T Cell Responsiveness Through the Ages: Functional Diversity of Age-Dependent Antiviral Responses

An organism’s age impacts its susceptibility to disease, which varies according to the type of insult or causal pathogen. Much work remains to delineate these complexities, especially within younger individuals. Indeed, pediatric disease-driven immunity is less characterized than adult and aging populations due to two main factors: 1) descriptions through multiple stages of development are required, as the immune system undergoes massive changes from gestation through the end of adolescence, and 2) the complex nature of pediatric research decreases the availability of robust and comprehensive studies. Importantly, studying the immune system in relation to age requires a foundational knowledge within adult individuals to adequately assess the unique characteristics of the developing and aged systems. This body of work contributes to the field of age-dependent immunity via the study of repair-associated T cell subsets in pediatric acute respiratory distress syndrome (pARDS), γδ T cells in murine cytomegalovirus (MCMV), and multiple immune mediators and cell populations in adult severe influenza infection. Single-cell RNA sequencing of tracheal aspirate cells from pediatric subjects experiencing acute respiratory failure (ARF) showed that distinct T cell subsets within the lower respiratory tract exhibited transcriptional similarity, termed functional redundancy. This similarity was repair-associated, and a defining gene of the transcriptional profile was amphiregulin (AREG). When quantified, T cells from subjects with a viral lower respiratory tract infection (LRTI) that did not progress to moderate or severe pARDS had significantly elevated repair scores. This was reflected within tissue resident memory (TRM) CD8 T cells, activated regulatory CD4 T cells (Tregs), and activated AREG+ γδ T cells. The repair profile was then applied across publicly available datasets spanning ages, tissue types, etiologies, and severities, and functional redundancy was only observed within the same three subsets of tracheal aspirate T cells from healthy pediatric subjects. Additional validation confirmed that nasal wash supernatant proteins from the repair profile were inversely correlated with age. Collectively, these findings indicated that T cells within the respiratory tract exhibited functional redundancy linked to tissue repair in an age-dependent manner, and that this redundancy was associated with decreased disease severity. Results from mouse models of MCMV infection demonstrated that the functionality of γδ T cells is shaped by infection in an age-specific manner. γδ T cells from neonates infected with MCMV underwent a shift in cytokine production that was absent in acutely infected adult, aged, and geriatric mice. Neonatal infection also affected the γδ T cell receptor (TCR) repertoire by modulating the hierarchy of segment usage. Single-cell RNA sequencing with paired TCR repertoire data from the lungs showed that both age and MCMV infection impacted γδ T cells in a manner determined by age of viral exposure, viral state, and age of the mouse at endpoint characterization. These data highlight age-associated functionality of γδ T cells in MCMV infection, and the role that age of exposure plays in shaping γδ T cell immunity. Lastly, a cohort of oseltamivir-treated adults with severe influenza infection were utilized to address 3 questions: 1) What is the relationship between patient risk and severity scores throughout severe influenza infection? 2) What immunological features underlay severe influenza infection? 3) What immune biomarkers are predictive of infection severity and clinical outcome? First, assessment of the relationship between risk and severity scores showed increased correlation between metrics that incorporated supplemental oxygen usage, as well as those which were less subjective in nature. No correlations were observed for intake risk metrics or subjective severity scoring. Second, a decrease in protection-associated cytokines and innate immune mediators was observed over the course of severe infection across all individuals. Additionally, subjects with heightened severity exhibited decreased upper respiratory and peripheral pro-inflammatory and pleiotropic cytokines at study day 0, decreased T cells spanning naive and memory phenotypes at study days 0, 3, and 28, and decreased peripheral eotaxin at study day 28. Third, peripheral myeloid analytes were positively associated with severity based on intake vitals, while cytotoxic natural killer T (NKT) cells were negatively associated. Multiple circulating and upper respiratory cytokines were predictive of peak infection severity, as was the frequency of circulating eosinophils. For correlative analyses, age was included in all linear regression modeling, since the study included both adult and elderly individuals. In conclusion, these data established the presence of functionally redundant pediatric T cells in the airway, identified age-associated features of γδ T cells in MCMV-infected lungs, and laid the foundation for studies of severe influenza infection in antiviral-treated individuals across different ages. The unique functions of pediatric T cells in this body of work widen the scope of future age-associated immune studies, which will impact study design, interpretation, and subsequent therapeutic development

Exemestane may be less detrimental than letrozole to bone health in women homozygous for the UGT2B17*2 gene deletion

Purpose: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer. Methods: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2. Results: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05). Conclusion: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation

Partial Meal Replacement Plan and Quality of the Diet at 1 Year: Action for Health in Diabetes (Look AHEAD) Trial

Little is known about diet quality with a reduced-energy, low-fat, partial meal replacement (PMR) plan, especially in individuals with type 2 diabetes. The Action for Health in Diabetes (Look AHEAD) trial implemented a PMR plan in the intensive lifestyle intervention (ILI)

Inequalities and Agencies in Workplace Learning Experiences: International Student Perspectives

The final publication is available at Springer via http://dx.doi.org/10.1007/s12186-016-9167-2National systems of vocational education and training around the globe are facing reform driven by quality, international mobility, and equity. Evidence suggests that there are qualitatively distinctive challenges in providing and sustaining workplace learning experiences to international students. However, despite growing conceptual and empirical work, there is little evidence of the experiences of these students undertaking workplace learning opportunities as part of vocational education courses. This paper draws on a four-year study funded by the Australian Research Council that involved 105 in depth interviews with international students undertaking work integrated learning placements as part of vocational education courses in Australia. The results indicate that international students can experience different forms of discrimination and deskilling, and that these were legitimised by students in relation to their understanding of themselves as being an ‘international student’ (with fewer rights). However, the results also demonstrated the ways in which international students exercised their agency towards navigating or even disrupting these circumstances, which often included developing their social and cultural capital. This study, therefore, calls for more proactively inclusive induction and support practices that promote reciprocal understandings and navigational capacities for all involved in the provision of work integrated learning. This, it is argued, would not only expand and enrich the learning opportunities for international students, their tutors, employers, and employees involved in the provision of workplace learning opportunities, but it could also be a catalyst to promote greater mutual appreciation of diversity in the workplace

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms