The Presence of HLA-E-Restricted, CMV-Specific CD8(+) T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection

The human cytomegalovirus (CMV) immune evasion protein, UL40, shares an identical peptide sequence with that found in the leader sequence of many human leukocyte antigen (HLA)-C alleles and when complexed with HLA-E, can modulate NK cell functions via interactions with the CD94-NKG2 receptors. However the UL40-derived sequence can also be immunogenic, eliciting robust CD8+ T cell responses. In the setting of solid organ transplantation these T cells may not only be involved in antiviral immunity but also can potentially contribute to allograft rejection when the UL40 epitope is also present in allograft-encoded HLA. Here we assessed 15 bilateral lung transplant recipients for the presence of HLA-E-restricted UL40 specific T cells by tetramer staining of peripheral blood mononuclear cells (PBMC). UL40-specific T cells were observed in 7 patients post-transplant however the magnitude of the response varied significantly between patients. Moreover, unlike healthy CMV seropositive individuals, longitudinal analyses revealed that proportions of such T cells fluctuated markedly. Nine patients experienced low-grade acute cellular rejection, of which 6 also demonstrated UL40-specific T cells. Furthermore, the presence of UL40-specific CD8+ T cells in the blood was significantly associated with allograft dysfunction, which manifested as Bronchiolitis Obliterans Syndrome (BOS). Therefore, this study suggests that minor histocompatibility antigens presented by HLA-E can represent an additional risk factor following lung transplantation

Influenza, but not SARS-CoV-2, infection induces a rapid interferon response that wanes with age and diminished tissue-resident memory CD8(+) T cells

Older individuals exhibit a diminished ability to respond to and clear respiratory pathogens and, as such, experience a higher rate of lung infections with a higher mortality rate. It is unclear why respiratory pathogens impact older people disproportionately. Using human lung tissue from donors aged 22-68 years, we assessed how the immune cell landscape in lungs changes throughout life and investigated how these immune cells respond following in vitro exposure to influenza virus and SARS-CoV-2, two clinically relevant respiratory viruses. While the frequency of most immune cell subsets profiled in the human lung remained stable with age, memory CD8+ T cells declined, with the tissue-resident memory (Trm) CD8+ T-cell subset being most susceptible to age-associated attrition. Infection of lung tissue with influenza virus resulted in an age-associated attenuation in the antiviral immune response, with aged donors producing less type I interferon (IFN), GM-CSF and IFNγ, the latter correlated with a reduction of IFNγ-producing memory CD8+ T cells. In contrast, irrespective of donor age, exposure of human lung cells to SARS-CoV-2, a pathogen for which all donors were immunologically naïve, did not trigger activation of local immune cells and did not result in the induction of an early IFN response. Our findings show that the attrition of tissue-bound pathogen-specific Trm in the lung that occurs with advanced age, or their absence in immunologically naïve individuals, results in a diminished early antiviral immune response which creates a window of opportunity for respiratory pathogens to gain a greater foothold

Risky sexual behavior and substance use among adolescents: A meta-analysis

This study presents the results of a meta-analysis of the association between substance use and risky sexual behavior among adolescents. 87 studies fit the inclusion criteria, containing a total of 104 independent effect sizes that incorporated more than 120,000 participants. The overall effect size for the relationship between substance use and risky sexual behavior was in the small to moderate range (r = .22, CI = .18, .26). Further analyses indicated that the effect sizes did not substantially vary across the type of substance use, but did substantially vary across the type of risky sexual behavior being assessed. Specifically, mean effect sizes were smallest for studies examining unprotected sex (r = .15, CI = .10, .20), followed by studies examining number of sexual partners (r = .25, CI = .21, .30), those examining composite measures of risky sexual behavior (r = .38, CI = .27, .48), and those examining sex with an intravenous drug user (r = .53, CI = .45, .60). Furthermore, our results revealed that the relationship between drug use and risky sexual behavior is moderated by several variables, including sex, ethnicity, sexuality, age, sample type, and level of measurement. Implications and future directions are discussed

Comparison of diagnoses of early-onset sepsis associated with use of Sepsis Risk Calculator versus NICE CG149: a prospective, population-wide cohort study in London, UK, 2020–2021

Objective We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks’ gestation identified >24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance.Design and setting Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE).Participants All live births ≥34 weeks’ gestation between September 2020 and August 2021.Outcome measures EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age. We evaluated the incidence of EOS identified by culture obtained >24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced >24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures.Results Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (<72 hours) was 0.64/1000 live births. The incidence of EOS identified >24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced >24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals.Conclusion There was no significant difference in the incidence of EOS identified >24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life