Development and Outcomes of Returning Polycyclic Aromatic Hydrocarbon Exposure Results in the Washington Heights, NYC Community.

Report-back of research results (RBRR) is becoming standard practice for environmental health research studies. RBRR is thought to increase environmental health literacy (EHL), although standardized measurements are limited. For this study, we developed a report back document on exposure to air pollutants, Polycyclic Aromatic Hydrocarbons, during pregnancy through community engaged research and evaluated whether the report increased EHL. We used focus groups and surveys to gather feedback on the report document from an initial group of study participants (Group 1, n = 22) and then sent the revised report to a larger number of participants (Group 2, n = 168). We conducted focus groups among participants in Group 1 and discussed their suggested changes to the report and how those changes could be implemented. Participants in focus groups demonstrated multiple levels of EHL. While participant engagement critically informed report development, a survey comparing feedback from Group 1 (initial report) and Group 2 (revised report) did not show a significant difference in the ease of reading the report or knowledge gained about air pollutants. We acknowledge that our approach was limited by a lack of EHL tools that assess knowledge and behavior change, and a reliance on quantitative methodologies. Future approaches that merge qualitative and quantitative methodologies to evaluate RBRR and methodologies for assessing RBRR materials and subsequent changes in knowledge, attitudes, and behavior, may be necessary.

Estimation of the optimal radiotherapy utilization rate for childhood neuroblastoma.

BACKGROUND AND PURPOSE: The optimal utilization rate of radiotherapy (oRUR) serves as a benchmark for assessing service demand and improving access to cancer care. While it is estimated that approximately 50 % of adult cancer patients require external beam radiotherapy during their treatment, there is a scarcity of data regarding the optimal use of radiotherapy in pediatric cancer. In this study, we adopted an established method and developed a model to estimate the oRUR in childhood neuroblastoma. MATERIALS AND METHODS: We developed a decision tree model to calculate the oRUR using indications for radiotherapy and corresponding epidemiological data collected through systematic review and meta-analysis. Sensitivity analyses were performed to evaluate the impact of variations in radiotherapy indications between treatment protocols and variables in the model. We calculated and compared the oRUR for global, high-income, and low- and middle-income settings. RESULTS: The oRUR for pediatric neuroblastoma was 64 % (95 % CI: 58 %-71 %) in the global setting, 50 % in high-income countries, and 68 % in low- and middle-income countries. The impact of variation in radiotherapy indications between major international treatment protocols was negligible. CONCLUSION: The knowledge of oRUR is crucial for evaluating current practices, identifying gaps in access, and planning future radiotherapy services for treating childhood cancer. Based on our results, 64 % of children with neuroblastoma have an indication for radiotherapy. Patients in low- and middle-income countries have more indications for radiotherapy than those in high-income countries, due to a more adverse tumour stage distribution caused by limited access to healthcare resources.

A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity.

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.

Unstructured linker regions play a role in the differential splicing activities of paralogous RNA binding proteins PTBP1 and PTBP2.

RNA Binding Proteins regulate, in part, alternative pre-mRNA splicing and, in turn, gene expression patterns. Polypyrimidine tract binding proteins PTBP1 and PTBP2 are paralogous RNA binding proteins sharing 74% amino acid sequence identity. Both proteins contain four structured RNA-recognition motifs (RRMs) connected by linker regions and an N-terminal region. Despite their similarities, the paralogs have distinct tissue-specific expression patterns and can regulate discrete sets of target exons. How two highly structurally similar proteins can exert different splicing outcomes is not well understood. Previous studies revealed that PTBP2 is post-translationally phosphorylated in the unstructured N-terminal, Linker 1, and Linker 2 regions that share less sequence identity with PTBP1 signifying a role for these regions in dictating the paralog's distinct splicing activities. To this end, we conducted bioinformatics analysis to determine the evolutionary conservation of RRMs versus linker regions in PTBP1 and PTBP2 across species. To determine the role of PTBP2 unstructured regions in splicing activity, we created hybrid PTBP1-PTBP2 constructs that had counterpart PTBP1 regions swapped to an otherwise PTBP2 protein and assayed on differentially regulated exons. We also conducted molecular dynamics studies to investigate how negative charges introduced by phosphorylation in PTBP2 unstructured regions can alter their physical properties. Collectively, results from our studies reveal an important role for PTBP2 unstructured regions and suggest a role for phosphorylation in the differential splicing activities of the paralogs on certain regulated exons.

Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors.

Understanding cellular decisions due to receptor-ligand interactions at cell-cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands-called CombiCells-to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor-ligand interactions at cell-cell interfaces.

Does Tibial Tuberosity Osteotomy Improve Outcomes When Combined With Medial Patellofemoral Ligament Reconstruction in the Presence of Increased Tibial Tuberosity-Trochlear Groove Distance? A Systematic Review and Meta-analysis.

Background: There has been recent debate regarding the optimal surgical management strategy for recurrent patellofemoral instability in the presence of an increased tibial tuberosity-trochlear groove (TT-TG) distance. In particular, performing a combined tibial tuberosity osteotomy (TTO) and medial patellofemoral ligament reconstruction (MPFLR) for patients with a TT-TG >20 mm has been questioned, with the hypothesis that an isolated MPFLR (iMPFLR) would be just as effective. Purpose: To pool and compare outcomes after MPFLR+TTO versus iMPFLR in patients with a TT-TG >20 mm. Study Design: Systematic review; Level of evidence, 4. Methods: PubMed-MEDLINE, Embase, Web of Science, and Cochrane Central were searched, and a systematic review was performed. Included were studies that reported postoperative redislocation rates and/or functional outcome scores for patients with recurrent patellar instability and a TT-TG >20 mm who underwent either MPFLR+TTO or iMPFLR and had minimum 2-year follow-up data. Methodologic quality was assessed using the modified Coleman Methodology Score (mCMS). A proportional meta-analysis comparing redislocation, subjective instability, and total complication rates was performed, and mean postoperative functional outcome scores were pooled using a random-effects model with a restricted maximum likelihood estimator. Results: In total, 1548 studies were screened, from which 13 were included for analysis. Of the 386 included patients (406 knees), 276 underwent MPFLR+TTO and 110 underwent iMPFLR. The mean mCMS was 61.3 ± 10.5 (range, 48-77). The pooled postoperative redislocation rate was 1.22% (95% CI, 0.22%-7%), with no significant difference between the study groups (P = .9995). The pooled complication rate was 10.17% (95% CI, 6.2%-16.3%) with no difference between groups (P = .9275), although the MPFLR+TTO group had higher heterogeneity in complication rates (I2 = 79.4%) compared with iMPFLR (I2 = 0%). There was no group difference in the pooled postoperative Lysholm scores (P = .5177), but patients who underwent iMPFLR had significantly higher postoperative Kujala scores compared with those who underwent MPFLR+TTO (P = .0283). Conclusion: Even in the presence of previously indicative anatomic factors (TT-TG >20 mm), TTO combined with MPFLR does not seem to confer additional benefit compared with iMPFLR. This finding could be advantageous in minimizing the burden of additional surgery with its associated risks. The study findings should, however, be interpreted with caution given the heterogeneity of the studies.