RheumMadness Over Two Years: Engaging Participants in Active Learning and Connecting Early Trainees to the Rheumatology Community.

OBJECTIVE: RheumMadness is an online learning collaborative that seeks to actively engage the rheumatology community. The objective of this manuscript is to analyze the educational experience of RheumMadness over two years. METHODS: Direct measures of participant engagement were obtained using web-based analytics. An electronic survey was created after the tournament to capture self-reported engagement and educational experience using the Community of Inquiry framework. Data were analyzed according to the following objectives: (1) compare demographics, engagement, and educational experience of participants between 2021 and 2022; (2) describe the educational experience of those who created scouting reports; (3) explore the impact of RheumMadness on early learners (medical students and residents). RESULTS: Compared with 2021, the 2022 tournament had more participants who submitted a bracket, more early learners, and more scouting report creators. Self-reported engagement and educational experience was high in both years of the tournament among all participants. Over 85% of scouting report creators reported that making a report was a fun and valuable learning experience. Early learners reported significantly higher levels of knowledge integration, sense of belonging in the rheumatology community, social connection, and overall learning experience compared with more advanced participants. Eighty-five percent of early learners reported that RheumMadness increased their interest in rheumatology. CONCLUSION: RheumMadness expanded from 2021 to 2022, engaging more participants in collaborative learning. Our results demonstrate that RheumMadness is particularly impactful among medical students and residents by helping them explore rheumatology topics and connect with the rheumatology community.

Antigen-loaded Monocyte Administration and Flt3 Ligand Augment the Antitumor Efficacy of Immune Checkpoint Blockade in a Murine Melanoma Model.

Undifferentiated monocytes can be loaded with tumor antigens (Ag) and administered intravenously to induce antitumor cytotoxic T lymphocyte (CTL) responses. This vaccination strategy exploits an endogenous Ag cross-presentation pathway, where Ag-loaded monocytes (monocyte vaccines) transfer their Ag to resident splenic dendritic cells (DC), which then stimulate robust CD8 + CTL responses. In this study, we investigated whether monocyte vaccination in combination with CDX-301, a DC-expanding cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), could improve the antitumor efficacy of anti-programmed cell death (anti-PD-1) immune checkpoint blockade. We found that Flt3L expanded splenic DC over 40-fold in vivo and doubled the number of circulating Ag-specific T cells when administered before monocyte vaccination in C57BL/6 mice. In addition, OVA-monocyte vaccination combined with either anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), or anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) suppressed subcutaneous B16/F10-OVA tumor growth to a greater extent than checkpoint blockade alone. When administered together, OVA-monocyte vaccination improved the antitumor efficacy of Flt3L and anti-PD-1 in terms of circulating Ag-specific CD8 + T cell frequency and inhibition of subcutaneous B16/F10-OVA tumor growth. To our knowledge, this is the first demonstration that a cancer vaccine strategy and Flt3L can improve the antitumor efficacy of anti-PD-1. The findings presented here warrant further study of how monocyte vaccines can improve Flt3L and immune checkpoint blockade as they enter clinical trials.

Screw fixation for syndesmotic injury is stronger and provides more contact area of the joint surface than TightRope®: A biomechanical study.

BACKGROUND: The rupture of syndesmotic ligaments is treated with a screw fixation as the gold standard. An alternative is the stabilization with a TightRope®. A couple of studies investigated the different clinical outcome and some even looked at the stability in the joint, but none of them examined the occurring pressure after fixation. OBJECTIVE: Is there a difference in pressure inside the distal tibiofibular joint between a screw fixation and a TightRope®? Does the contact area differ in these two treatment options? METHODS: This biomechanical study aimed to investigate the differences in fixation of the injured syndesmotic ligaments by using a fixation with one quadricortical screw versus singular TightRope® both implanted 1 cm above the joint. By using 12 adult lower leg cadaveric specimens and pressure recording sensor, we recorded the pressure across the distal tibiofibular joint. Additionally we measured the contact surface area across the joint. RESULTS: The mean of the pressure across the distal tibiofibular joint from the start of the insertion of the fixation device to the complete fixation was 0.05 Pascal for the TightRope® and 0.1 for the screw (P= 0.016). The mean of the maximum pressure across the joint (after completion of fixation and releasing the reduction clamp) was 1.750 mega Pascal with the screw fixation and 0.540 mega Pascal with TightRope® (P= 0.008). The mean of the measured contact area of the distal tibiofibular joint after fixation was 250 mm2 in the TightRope® group and of 355 mm2 in the screw fixation (P= 0.123). CONCLUSIONS: The screw fixation is stronger and provides a larger surface contact area, which leads us to the conclusion that it provides a better stability in the joint. While previous clinical studies did not show significant clinical difference between the two methods of fixation, the biomechanical construct varied. Long term clinical studies are required to establish whether this biomechanical distinction will contribute to various clinical outcomes.

Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection.

Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen's characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined Cryptococcus neoformans isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants' survival, meningitis disease parameters, immunologic phenotypes, and pathogen in vitro growth characteristics. We compared those clinical data to whole-genome sequences from 38 C. neoformans isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan Cryptococcus clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate Cryptococcus genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human Cryptococcus infections.IMPORTANCE Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus Cryptococcus neoformans and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific C. neoformans genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related C. neoformans strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40 C. neoformans genes are associated with human disease. Surprisingly, many of these genes are specific to Cryptococcus and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify C. neoformans genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.