Comparison of Human Memory CD8 T Cell Responses to Adenoviral Early and Late Proteins in Peripheral Blood and Lymphoid Tissue

Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs) targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977) and late protein hexon (H-892) were compared in peripheral blood (PB) and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly higher frequency of P-977+CD8+ T cells compared to H-892+CD8+ T cells; this trend was reversed in PB. Tonsil epitope-specific CD8+ T cells expressed IFN-γ and IL-2 but not perforin or TNF-α, whereas PB T cells were positive for IFN-γ, TNF-α, and perforin. Tonsil epitope-specific T cells expressed lymphoid homing marker CCR7 and exhibited lower levels of the activation marker CD25 but higher proliferative potential than PB T cells. Finally, in parallel with the kinetics of mRNA expression, P-977-specific CTLs lysed targets as early as 8 hrs post infection. In contrast, H-892-specific CTLs did not kill unless infected fibroblasts were pretreated with IFN-γ to up regulate HLA class I antigens, and cytotoxicity was delayed until 16–24 hours. These data show that, in contrast to hexon CTLs, central memory type DNA polymerase CTLs dominate the lymphoid compartment and kill fibroblasts earlier after infection without requiring exogenous IFN-γ. Thus, use of CTLs targeted to both early and late Ad proteins may improve the efficacy of immunotherapy for life-threatening Ad disease in SCT recipients

Breaking boundaries: Towards consistent gender-sensitive language in sexual and reproductive health guidelines

This review assesses gender-sensitive language in sexual and reproductive health (SRH) guidelines, including a guideline for polycystic ovary syndrome. We conducted a systematic search across databases like Medline, EMBASE, and Cochrane until July 31, 2023, using terms related to gender-inclusivity, SRH, and guideline protocols. Criteria for inclusion were gender-sensitive language, SRH focus, and guideline relevance, excluding non-English articles or those without policy considerations. Our search yielded 25 studies, with 6 included for qualitative synthesis. Results showed significant gaps in using gender-sensitive language in SRH guidelines. The debate on this language mirrors broader societal discourse. Recognizing gender diversity is essential for research, clinical practices, and societal norms. While promoting inclusion, drawbacks like unintended erasure or miscommunication should also be addressed. A gender-additive approach balances inclusivity and biological accuracy. Precise and inclusive discourse is crucial. Future research should focus on systemic approaches in the SRH sector

An Obesity-Associated FTO Gene Variant and Increased Energy Intake in Children

Background: Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. Methods: We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. Results: In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). Conclusions: The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods.</p

Unplanned medication discontinuation as a potential pharmacovigilance signal : a nested young person cohort study

Because of relatively small treatment numbers together with low adverse drug reaction (ADR) reporting rates the timely identification of ADRs affecting children and young people is problematic. The primary objective of this study was to assess the utility of unplanned medication discontinuation as a signal for possible ADRs in children and young people. Using orlistat as an exemplar, all orlistat prescriptions issued to patients up to 18 years of age together with patient characteristics, prescription duration, co-prescribed medicines and recorded clinical (Read) codes were identified from the Primary Care Informatics Unit database between 1st Jan 2006-30th Nov 2009. Binary logistic regression was used to assess association between characteristics and discontinuation. During the study period, 79 patients were prescribed orlistat (81% female, median age 17 years). Unplanned medication discontinuation rates for orlistat were 52% and 77% at 1 and 3-months. Almost 20% of patients were co-prescribed an anti-depressant. One month unplanned medication discontinuation was significantly lower in the least deprived group (SIMD 1-2 compared to SIMD 9-10 OR 0.09 (95% CI0.01 - 0.83)) and those co-prescribed at least one other medication. At 3 months, discontinuation was higher in young people (≥17 yr versus, OR 3.07 (95% CI1.03 - 9.14)). Read codes were recorded for digestive, respiratory and urinary symptoms around the time of discontinuation for 24% of patients. Urinary retention was reported for 7.6% of patients. Identification of unplanned medication discontinuation using large primary care datasets may be a useful tool for pharmacovigilance signal generation and detection of potential ADRs in children and young people

Relationship Between Aminotransferases Levels and Components of the Metabolic Syndrome Among Multiethnic Adolescents

Data evaluating the frequency of elevated aminotransferases (as a surrogate for non-alcoholic fatty liver disease [NAFLD]) and metabolic syndrome (MS) components among overweight multiethnic children/adolescents originating predominantly from South/Central America and the Caribbean are limited. A sample (N = 284) of multiethnic (75% Latino, 25% Afro Caribbean/non-Hispanic black) overweight children/ adolescents' (mean age 12.24 +/- 3.48) overnight fasting insulin and glucose, systolic/diastolic blood pressure, HDL/LDL/total cholesterol, triglyceride, aspartate aminotransferase (AST) and alanine aminostransferase (ALT) were analyzed. A total of 22% of the sample had elevated ALT (> or = 30 U/L; mean 25.94 U/L for Hispanics, 23.05 U/L for blacks) and 8% had elevated AST (> or = 35 U/L; mean 23.05 U/L for Hispanics, 24.68 U/L for blacks). AST and ALT were significantly correlated with triglycerides (r = 0.23, P < .01; r = 0.18, P < .05, respectively) for the overall sample. Among overweight adolescents, MS components are associated with NALFD in subgroups of major ethnic groups suggesting that AST and ALT as surrogate markers for NAFLD should be included in addition to the standard cardio metabolic tests