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Anti-T3SS Humoral and Cellular Immunity in Vaccine-Mediated Control of P. aeruginosa Infection
No full textPseudomonas aeruginosa (PA) is a gram-negative bacterium that is ubiquitous in the environment and is often resistant to multiple antibiotics. In healthcare settings, PA is one of the most common causes of ventilator associated pneumonia and several other types of mucosal and systemic infections, in part through its ability to form biofilms on medical devices and to persist in harsh environments. As an alternative to antibiotics, vaccination against PA can protect those at risk of morbidity and mortality. Intranasal vaccination can protect against localized respiratory PA infections in addition to systemic PA infections.
We designed a PA vaccine using tobacco mosaic virus (TMV), a plant virus that is harmless to humans, as a platform to present recombinant whole protein antigens. PcrV, the tip protein of PA’s type 3 secretion system (T3SS), was chemically conjugated to TMV and evaluated as the primary vaccine antigen. Curdlan (c), a β-glucan exopolysaccharide, was used as an adjuvant. The vaccine was given to mice intranasally to assess protection against a mouse model of acute PA pneumonia. We examined humoral and cellular immune responses elicited by the vaccine to determine whether curdlan enhanced the protective efficacy of the TMV-PcrV vaccine, to identify immune correlates of protection, and to elucidate the effector functions of vaccine-induced antibodies.
TMV-PcrV+c, the adjuvanted vaccine, was 56% protective against a 22.5 LD50 dose of PA. The TMV platform significantly enhanced production of localized IgA in the lungs compared to the unconjugated recombinant PcrV protein subunit vaccines. Systemically, serum anti-PcrV IgG1 was primarily associated with survival after a PA challenge, identifying IgG1 as a potential correlate of protection. We also found that serum antibodies could neutralize the release of toxic exoenzymes secreted from the T3SS.
PA infections are primarily cleared by phagocytes, as PA is an extracellular bacterium. Macrophages and neutrophils are activated and recruited to the site of infection by TH1 and TH17 signaling, respectively. Interferon gamma, the prototypical TH1 cytokine, and interleukin-17, the prototypical TH17 cytokine, were secreted by lung and spleen cells from vaccinated mice in response to restimulation with rPcrV. Cells from mice given vaccines containing curdlan were more responsive than cells from mice given unadjuvanted vaccines. Neutrophils were quickly recruited to the lungs after PA infection, but in mice that received TMV-conjugate and curdlan-containing vaccines, they declined more rapidly than in unvaccinated mice and mice that were vaccinated with unconjugated PcrV. Blockade of interleukin-17 during PA challenge enhanced protection of vaccinated mice. This suggests that excessive or prolonged infiltration of neutrophils can lead to acute tissue damage, morbidity, and mortality. In contrast, vaccinated mice recruited macrophages to the site of infection more quickly than unvaccinated mice. Moreover, interferon gamma blockade during PA challenge delayed clearance of PA from infected mice, suggesting that recruiting macrophages to the site of infection is beneficial for PA clearance and host survival.
We also tested four additional vaccine antigens: OprF, OprI, ExoAt, and FliC. Serum antibodies raised against these antigens could bind to native PA proteins and the vaccines elicited antibody responses. However, these vaccines were not protective against a lethal dose of PA. Despite the lack of in vivo protection, anti-ExoAt serum profoundly neutralized ExoA-mediated apoptosis of mouse cells when analyzed in vitro, suggesting a potential therapeutic use of antibodies targeting ExoA for high-risk patients with PA infections.
Overall, these results suggest that both humoral and cellular immunity contribute to vaccine-mediated protection against PA. The adjuvanted TMV-PcrV+c vaccine was more protective than its unadjuvanted counterpart. Vaccine-induced antibodies do not appear to be bactericidal, but they do appear to have a neutralizing function, which can prevent tissue damage that would otherwise be induced by PA’s secreted toxins. Vaccination also enhances T cell responses and appropriate recruitment of phagocytes to the site of infection to engulf and kill PA. Together, TMV-PcrV+c vaccine-mediated humoral and cellular responses can clear PA infections while limiting acute tissue damage derived from host and pathogen factors to ultimately improve morbidity and mortality after PA infections
Symposium #33
No full textRemarks and Moderator: Edward C. Halperin, M.D., M.A. What is recommended for flu, COVID and RSV vaccines this fall? : Edward C. Halperin, M.D., M.A.; Marisa A. Montecalvo, M.D., Lori A. Weir Solomon, M.D. \u2799, M.P.H. \u2709 What is the status of monitoring infectious diseases in the community with wastewater measurements?: Salomon Amar, D.D.S., D.M.D., Ph.D., M.S. Aren\u27t you going to give my child a prescription, doctor? —Are we over-prescribing antibiotics for children?: Tami Hendriksz, DO, FACOP, FAAP De-escalation of therapy for multiple sclerosis: Stephanie Gandelman, M.D. What we do and don\u27t know about the long-term effects of immunosuppressive therapy for multiple sclerosis, rheumatoid arthritis, lupus, and other diseases on oral health: Aaron Yancoskie, D.D.S. Q & A: Edward C. Halperin, M.D., M.A.https://touroscholar.touro.edu/ninety_minutes/1010/thumbnail.jp
A Community-Based Analysis of Security Practices Regarding Over-The-Counter Skincare Products in Nationwide Retail Drug Stores
No full textAccess to over-the-counter (OTC) skincare products is critical for managing a wide range of dermatologic conditions, yet recent trends in urban retail stores may jeopardize this accessibility and exacerbate healthcare disparities. However, the emerging trend of securing skincare products behind security glass in urban retail environments poses significant risks to healthcare equity and accessibility. Herein, we aim to quantify the prevalence of skincare products behind security glass in pharmacies within a 25-mile radius of Times Square, New York City. An observational, cross-sectional study was conducted, selecting 50 pharmacies from a total of 389 identified in the target radius. Digital photographs of skincare product aisles were taken, and the percentage of products secured behind glass was calculated for various categories and brands. The study found significant disparities in the availability of skincare products, with significantly higher percentages of products behind security glass in pharmacies located in urban areas compared to suburban regions. Among the four brands analyzed, Olay, L’Oréal, La Roche-Posay, and Vichy, there was no significant difference in the proportion of products behind security glass. Barriers to accessing skincare products, such as physical restrictions, time constraints, stigma, and privacy issues, may hinder individuals from obtaining necessary treatments, leading to potential delays in care and poorer health outcomes. Our study underscores the urgent need for dermatologists and healthcare policymakers to advocate for alternative security measures that do not compromise product accessibility. Facilitating easier access to OTC skincare products could dramatically improve treatment adherence and patient outcomes, particularly in urban settings where disparities are most pronounced
Survivin in Cardiovascular Diseases and Its Therapeutic Potential
No full textAberrant changes in cell behaviors, such as proliferation, apoptosis, and migration, are some of the contributing factors to the development of various cardiovascular diseases (CVDs) and pathologies, including atherosclerosis, neointimal hyperplasia, and heart failure. In recent years, numerous studies have identified survivin, a key player in the anti-apoptotic pathway, to be extensively involved in modulating cellular functioning in cancer, with many reaching clinical trials. Though seemingly different, CVDs and cancer share abundant similarities regarding abnormal cell modifications and behaviors. This overlap has sparked growing interest in investigating survivin as a therapeutic target in the context of CVD. With new findings emerging rapidly, a comprehensive understanding of survivin\u27s role in cardiovascular pathology is crucial to revealing its full therapeutic potential and translating these discoveries into effective treatments. This review discusses recent findings of survivin in CVDs and related pathologies, focusing on its dual role in promoting proliferation and inhibiting apoptosis, specifically in atherosclerosis, neointimal hyperplasia, stroke, hypertension, myocardial infarction, and heart failure. Across different cell types and pathological contexts, survivin plays a pivotal role throughout the disease progression–from the onset of disease development to the facilitation of compensatory mechanisms post-injury–primarily through its function in regulating cell proliferation and apoptosis. Furthermore, given the limited research on survivin as a therapeutic target for CVDs, potential clinical avenues, including YM155 (a survivin inhibitor) or adenoviral, adeno-associated, and lentiviral vectors, are also discussed. Overall, this review highlights survivin as a promising target for mitigating the detrimental effects of CVDs and to provide new perspectives to advance research on the intervention of CVDs and associated pathologies
The Long Run: A Tribute to Arthur Joseph Lawrence Cooper
No full textIn this issue of Analytical Biochemistry, we honor the life and legacy of Arthur Joseph Lawrence Cooper (1946–2024). Born in London, Arthur made pioneering contributions to medical science, particularly in understanding the role of glutamine in the brain and cancer cell metabolism. His research revealed how glutamine supports neurotransmitter synthesis, energy production, and ammonia detoxification, as well as its critical role in cancer cell growth. His work has greatly advanced both neuroscience and cancer biology, offering insights that could lead to new therapeutic strategies targeting glutamine metabolism
Prediction of Mortality After Convulsive Status Epilepticus: The Status Epilepticus M3A2S2H Score
No full textPurpose: This study aimed to investigate in-patient mortality and predictors of death associated with convulsive status epilepticus (CSE) in a large nationwide cohort and create a simplified predictive score for in-hospital mortality. Methods: Retrospective data from the National Inpatient Sample (NIS) database between 2007 and 2014 were analyzed, including 123,082 adults with CSE. Univariate logistic testing identified admission variables, neurological and medical complications associated with mortality. A simplified clinical prediction score, called M3A2S2H, was generated using variables that were frequent (\u3e1%) and had a significant impact on mortality. Results: The overall hospital mortality rate was 3.5%. Univariate analysis revealed that older age, female gender, past medical history, and acute hospital conditions were related to mortality. After reclassification, a final multivariable model with 27 clinical variables was constructed, and the eight strongest predictors were included in the M3A2S2H score: hypoxic-ischemic encephalopathy/cardiac arrest (2 points); age \u3e60 years, acute symptomatic CSE, invasive mechanical ventilation, sepsis, metastases, and chronic liver failure (all 1 point); and medication nonadherence (−1 point). The mortality rate among patients with ≤0, 1, 2, 3, 4, or ≥5 of these risk factors progressively increased from 0.2%, 2.1%, 7.8%, 20.3%, 31.9%, to 50.0% (P \u3c 0.0001). Additionally, a similar stepwise trend was observed regarding discharge to a facility versus home without services (P \u3c 0.0001). Conclusions: This study demonstrates that mortality in CSE cases occurs in 3.5% of adult hospital admissions. Identification of specific acute and chronic conditions using the standardized M3A2S2H score can help predict the risk of death or disability even in hospitals without advanced brain monitoring
Minimally Invasive Repair of Sinus Venosus Atrial Septal Defects and Anomalous Pulmonary Venous Connections via Vertical Right Axillary Thoracotomy
No full text(1) Background: There has been an increase in the utilization of the minimally invasive vertical right axillary thoracotomy approach for repairing congenital heart defects in children recently. We aim, in the current study, to evaluate the outcomes of this approach in repairing anomalous pulmonary venous connections with or without an associated sinus venosus defect. (2) Methods: A total of 23 consecutive patients underwent surgical repair of anomalous pulmonary venous connections between April 2018 and February 2024. Perioperative and clinical follow-up data were obtained. (3) Results: The median age and weight were 36 months (1–277 months) and 14.4 kg (3.6–79.4 kg), respectively. More than half were females (13; 56.5%). There was no conversion to sternotomy. Partial anomalous pulmonary venous connections were the most frequent primary diagnoses (14; 60.9%), followed by scimitar syndrome (3; 13%), while two patients (8.7%) had total anomalous pulmonary venous connections. Repair techniques included single patch in 10 patients (43.5%), Warden in 6 (26.1%), and two-patch technique in 4 (17.4%). The median cardiopulmonary bypass and aortic cross-clamp times were 91 and 62 min, respectively. All patients were extubated in the operating room. The median length of hospital stay was 2 days. There were no mortalities or reoperations for pulmonary/systemic venous pathway obstruction. (4) Conclusions: Vertical right axillary thoracotomy is a valuable approach for repairing anomalous pulmonary venous connections with or without sinus venosus defects. All repair techniques, including Warden and scimitar, can be performed safely through this approach. The cosmetic superiority and short hospital stay make this approach worth considering
Moderate- to High-Grade Blunt Liver and Spleen Injuries Warrant Repeat Imaging to Identify Treatable Complications Results of the Radiographic Evaluation of Delayed Solid Organ Complications EAST Multicenter Trial
No full textObjective: The aim of this study was to assess whether blunt liver (BLI) and blunt spleen (BSI) injury patients benefit from repeat imaging to identify injury-related complications. Background: No consensus guidelines exist regarding the necessity of, or optimal timing for, repeat imaging in BLI and BSI patients undergoing nonoperative management (NOM). We hypothesize that scheduled repeat imaging of patients undergoing NOM for moderate- to high-grade BLI and BSI would result in identification of complications earlier than if repeat imaging is performed in response to a change in clinical condition. Methods: We performed a 4-year, 43-center, multinational, prospective observational study of adult patients undergoing initial NOM of BLI and/or BSI. Patients were grouped by reason for repeat imaging: scheduled imaging (SI) or imaging performed for clinical change (CC), and by whether findings on repeat imaging resulted in procedural or operative intervention. Results: We identified 2341 BLI and 2143 BSI patients (528 concomitant BLI/BSI). Repeat imaging was performed in 822 (35.1%) BLI patients [SI: 457 (55.5%), CC: 365 (44.5%)] and 758 (27.9%) BSI patients [SI: 478 (63.1%), CC: 280 (37.0%)]. Complications were identified on repeat imaging in BLI: 167 (7.1%) [SI: 72 (43.1%), CC: 95 (56.9%)] and BSI: 203 (7.5%) [SI: 91 (44.8%), CC: 112 (55.2%)]. Of patients with BLI complications, 96 (57.8%) [SI: 37 (38.5%), CC: 59 (61.5%)] underwent an intervention. Of patients with BSI complications, 133 (65.5%) [SI: 56 (42.1%), CC: 77 (57.9%)] underwent an intervention. Our data demonstrate that in BLI and BSI, most complications were identified within 48 to 72 hours. Conclusions: Scheduled repeat imaging for asymptomatic patients with BLI grade 4 to 5 and BSI grade 3 to 5 within 48 to 72 hours from time of diagnosis allows for identification of complications before a change in the patient’s clinical condition
Proportion of Confirmed Lyme Neuroborreliosis Cases Among Adult Patients With Suspected Early European Lyme Neuroborreliosis
No full textPurpose: To determine the frequency of confirmed Lyme neuroborreliosis (LNB) cases in adult patients with three different clinical presentations consistent with early LNB. Methods: Data were obtained through routine health care at the UMC Ljubljana, Slovenia from 2005 to 2022, using clinical pathways. The patients were classified into three groups: (i) radicular pain of new onset (N = 332); or (ii) involvement of cranial nerve(s) but without radicular pain (N = 997); or (iii) erythema migrans (EM) skin lesion(s) in conjunction with symptoms suggestive of nervous system involvement but without either cranial nerve palsy or radicular pain (N = 240). The diagnosis of LNB considered the following variables: the presence of: (1) neurologic symptoms consistent with LNB (with no other obvious explanation); (2) cerebrospinal fluid (CSF) pleocytosis (\u3e 5 × 106 leukocytes/L); and (3) demonstration of intrathecal synthesis of borrelial antibodies, and/or cultivation of borrelia from CSF, and/or the presence of EM. Patients fulfilling only the first two criteria were interpreted as having possible LNB, while those who satisfied all three criteria were regarded as having confirmed LNB. Results: Of 1569 adult patients, 348 (22.2%) had confirmed LNB and 70 (4.5%) others had possible LNB. The proportion of confirmed LNB cases was the highest for patients with radicular pain (217/332, 65.4%), followed by the group with EM and neurologic symptoms (47/240, 19.6%), and those with cranial neuritis (84/997, 8.4%). Conclusion: Only 22% of patients evaluated had confirmed LNB. The proportion of confirmed LNB cases correlated with clinical presentation and was highest among patients with recent onset of radicular pain
