to date and provides a uniquely valuable resource for conducting in-depth studies to evaluate health conditions affecting 1990-1991 GW-era Veterans.

Rapid, label-free enrichment of lymphocytes in a closed system using a flow-through microfluidic device.

The majority of adoptive cellular therapies are produced from peripheral mononuclear cells obtained via leukapheresis and further enriched for the cells of interest (e.g., T cells). Here, we present a first-of-its-kind closed system, which effectively removes ~85% of monocytes and ~88% of platelets, while recovering ~88% of concentrated T cells in a separate output stream, as the leukapheresis sample flows through a microfluidic device at 5 mL/min. The system is driven by a common peristaltic pump, enabled by a novel pressure wave dampener, and operates in a closed bag-to-bag configuration, without requiring any specialized, dedicated equipment. When compared to standard density gradient centrifugation on paired samples, the new system demonstrated a 1.5-fold increase in T cell recovery and a 2-fold reduction in inter-sample variability for this separation outcome. The T cell-to-monocyte ratio of the leukapheresis sample was increased to 20:1, whereas with density gradient processing it decreased to 2:1. As a result of superior purity and/or gentler processing, T cells enriched by the system showed a 2.7-times higher fold expansion during subsequent culture, and an overall 3.5-times higher cumulative yield. This centrifugation-free and label-free closed system for enriching lymphocytes could significantly simplify and standardize the manufacturing of life-saving cellular therapies.