pulmonary-embolism-in-transit-crossing-the-mitral-and-aortic-valve

Pulmonary Embolism In-Transit Crossing the Mitral and Aortic Valve

Hemodynamically significant pulmonary embolisms (PE) in the pulmonary artery or those crossing a patent foramen ovale (PFO) can become life-threatening ...

University of Florida

The antibiotic formulary is threatened by high rates of antimicrobial resistance (AMR) among enteropathogens. Enteric bacteria are exposed to anaerobic conditions within the gastrointestinal tract, yet little is known about how oxygen exposure influences AMR. The facultative anaerobe  was chosen as a model to address this knowledge gap. We obtained  isolates from 66 cholera patients, sequenced their genomes, and grew them under anaerobic and aerobic conditions with and without three clinically relevant antibiotics (ciprofloxacin, azithromycin, doxycycline). For ciprofloxacin and azithromycin, the minimum inhibitory concentration (MIC) increased under anaerobic conditions compared to aerobic conditions. Using standard resistance breakpoints, the odds of classifying isolates as resistant increased over 10 times for ciprofloxacin and 100 times for azithromycin under anaerobic conditions compared to aerobic conditions. For doxycycline, nearly all isolates were sensitive under both conditions. Using genome-wide association studies, we found associations between genetic elements and AMR phenotypes that varied by oxygen exposure and antibiotic concentrations. These AMR phenotypes were more heritable, and the AMR-associated genetic elements were more often discovered, under anaerobic conditions. These AMR-associated genetic elements are promising targets for future mechanistic research. Our findings provide a rationale to determine whether increased MICs under anaerobic conditions are associated with therapeutic failures and/or microbial escape in cholera patients. If so, there may be a need to determine new AMR breakpoints for anaerobic conditions.

Genome-wide association studies reveal distinct genetic correlates and increased heritability of antimicrobial resistance in  under anaerobic conditions.

After three years with no confirmed cholera cases in Haiti, an outbreak of  O1 emerged in October 2022. Levels of pre-existing antibodies provide an estimate of prior immunologic exposure, reveal potentially relevant immune responses, and set a baseline for future serosurveillance. We analyzed dried blood spots collected in 2021 from a population-weighted representative cross-sectional serosurvey in two communes in the Ouest Department of Haiti. We found lower levels of circulating IgG and IgA antibodies against  lipopolysaccharide (LPS, IgG and IgA p<0.0001) in those below 5 years of age compared to those five years and older. Among a subset of patients with higher titers of antibodies, we were unable to detect any functional (vibriocidal) antibodies. In conclusion, the lack of detectable functional antibodies, and age-discordant levels of  LPS IgG, suggest that populations in Haiti may be highly susceptible to cholera disease, especially among young children.

A population-based serological survey of  antibody titers in Ouest Department, Haiti in the year prior to the 2022 cholera outbreak.

Despite an increasingly detailed picture of the molecular mechanisms of phage-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. Here we report a year-long, nation-wide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantified  (prey) and its virulent phages (predators) using metagenomics and quantitative PCR, while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressed  to varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of anti-phage defenses, predation was 'effective,' with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of anti-phage defenses, predation was 'ineffective,' with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics.

Phage predation, disease severity and pathogen genetic diversity in cholera patients.

A Vibrio cholerae O1 outbreak emerged in Haiti in October 2022 after years of cholera absence. In samples from a 2021 serosurvey, we found lower circulating antibodies against V. cholerae lipopolysaccharide in children <5 years of age and no vibriocidal antibodies, suggesting high susceptibility to cholera, especially among young children.

Population-Based Serologic Survey of Vibrio cholerae Antibody Titers before Cholera Outbreak, Haiti, 2022.

Nitric oxide (NO) is a gas naturally produced by the human body that plays an important physiological role. Specifically, it binds guanylyl cyclase to induce smooth muscle relaxation. NO's other protective functions have been well documented, particularly its protective endothelial functions, effects on decreasing pulmonary vascular resistance, antiplatelet, and anticoagulation properties. The use of nitric oxide donors as vasodilators has been known since 1876. Inhaled nitric oxide has been used as a pulmonary vasodilator and to improve ventilation perfusion matching since the 1990s. It is currently approved by the United States Food and Drug Administration for neonates with hypoxic respiratory failure, however, it is used off-label for acute respiratory distress syndrome, acute bronchiolitis, and COVID-19.

The biological role and future therapeutic uses of nitric oxide in extracorporeal membrane oxygenation, a narrative review.

Despite an increasingly detailed picture of the molecular mechanisms of bacteriophage (phage)-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. In this work, we report a year-long, nationwide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantified  (prey) and its virulent phages (predators) using metagenomics and quantitative polymerase chain reaction while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressed  to varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of antiphage defenses, predation was "effective," with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of antiphage defenses, predation was "ineffective," with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics.

Phage predation, disease severity, and pathogen genetic diversity in cholera patients.

Hypercyanotic spells are one of the defining clinical features of Tetralogy of Fallot (TOF). Limited data exist on peak Doppler right ventricular outflow tract (RVOT) gradient as a risk factor for the development of hypercyanotic spells, frequency of prophylactic use of propranolol based on peak RVOT gradient, and its impact on preventing the occurrence of hypercyanotic spells. We aimed to quantify peak RVOT gradients as measured on transthoracic echocardiography in infants with unrepaired TOF and assess for correlation with clinical symptoms of hypercyanotic spells. We also assessed the frequency of pre-operative use of propranolol, indication for medication initiation, and occurrence of hypercyanotic spells with or without propranolol use. Retrospective analysis was performed on patients at our institution who were born between February 1, 2011 and May 31, 2023. Patients were excluded if they were maintained on prostaglandin infusion or underwent palliative shunt placement or balloon valvuloplasty prior to complete surgical repair. Demographics, occurrence of hypercyanotic spells, propranolol use, peripheral oxygen saturation, age at surgical repair, and peak RVOT gradient at the time of propranolol initiation were collected from the electronic medical record. If no propranolol use was recorded, the single highest maximum RVOT gradient prior to surgery was collected. 203 patients were identified, of which 92 patients were included in analysis. Thirty-six (39%) patients received propranolol and 19% of patients developed hypercyanotic spells prior to surgery. Patients with higher peak RVOT gradients were more likely to be started on propranolol even in the absence of overt symptoms, and they also demonstrated more systemic desaturation. Additionally, peak RVOT gradient was found to be a poor predictor for the development of hypercyanotic spells. Wide clinical variation exists in the prophylactic use of propranolol for prevention of hypercyanotic spells. Peak RVOT gradient is not a reliable tool for prophylactic propranolol initiation to prevent hypercyanotic spells.

Propranolol Therapy in Tetralogy of Fallot: Treating the Echocardiogram or Treating the Patient.

We investigated factors associated with the longitudinal presence of neurodevelopmental delays in pediatric heart transplant recipients.

Analysis of UNOS: Longitudinal Cognitive and Motor Delay After Pediatric Heart Transplantation and Associated Survival.

Cholera is a diarrhoeal disease caused by . It remains a major public health challenge in the endemic region around the Bay of Bengal. Over decadal time scales, one lineage typically dominates the others and spreads in global pandemic waves. However, it remains unclear to what extent diverse lineages co-circulate during a single outbreak season. Defining the pool of diversity during finer time scales is important because the selective pressures that impact  - namely antibiotics and phages - are dynamic on these time scales. To study the nationwide diversity of , we long-read sequenced 273  genomes from seven hospitals over one year (2018) in Bangladesh. Four major  lineages were identified: known lineages BD-1, BD-2a, and BD-2b, and a novel lineage that we call BD-3. In 2022, BD-1 caused a large cholera outbreak in Dhaka, apparently outcompeting BD-2 lineages. We show that, in 2018, BD-1 was already dominant in the five northern regions, including Dhaka, consistent with an origin from India in the north. By contrast, we observed a higher diversity of lineages in the two southern regions near the coast. The four lineages differed in pangenome content, including integrative and conjugative elements (ICEs) and genes involved in resistance to bacteriophages and antibiotics. Notably, BD-2a lacked an ICE and is predicted to be more sensitive to phages and antibiotics, but nevertheless persisted throughout the year-long sampling period. Genes associated with antibiotic resistance in  from Bangladesh in 2006 were entirely absent from all lineages in 2018-19, suggesting shifting costs and benefits of encoding these genes. Together, our results highlight the dynamic nature of the  pangenome and the geographic structure of its lineage diversity.

 lineage and pangenome diversity varies geographically across Bangladesh over one year.

A gap in knowledge exists related to optimal bivalirudin dosing in children. The purpose of our analysis is to use quantitative methods and baseline data to quickly predict the optimal therapeutic bivalirudin dose for children.

Quantitative methods to improve bivalirudin dosing in pediatric cardiac ICU patients.

Intra-aortic balloon pumps (IABPs) have been employed to stabilize patients with acute-on-chronic cardiogenic shock. The use of IABP to optimize patients for successful left ventricular assist device (LVAD) implantation has not been well-studied.

Preoperative use of intra-aortic balloon pump before left ventricular assist device implantation.

Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and fetal mortality worldwide. Early detection and risk stratification are critical for timely intervention to prevent severe complications such as eclampsia, stroke, and preterm delivery. However, traditional clinical methods often lack the precision needed to identify high-risk individuals effectively. Machine learning (ML) has emerged as a powerful tool, leveraging complex data to enhance prediction, diagnosis, and clinical decision-making in HDP. This review aims to systematically evaluate ML applications in HDP, highlighting trends, methodologies, and gaps to guide future research and improve maternal and fetal outcomes.

AI in Hypertensive Disorders of Pregnancy: Review.

Patients with Fontan physiology are predisposed to congestive hepatopathy, progressive liver fibrosis, and end-stage liver disease. Ultrasound-based shear wave elastography (SWE) is a non-invasive tool to diagnose and monitor liver fibrosis. We sought to determine whether the degree of hemodynamic derangement prior to and after the Fontan operation is associated with increased liver stiffness measured by SWE.

A Tense Race: Correlation of Liver Stiffness with Ultrasound Elastography and Hemodynamics in Fontan Patients.

This pilot study evaluated the impact of a revised interview scoring form, incorporating holistic elements, on the assessment of surgical residency applicants.

Developing a Holistic Rubric for Surgery Residency Interview Evaluations: A Pilot Study for Interview Use.

Liver biopsy remains the gold standard for evaluating Fontan-associated liver disease. Prior studies show that unfavorable Fontan hemodynamics are associated with a higher risk of developing liver disease. We sought to determine whether hemodynamics pre- and post-Fontan, severity of atrioventricular valve regurgitation (AVV), and systemic ventricular dysfunction by echocardiography correlate with the degree of liver disease on biopsy. In this single-center retrospective study, we included patients with Fontan physiology who had a liver biopsy between January 2008 and May 2024. Pre- and post-Fontan catheterization data, as well as post-Fontan echocardiogram data, were reviewed. Severity of liver fibrosis was classified by the congestive hepatic fibrosis score. Data was analyzed using dichotomization (low grade score 0-2B and high grade 3-4) with χ and Fisher's tests. 154 Post-Fontan liver biopsies corresponding to 120 patients were analyzed. The median time between the Fontan operation and liver biopsy was 23 years [IQR 17, 28]. The median Glenn pressure was 14 mmHg at pre-Fontan catheterization [IQR 11, 15]. On post-Fontan catheterization, median Fontan pressure was 18 mmHg [IQR 16, 22], and median systemic oxygen saturation was 92% [IQR 85, 95]. High-grade hepatic fibrosis did not significantly correlate with time from Fontan, elevated Glenn pressure, post-Fontan systemic venous pressure, or post-Fontan systemic ventricular function. The correlation between moderate or worse systemic AVV regurgitation approached but did not reach statistical significance (p = 0.051). No correlation was found between time from Fontan procedure, pre- or post-Fontan hemodynamics, significant AVV regurgitation, or degree of systemic ventricular dysfunction with high-grade liver fibrosis in patients with Fontan physiology.

Article	Year
Genome-wide association studies reveal distinct genetic correlates and increased heritability of antimicrobial resistance in under anaerobic conditions. Microbial genomics\| PubMed ID: 36748512	2022
A population-based serological survey of antibody titers in Ouest Department, Haiti in the year prior to the 2022 cholera outbreak. medRxiv : the preprint server for health sciences\| PubMed ID: 36798289	2023
Phage predation, disease severity and pathogen genetic diversity in cholera patients. bioRxiv : the preprint server for biology\| PubMed ID: 37398242	2024
Population-Based Serologic Survey of Vibrio cholerae Antibody Titers before Cholera Outbreak, Haiti, 2022. Emerging infectious diseases\| PubMed ID: 37487168	2023
The biological role and future therapeutic uses of nitric oxide in extracorporeal membrane oxygenation, a narrative review. Perfusion\| PubMed ID: 38226651	2025
Phage predation, disease severity, and pathogen genetic diversity in cholera patients. Science (New York, N.Y.)\| PubMed ID: 38669570	2024
Propranolol Therapy in Tetralogy of Fallot: Treating the Echocardiogram or Treating the Patient. Pediatric cardiology\| PubMed ID: 39017729	2024
Analysis of UNOS: Longitudinal Cognitive and Motor Delay After Pediatric Heart Transplantation and Associated Survival. The Annals of thoracic surgery\| PubMed ID: 39047962	2025
lineage and pangenome diversity varies geographically across Bangladesh over one year. bioRxiv : the preprint server for biology\| PubMed ID: 39605465	2024
Quantitative methods to improve bivalirudin dosing in pediatric cardiac ICU patients. Perfusion\| PubMed ID: 40014868	2025
Preoperative use of intra-aortic balloon pump before left ventricular assist device implantation. JHLT open\| PubMed ID: 40144729	2025
AI in Hypertensive Disorders of Pregnancy: Review. American journal of hypertension\| PubMed ID: 40202855	2025
A Tense Race: Correlation of Liver Stiffness with Ultrasound Elastography and Hemodynamics in Fontan Patients. Congenital heart disease\| PubMed ID: 40406458	2025
Developing a Holistic Rubric for Surgery Residency Interview Evaluations: A Pilot Study for Interview Use. Journal of surgical education\| PubMed ID: 40414174	2025
Do Hemodynamic and Echocardiographic Derangements After the Fontan Operation Correlate with Severity of Liver Disease on Biopsy? Pediatric cardiology\| PubMed ID: 40540016	2025

Lindsey Brinkley

Biography

JoVE Journal Publications

Other Publications