Outcomes of acute ischemic stroke among patients with renal cell carcinoma: A nationwide analysis.

INTRODUCTION: Renal cell carcinoma (RCC) has been associated with an increased risk for acute ischemic stroke (AIS). As individuals with cancer who experience AIS tend to face higher mortality rates compared to AIS patients without cancer, recognizing the implications of RCC in AIS is crucial for identifying high-risk patients for major complications and directing management strategies. OBJECTIVE: To examine risk factors, interventions, and outcomes for patients with AIS stratified by their RCC diagnosis. METHODS: The National Inpatient Sample (NIS) database was queried for the period 2010-2019 using International Classification of Disease 10th Edition (ICD-10) codes for acute ischemic stroke and renal malignancies. We assessed demographic information, comorbidities, and clinical interventions between patients presenting with AIS, with and without renal malignancies. A logistic regression model was employed to further examine mortality outcomes. RESULTS: Among 1,609,817 patients identified with AIS, 2,068 (0.12%) had a concomitant diagnosis of RCC. AIS patients with RCC were older (72.09 yrs. vs. 70.9 yrs., p < 0.01), more often white (72.05% vs. 68.16%, p < 0.01), and had similar stroke severity scores. RCC patients received less tissue plasminogen activator (tPA; 4.98% vs. 6.2%, p = 0.02) but underwent endovascular mechanical thrombectomy (MT) at similar rates. RCC patients had more complications (p < 0.01) as well as longer hospital stays (8.19 days vs. 5.98 days, p < 0.01), and higher rates of mortality (11.27% vs. 5.63%, p < 0.01), when compared to their non-RCC counterparts. Propensity score-adjusted analysis largely confirmed these findings, with RCC being positively associated with in-hospital mortality (OR: 1.373, p < 0.01) and longer stays (OR: 2.591, p < 0.01). CONCLUSION: In addition to describing the demographics and clinical course of AIS patients diagnosed with RCC, our study underscores the substantial impact of RCC on AIS outcomes. Despite experiencing strokes of similar severity, AIS patients diagnosed with RCC are at a heightened risk of complications, including thromboembolic events and infections, leading to elevated in-hospital mortality rates and prolonged hospital stays.

Decision-Making During Asynchronous Electives: Insights From Emergency Medicine-Bound Medical Students.

Introduction While asynchronous learning is gaining popularity, little is known about learners' decisions regarding compliance with assigned asynchronous material. We sought to explore how medical students make decisions about the use of their time when engaging in asynchronous learning during the residency interview season.  Methods After implementing a four-week blended elective for emergency medicine-bound fourth-year medical students, we conducted a mixed methods study with an explanatory sequential design. We analyzed weekly surveys regarding accountability and barriers to assignment completion and conducted semi-structured focus groups exploring the decisions students made regarding compliance with asynchronous assignments. Using a constructivist approach, we performed a thematic analysis of the transcripts. Results The average assignment completion rate was 36%, with the highest rates for podcasts (58%) and the lowest rates for textbook readings (20%). Compliance with assignments was enhanced by a desire for increased ownership of learning but was hindered by a lack of accountability, learner burnout, and higher prioritization of interviews. Students preferentially selected resources that were shorter in length, entertaining, and more convenient for travel. Conclusion Our study highlights factors impacting student compliance when engaging in asynchronous learning and offers insights into educational and institutional strategies that can be utilized to enhance learner motivation.

Profiling the antibody response of humans protected by immunization with Plasmodium vivax radiation-attenuated sporozoites.

Malaria sterile immunity has been reproducibly induced by immunization with Plasmodium radiation-attenuated sporozoites (RAS). Analyses of sera from RAS-immunized individuals allowed the identification of P. falciparum antigens, such as the circumsporozoite protein (CSP), the basis for the RTS, S and R21Matrix-M vaccines. Similar advances in P. vivax (Pv) vaccination have been elusive. We previously reported 42% (5/12) of sterile protection in malaria-unexposed, Duffy-positive (Fy +) volunteers immunized with PvRAS followed by a controlled human malaria infection (CHMI). Using a custom protein microarray displaying 515 Pv antigens, we found a significantly higher reactivity to PvCSP and one hypothetical protein (PVX_089630) in volunteers protected against P. vivax infection. In mock-vaccinated Fy + volunteers, a strong antibody response to CHMI was also observed. Although the Fy- volunteers immunized with non-irradiated Pv-infected mosquitoes (live sporozoites) did not develop malaria after CHMI, they recognized a high number of antigens, indicating the temporary presence of asexual parasites in peripheral blood. Together, our findings contribute to the understanding of the antibody response to P. vivax infection and allow the identification of novel parasite antigens as vaccine candidates.Trial registration: ClinicalTrials.gov number: NCT01082341.

Impact of sex on humoral immunity with live influenza B virus vaccines in mice.

Influenza B virus (FLUBV) poses a significant infectious threat, with frequent vaccine mismatch limiting its effectiveness. Our previous work investigated the safety and efficacy of modified live attenuated FLUBV vaccines with rearranged genomes (FluB-RAM and FluB-RANS) or a temperature-sensitive PB1 segment with a C-terminal HA tag (FluB-att). In this study, we compared the immune responses of female and male DBA/2J mice vaccinated with these vaccines, including versions containing a chimeric HA segment with an N-terminal IgA-inducing peptide (IGIP). Importantly, both recombinant viruses with and without IGIP remained genetically stable during egg passage. We found that introducing IGIP strengthened vaccine attenuation, particularly for FluB-RAM/IGIP. Prime-boost vaccination completely protected mice against lethal challenge with a homologous FLUBV strain. Notably, recombinant viruses induced robust neutralizing antibody responses (hemagglutination inhibition titers ≥40) alongside antibodies against NA and NP. Interestingly, female mice displayed a consistent trend of enhanced humoral and cross-reactive IgG and IgA responses against HA, NA, and NP compared to male counterparts, regardless of the vaccine used. However, the presence of IGIP generally led to lower anti-HA responses but higher anti-NA and anti-NP responses, particularly of the IgA isotype. These trends were further reflected in mucosal and serological responses two weeks after challenge, with clear distinctions based on sex, vaccine backbone, and IGIP inclusion. These findings hold significant promise for advancing the development of universal influenza vaccines.

Broad antibody and T cell responses to Ebola, Sudan, and Bundibugyo ebolaviruses using mono- and multi-valent adjuvanted glycoprotein vaccines.

Currently, there are two approved vaccine regimens designed to prevent Ebola virus (EBOV) disease (EVD). Both are virus-vectored, and concerns about cold-chain storage and pre-existing immunity to the vectors warrant investigating additional vaccine strategies. Here, we have explored the utility of adjuvanted recombinant glycoproteins (GPs) from ebolaviruses Zaire (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) for inducing antibody (Ab) and T cell cross-reactivity. Glycoproteins expressed in insect cells were administered to C57BL/6 mice as free protein or bound to the surface of liposomes, and formulated with toll-like receptor agonists CpG and MPLA (agonists for TLR 9 and 4, respectively), with or without the emulsions AddaVax or TiterMax. The magnitude of Ab cross-reactivity in binding and neutralization assays, and T cell cross-reactivity in antigen recall assays, correlated with phylogenetic relatedness. While most adjuvants screened induced IgG responses, a combination of CpG, MPLA and AddaVax emulsion ("IVAX-1") was the most potent and polarized in an IgG2c (Th1) direction. Breadth was also achieved by combining GPs into a trivalent (Tri-GP) cocktail with IVAX-1, which did not compromise antibody responses to individual components in binding and neutralizing assays. Th1 signature cytokines in T cell recall assays were undetectable after Tri-GP/IVAX-1 administration, despite a robust IgG2c response, although administration of Tri-GP on lipid nanoparticles in IVAX-1 elevated Th1 cytokines to detectable levels. Overall, the data indicate an adjuvanted trivalent recombinant GP approach may represent a path toward a broadly reactive, deployable vaccine against EVD.

Tissue-specific sex differences in pediatric and adult immune cell composition and function.

Sex-based differences in immune cell composition and function can contribute to distinct adaptive immune responses. Prior work has quantified these differences in peripheral blood, but little is known about sex differences within human lymphoid tissues. Here, we characterized the composition and phenotypes of adaptive immune cells from male and female ex vivo tonsils and evaluated their responses to influenza antigens using an immune organoid approach. In a pediatric cohort, female tonsils had more memory B cells compared to male tonsils direct ex vivo and after stimulation with live-attenuated but not inactivated vaccine, produced higher influenza-specific antibody responses. Sex biases were also observed in adult tonsils but were different from those measured in children. Analysis of peripheral blood immune cells from in vivo vaccinated adults also showed higher frequencies of tissue homing CD4 T cells in female participants. Together, our data demonstrate that distinct memory B and T cell profiles are present in male vs. female lymphoid tissues and peripheral blood respectively and suggest that these differences may in part explain sex biases in response to vaccines and viruses.

FLUAV RAM-IGIP: A modified live influenza virus vaccine that enhances humoral and mucosal responses against influenza.

Current influenza A vaccines fall short, leaving both humans and animals vulnerable. To address this issue, we have developed attenuated modified live virus (MLV) vaccines against influenza using genome rearrangement techniques targeting the internal gene segments of FLUAV. The rearranged M2 (RAM) strategy involves cloning the M2 ORF downstream of the PB1 ORF in segment 2 and incorporating multiple early stop codons within the M2 ORF in segment 7. Additionally, the IgA-inducing protein (IGIP) coding region was inserted into the HA segment to further attenuate the virus and enhance protective mucosal responses. RAM-IGIP viruses exhibit similar growth rates to wild type (WT) viruses in vitro and remain stable during multiple passages in cells and embryonated eggs. The safety, immunogenicity, and protective efficacy of the RAM-IGIP MLV vaccine against the prototypical 2009 pandemic H1N1 strain A/California/04/2009 (H1N1) (Ca/04) were evaluated in Balb/c mice and compared to a prototypic cold-adapted live attenuated virus vaccine. The results demonstrate that the RAM-IGIP virus exhibits attenuated virulence in vivo. Mice vaccinated with RAM-IGIP and subsequently challenged with an aggressive lethal dose of the Ca/04 strain exhibited complete protection. Analysis of the humoral immune response revealed that the inclusion of IGIP enhanced the production of neutralizing antibodies and augmented the antibody-dependent cellular cytotoxicity response. Similarly, the RAM-IGIP potentiated the mucosal immune response against various FLUAV subtypes. Moreover, increased antibodies against NP and NA responses were observed. These findings support the development of MLVs utilizing genome rearrangement strategies in conjunction with the incorporation of immunomodulators. IMPORTANCE: Current influenza vaccines offer suboptimal protection, leaving both humans and animals vulnerable. Our novel attenuated MLV vaccine, built by rearranging FLUAV genome segments and incorporating the IgA-inducing protein, shows promising results. This RAM-IGIP vaccine exhibits safe attenuation, robust immune responses, and complete protection against lethal viral challenge in mice. Its ability to stimulate broad-spectrum humoral and mucosal immunity against diverse FLUAV subtypes makes it a highly promising candidate for improved influenza vaccines.