Deaths involving synthetic opioids other than methadone (synthetic opioids), which largely consist of illicitly manufactured fentanyl; psychostimulants with abuse potential (e.g., methamphetamine); ...and cocaine have increased in recent years, particularly since 2013 (1,2). In 2019, a total of 70,630 drug overdose deaths occurred, corresponding to an age-adjusted rate of 21.6 per 100,000 population and a 4.3% increase from the 2018 rate (20.7) (3). CDC analyzed trends in age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, heroin, and prescription opioids during 2013-2019, as well as geographic patterns in synthetic opioid- and psychostimulant-involved deaths during 2018-2019. From 2013 to 2019, the synthetic opioid-involved death rate increased 1,040%, from 1.0 to 11.4 per 100,000 age-adjusted (3,105 to 36,359). The psychostimulant-involved death rate increased 317%, from 1.2 (3,627) in 2013 to 5.0 (16,167) in 2019. In the presence of synthetic opioid coinvolvement, death rates for prescription opioids, heroin, psychostimulants, and cocaine increased. In the absence of synthetic opioid coinvolvement, death rates increased only for psychostimulants and cocaine. From 2018 to 2019, the largest relative increase in the synthetic opioid-involved death rate occurred in the West (67.9%), and the largest relative increase in the psychostimulant-involved death rate occurred in the Northeast (43.8%); these increases represent important changes in the geographic distribution of drug overdose deaths. Evidence-based prevention and response strategies including substance use disorder treatment and overdose prevention and response efforts focused on polysubstance use must be adapted to address the evolving drug overdose epidemic.
Virtual memory T (T
) cells are antigen-naïve CD8
T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) ...has been proposed as a defining metabolic characteristic of antigen-experienced memory T (T
) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of T
cells and their altered functionality with age, here we investigate T
cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of T
, but not T
, cells and it increases with age in both subsets. The elevated SRC observed in aged mouse T
cells and human CD8
T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of T
, but not T
, cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8
T cells.
T cell survival, differentiation after stimulation, and function are intrinsically linked to distinct cellular metabolic states. The ability of T cells to readily transition between metabolic states ...enables flexibility to meet the changing energy demands defined by distinct effector states or T cell lineages. Immune aging is characterized, in part, by the loss of naïve T cells, accumulation of senescent T cells, severe dysfunction in memory phenotype T cells in particular, and elevated levels of inflammatory cytokines, or ‘inflammaging’. Here, we review our current understanding of the phenotypic and functional changes that occur with aging in T cells, and how they relate to metabolic changes in the steady state and after T cell activation. We discuss the apparent contradictions in the aging T cell phenotype - where enhanced differentiation states and metabolic profiles in the steady state can correspond to a diminished capacity to adapt metabolically and functionally after T cell activation. Finally, we discuss key recent studies that indicate the enormous potential for aged T cell metabolism to induce systemic inflammaging and organism-wide multimorbidity, resulting in premature death.
The anti-viral T cell response is drawn from the naive T cell repertoire. During influenza infection, the CD8+ T cell response to an H-2Db-restricted nucleoprotein epitope (NP366) is characterized by ...preferential expansion of T cells bearing TRBV13+ T cell receptors (TCRs) and avoidance of TRBV17+ T cells, despite the latter dominating the naive precursor repertoire. We found two TRBV17+ TCRs that bound H-2Db-NP366 with a 180° reversed polarity compared to the canonical TCR-pMHC-I docking. The TRBV17 β-chain dominated the interaction and, whereas the complementarity determining region-3 (CDR3) loops exclusively mediated contacts with the MHC-I, peptide specificity was attributable to germline-encoded recognition. Nevertheless, the TRBV17+ TCR exhibited moderate affinity toward H-2Db-NP366 and was capable of signal transduction. Thus, the naive CD8+ T cell pool can comprise TCRs adopting reversed pMHC-I docking modes that limit their involvement in the immune response.
•TCRs found on naive T cells ligate pMHC-I in a 180° reversed orientation•CD8+ T cells expressing “reversed” TCRs contribute minimally to the immune response•Reversed TCR recognition drives limited signal transduction and T cell function•Unconventionally docking TCRs may be prevalent in the naive pool
Gras et al. show that TCRs from the naive repertoire recognize pMHC-I in a reversed orientation in comparison to the consensus TCR-pMHC-I docking. This reversed docking was associated with poor CD8+ T cell responses. Thus, naive T cells may exhibit a range of unconventional TCR-pMHC-I docking modes.
Age-associated decreases in primary CD8+ T cell responses occur, in part, due to direct effects on naive CD8+ T cells to reduce intrinsic functionality, but the precise nature of this defect remains ...undefined. Aging also causes accumulation of antigen-naive but semi-differentiated “virtual memory” (TVM) cells, but their contribution to age-related functional decline is unclear. Here, we show that TVM cells are poorly proliferative in aged mice and humans, despite being highly proliferative in young individuals, while conventional naive T cells (TN cells) retain proliferative capacity in both aged mice and humans. Adoptive transfer experiments in mice illustrated that naive CD8 T cells can acquire a proliferative defect imposed by the aged environment but age-related proliferative dysfunction could not be rescued by a young environment. Molecular analyses demonstrate that aged TVM cells exhibit a profile consistent with senescence, marking an observation of senescence in an antigenically naive T cell population.
Display omitted
•Aged TVM cells exhibit a defect in proliferation with TCR, but not IL-15, signaling•Transfer of aged CD8 T cells to a young environment cannot recover the TVM defect•By contrast, TN cells show a marked retention of proliferative capacity with age•Aged TVM cells exhibit a profile consistent with senescence, not exhaustion
CD8 T cell responses decline with age, but virtual memory T (TVM) cells accumulate. Quinn et al. demonstrate that TVM cells lose the ability to proliferate in response to TCR signals, but not IL-15, with increasing age. Aged TVM cells express transcriptional and phenotypic markers of senescence, rather than exhaustion.
CD8 virtual memory T (TVM) cells are Ag-naive CD8 T cells that have undergone partial differentiation in response to common γ-chain cytokines, particularly IL-15 and IL-4. TVM cells from young ...individuals are highly proliferative in response to TCR and cytokine stimulation but, with age, they lose TCR-mediated proliferative capacity and exhibit hallmarks of senescence. Helminth infection can drive an increase in TVM cells, which is associated with improved pathogen clearance during subsequent infectious challenge in young mice. Given the cytokine-dependent profile of TVM cells and their age-associated dysfunction, we traced proliferative and functional changes in TVM cells, compared with true naive CD8 T cells, after helminth infection of young and aged C57BL/6 mice. We show that IL-15 is essential for the helminth-induced increase in TVM cells, which is driven only by proliferation of existing TVM cells, with negligible contribution from true naive cell differentiation. Additionally, TVM cells showed the greatest proliferation in response to helminth infection and IL-15 compared with other CD8 T cells. Furthermore, TVM cells from aged mice did not undergo expansion after helminth infection due to both TVM cell-intrinsic and -extrinsic changes associated with aging.
There is continued interest in developing novel vaccine strategies that induce establish optimal CD8⁺ cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the ...recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4⁺ T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4⁺ T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8⁺ T cell memory established in the presence or absence of a concurrent CD4⁺ T cell response. We demonstrate that CD4⁺ T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with “unhelped” memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more “exhausted T cell” transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4⁺ T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8⁺ T cells.
The majority of drug overdose deaths in the United States involve opioids, and synthetic opioid-involved overdose death rates are increasing. Naloxone is a key prevention strategy yet estimates of ...its administration are limited.
We analyzed 2019 data from 37 states and the District of Columbia in CDC’s State Unintentional Drug Overdose Reporting System to estimate the percentage of decedents, by sociodemographic subgroup, who experienced a fatal opioid-involved overdose and had no evidence of naloxone administration.
A total of 77.3% of 33,084 opioid-involved overdose deaths had no evidence of naloxone administration. Statistically significant subgroup differences were observed for all sociodemographic groups examined except housing status. The highest percentages of decedents lacking evidence of naloxone administration were those with highest educational attainment (doctorate or professional degree, 87.0%), oldest (55–64 years, 83.4%; ≥65 years, 87.3%) and youngest ages (<15 years, 87.5%), and single marital status (84.5%). The lowest percentages of no evidence of naloxone administration were observed for non-Hispanic American Indian/Alaskan Native persons (66.2%) and those ages 15–24 years (70.8%).
More than three-quarters of opioid-involved overdose deaths had no evidence of naloxone administration, underscoring the need to ensure sufficient naloxone access and capacity for utilization. While fatal overdose data cannot fully characterize sociodemographic disparities in naloxone administration, naloxone education and access efforts can be informed by apparent inequities. Public health partners can assist persons who use drugs (PWUD) by maintaining naloxone supply and amplifying messages about the high risk of using drugs alone among PWUD and their social networks.
Background Active follow-up of chronic hepatitis C notifications to promote linkage to care is a promising strategy to support elimination. Aim This pilot study in Victoria, Australia, explored if ...the Department of Health could follow-up on hepatitis C cases through their diagnosing clinicians, to assess and support linkage to care and complete data missing from the notification. Methods For notifications received between 1 September 2021 and 31 March 2022 of unspecified hepatitis C cases (i.e. acquired > 24 months ago or of unknown duration), contact with diagnosing clinicians was attempted. Data were collected on risk exposures, clinical and demographic characteristics and follow-up care (i.e. HCV RNA test; referral or ascertainment of previous negative testing or treatment history). Reasons for unsuccessful doctor contact and gaps in care provision were investigated. Advice to clinicians on care and resources for clinical support were given on demand. Results Of 513 cases where information was sought, this was able to be obtained for 356 (69.4%). Reasons for unsuccessful contact included incomplete contact details or difficulties getting in touch across three attempts, particularly for hospital diagnoses. Among the 356 cases, 307 (86.2%) had received follow-up care. Patient-management resources were requested by 100 of 286 contacted diagnosing clinicians. Conclusions Most doctors successfully contacted had provided follow-up care. Missing contact information and the time taken to reach clinicians significantly impeded the feasibility of the intervention. Enhancing system automation, such as integration of laboratory results, could improve completeness of notifications and support further linkage to care where needed.
PDF
