Comparison of neonatal T regulatory cell function in Papua New Guinean and Australian newborns

Background:  Environmental changes, including declining microbial exposure, have been linked with the rising incidence of allergic and autoimmune diseases in ‘western’ populations. This potentially occurs by altering early development of immuno-regulatory pathways including T regulatory cells (Treg). There is now increasing evidence that such conditioning begins in utero. Methods:  We compared neonatal Treg from children born under typical western conditions (Australia, AUS) with those of neonates born under more traditional conditions of high microbial burden (Papua New Guinea, PNG). Results:  The frequency of neonatal Treg, defined as CD4+ Foxp3+ CD127− CD25+/high was found to be higher in the cord blood of AUS compared to PNG newborns. However, cord Tregsuppressive function in a small subset of children was qualitatively similar between PNG and AUS newborns in both a Treg depletion assay and a Treg supplementation assay. Conclusions:  These findings do not support the hypothesis that living in a ‘western’ versus more traditional environment leads to poor induction or suppressive function of neonatal Treg. However, environmentally-induced immuno-regulation may potentially occur via alternative mechanisms in PNG newborns that should now be investigated further

Neonatal antigen-presenting cells are functionally more quiescent in children born under traditional compared with modern environmental conditions

Background One explanation for the high burden of allergic and autoimmune diseases in industrialized countries is inappropriate immune development under modern environmental conditions. There is increasing evidence that the process of immune deviation already begins in utero, but the underlying immunologic mechanisms are not clear. Objective We sought to identify differences in the function of neonatal antigen-presenting cells (APCs) in children born in settings that are more traditional versus those of modern societies. Methods Cord blood mononuclear cells were collected from newborns from Papua New Guinea (PNG; traditional) and Australia (modern) and compared for differences in APCs and T-cell phenotype and function. Results Australian cord naive T cells (CD4+CD25−CD127+ cells) showed an enhanced and more rapid proliferative response in an autologous, APC-dependent culture system, a result of differences in neonatal APCs rather than T-cell function. This included an increased capacity to process antigen and to upregulate activation markers after stimulation. In contrast, resting PNG APCs exhibited higher baseline levels of activation and inhibitory markers and were less responsive or nonresponsive to stimulation in vitro. Conclusions This study supports the hypothesis that prenatal environments can influence the developing immune system in utero. Children born under modern environmental conditions exhibit increased APC reactivity at birth compared with children born under traditional environmental conditions. The functionally more quiescent nature of PNG neonatal APCs might protect against the development of harmful inflammatory responses in early life

Effect of early carriage of streptococcus pneumoniae on the development of pneumococcal protein-specific cellular immune responses in infancy

Background: The aim of this study was to examine the relationship between nasopharyngeal pneumococcal colonization in early life and the subsequent development of pneumococcal-specific T cell responses. <p/>Methods: Pernasal swabs were collected from Papua New Guinean infants at the ages of 1 and 2 weeks (n = 279). At 9 months, in vitro cellular immune responses to choline-binding protein A (n = 132), pneumococcal surface protein A (n = 132), pneumolysin (n = 99), and the pneumococcal conjugate vaccine carrier CRM197 were determined. Responses were compared based on the children's carriage status within the first 2 weeks of life. <p/>Results: Within the first 2 weeks of life, 40% of the study children carried Streptococcus pneumoniae. Early carriage was associated with lower interferon-γ and interleukin 10 responses to pneumococcal proteins at age 9 months when children had not received pneumococcal conjugate vaccines during the study period. <p/>Conclusions: Early pneumococcal carriage may result in enhanced disease susceptibility and suboptimal vaccine responses by modulating the development of pneumococcal immune responses

Total hip arthroplasties in young patients under 50 years: limited evidence for current trends. A descriptive literature review

Item does not contain fulltextWe examined all reported outcomes of uncemented and cemented total hip arthroplasty in patients younger than 50 years of age listed in Medline (1966- 1 January 2009) and PubMed, and scrutinised reference lists of relevant papers. In addition, we evaluated relevant data in the Swedish hip arthroplasty register. 109 relevant articles were identified, 37 of which had a mean follow-up longer than 10 years. Although uncemented implants are widely used in patients under 50 years of age, there are only 2 reports that fulfil the criteria published by the National Institute for Clinical Excellence (NICE) in the United Kingdom (follow-up of >10 yrs and survival of =90%). Current trends relating to implant selection remain unsupported by survival data, and additional information about the long-term results of newer implants is essential. As matters stand, the most reliable results relate to cemented implants

Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin

Background: Immune checkpoint inhibitors (ICI) improve overall survival (OS) in patients with locally advanced, unresectable, or metastatic urothelial carcinoma (aUC), but response rates can be modest. We compared outcomes between patients with and without prior intravesical Bacillus Calmette-Guerin (BCG), who received ICI for aUC, hypothesizing that prior intravesical BCG would be associated with worse outcomes. Patients and Methods: We performed a retrospective cohort study across 25 institutions in US and Europe. We compared observed response rate (ORR) using logistic regression; progression-free survival (PFS) and OS using Kaplan-Meier and Cox proportional hazards. Analyses were stratified by treatment line (first line/salvage) and included multivariable models adjusting for known prognostic factors. Results: A total of 1026 patients with aUC were identified; 614, 617, and 638 were included in ORR, OS, PFS analyses, respectively. Overall, 150 pts had history of prior intravesical BCG treatment. ORR to ICI was similar between those with and without prior intravesical BCG exposure in both first line and salvage settings (adjusted odds radios 0.55 [P= .08] and 1.65 [P= .12]). OS (adjusted hazard ratios 1.05 [P= .79] and 1.13 [P= .49]) and PFS (adjusted hazard ratios 1.12 [P= .55] and 0.87 [P= .39]) were similar between those with and without intravesical BCG exposure in first line and salvage settings. Conclusion: Prior intravesical BCG was not associated with differences in response and survival in patients with aUC treated with ICI. Limitations include retrospective nature, lack of randomization, presence of selection and confounding biases. This study provides important preliminary data that prior intravesical BCG exposure may not impact ICI efficacy in aUC. © 202

Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes

Objectives: To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs). Patients and Methods: We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni- and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line). Results: Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43–1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73–1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81–1.27). Patients with mixed-histology UTUC had a significantly lower ORR and shorter PFS vs mixed-histology LTUC (aOR 0.20, 95% CI 0.05–0.91 and aHR 1.66, 95% CI 1.06–2.59), respectively). Conclusion: Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed-histology UTUC had a lower ORR and shorter PFS compared to mixed-histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy. © 2021 The Authors BJU International © 2021 BJU International Published by John Wiley & Sons Lt