Patch Materials for Pulmonary Artery Arterioplasty and Right Ventricular Outflow Tract Augmentation: A Review.

Patch augmentation of the right ventricular outflow tract (RVOT) and pulmonary artery (PA) arterioplasty are relatively common procedures in the surgical treatment of patients with congenital heart disease. To date, several patch materials have been applied with no agreed upon clinical standard. Each patch type has unique performance characteristics, cost, and availability. There are limited data describing the various advantages and disadvantages of different patch materials. We performed a review of studies describing the clinical performance of various RVOT and PA patch materials and found a limited but growing body of literature. Short-term clinical performance has been reported for a multitude of patch types, but comparisons are limited by inconsistent study design and scarce histologic data. Standard clinical criteria for assessment of patch efficacy and criteria for intervention need to be applied across patch types. The field is progressing with improvements in outcomes due to newer patch technologies focused on reducing antigenicity and promoting neotissue formation which may have the ability to grow, remodel, and repair.

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Using Serologic Testing to Assess the Effectiveness of Outbreak Control Efforts, Serial Polymerase Chain Reaction Testing, and Cohorting of Positive Severe Acute Respiratory Syndrome Coronavirus 2 Patients in a Skilled Nursing Facility.

We characterized serology following a nursing home outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) where residents were serially tested by reverse-transcription polymerase chain reaction (RT-PCR) and positive residents were cohorted. When tested 46-76 days later, 24 of 26 RT-PCR-positive residents were seropositive; none of the 124 RT-PCR-negative residents had confirmed seropositivity, supporting serial SARS-CoV-2 RT-PCR testing and cohorting in nursing homes.

Genetic and environmental control of host-gut microbiota interactions.

Genetics provides a potentially powerful approach to dissect host-gut microbiota interactions. Toward this end, we profiled gut microbiota using 16s rRNA gene sequencing in a panel of 110 diverse inbred strains of mice. This panel has previously been studied for a wide range of metabolic traits and can be used for high-resolution association mapping. Using a SNP-based approach with a linear mixed model, we estimated the heritability of microbiota composition. We conclude that, in a controlled environment, the genetic background accounts for a substantial fraction of abundance of most common microbiota. The mice were previously studied for response to a high-fat, high-sucrose diet, and we hypothesized that the dietary response was determined in part by gut microbiota composition. We tested this using a cross-fostering strategy in which a strain showing a modest response, SWR, was seeded with microbiota from a strain showing a strong response, A×B19. Consistent with a role of microbiota in dietary response, the cross-fostered SWR pups exhibited a significantly increased response in weight gain. To examine specific microbiota contributing to the response, we identified various genera whose abundance correlated with dietary response. Among these, we chose Akkermansia muciniphila, a common anaerobe previously associated with metabolic effects. When administered to strain A×B19 by gavage, the dietary response was significantly blunted for obesity, plasma lipids, and insulin resistance. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes. Our publicly available data provide a resource for future studies.

Predictors of 30- and 90-day readmission following craniotomy for malignant brain tumors: analysis of nationwide data.

Hospital readmissions are a major contributor to increased health care costs and are associated with worse patient outcomes after neurosurgery. We used the newly released Nationwide Readmissions Database (NRD) to describe the association between patient, hospital and payer factors with 30- and 90-day readmission following craniotomy for malignant brain tumor. All adult inpatients undergoing craniotomy for primary and secondary malignant brain tumors in the NRD from 2013 to 2014 were included. We identified all cause readmissions within 30- and 90-days following craniotomy for tumor, excluding scheduled chemotherapeutic procedures. We used univariate and multivariate models to identify patient, hospital and administrative factors associated with readmission. We identified 27,717 admissions for brain tumor craniotomy in 2013-2014, with 3343 (13.2%) 30-day and 5271 (25.7%) 90-day readmissions. In multivariate analysis, patients with Medicaid and Medicare were more likely to be readmitted at 30- and 90-days compared to privately insured patients. Patients with two or more comorbidities were more likely to be readmitted at 30- and 90-days, and patients discharged to skilled nursing facilities or home health care were associated with increased 90-day readmission rates. Finally, hospital procedural volume above the 75th percentile was associated with decreased 90-day readmission rates. Patients treated at high volume hospitals are less likely to be readmitted at 90-days. Insurance type, non-routine discharge and patient comorbidities are predictors of postoperative non-scheduled readmission. Further studies may elucidate potentially modifiable risk factors when attempting to improve outcomes and reduce cost associated with brain tumor surgery.

The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities.

PURPOSE OF REVIEW: We provide an overview of our current understanding of the genetic architecture of coronary artery disease (CAD) and discuss areas of research that provide excellent opportunities for further exploration. RECENT FINDINGS: Large-scale studies in human populations, coupled with rapid advances in genetic technologies over the last decade, have clearly established the association of common genetic variation with risk of CAD. However, the effect sizes of the susceptibility alleles are for the most part modest and collectively explain only a small fraction of the overall heritability. By comparison, evidence that rare variants make a substantial contribution to risk of CAD has been somewhat disappointing thus far, suggesting that other biological mechanisms have yet to be discovered. Emerging data suggests that novel pathways involved in the development of CAD can be identified through complementary and integrative systems genetics strategies in mice or humans. There is also convincing evidence that gut bacteria play a previously unrecognized role in the development of CAD, particularly through metabolism of certain dietary nutrients that lead to proatherogenic metabolites in the circulation. A major effort is now underway to functionally understand the newly discovered genetic and biological associations for CAD, which could lead to the development of potentially novel therapeutic strategies. Other important areas of investigation for understanding the pathophysiology of CAD, including epistatic interactions between genes or with either sex and environmental factors, have not been studied on a broad scope and represent additional opportunities for future studies.

A Novel, Mutually Beneficial Student-Faculty Partnership to Develop Real-Time Formative Assessments Aligning with the Preclinical Undergraduate Medical Curriculum.

PROBLEM: A shortage of curriculum-aligned formative multiple-choice questions (FMCQs) remains despite their known learning benefits in preclinical medical education due to limitations on teaching faculty time and other reasons. In response, students often use extramural resources such as commercial or collaborative question banks; however, these options are often expensive and cannot be aligned with the content of each school's unique curriculum. In addition, students need feedback on their learning in a manner that parallels the format of summative assessments. In this pilot, the authors aimed to enhance student learning by creating an intramural formative practice resource that was developed as the curriculum unfolded under the direction of the faculty leading the concurrently running curricular units. APPROACH: The authors developed a workflow known as Professor-Reviewed Exam Practice (PREP) in 2023. PREP partnered preclinical medical students and faculty to create vignette-style, single best response FMCQs with feedback for every lecture and self-guided learning module in multiple preclinical blocks of The Ohio State University College of Medicine undergraduate medical curriculum. OUTCOMES: PREP established a sustainable, student-led, faculty-guided workflow that created high-quality, curriculum-aligned FMCQs for student use in the preclinical medical curriculum over a 14-month period. Usage rates were high across multiple preclinical blocks, reflecting high student demand for FMCQs of this nature and their value as a study aid. Survey data showed faculty agreed that their time commitment and role in the PREP workflow was appropriate. NEXT STEPS: Future work will evaluate the benefits of PREP to students by exploring the potential impact of PREP FMCQs on summative assessment performance and if writing FMCQs confers benefits to PREP team members. Faculty survey indicated that performance data from PREP FMCQs could be used to tailor upcoming teaching and learning methods, which is an area for future inquiry.

Perioperative Evaluation of Arterial and Venous Whole Blood in the Lamb (Ovis aries) Fontan Model.

Whole blood analysis can evaluate numerous parameters, including pH, pCO2, pO2, HCO3 - , base excess, glucose, electrolytes, lactate, blood urea nitrogen, creatinine, bilirubin, and hemoglobin. This valuable tool enables clinicians to make more informed decisions about patient care. However, the current body of literature describing perioperative whole blood analysis in Dorset sheep (Ovis aries) is small, so clinicians lack adequate information to guide their decision-making when evaluating test results. We evaluated arterial and venous whole blood pH, bicarbonate, pCO2, lactate, creatinine, and blood urea nitrogen before and for the first 24 hours after surgery in 2 cohorts of male and female Ovis arie s undergoing one of 2 major cardiovascular procedures, a Single-Stage Fontan or an inferior vena cava to pulmonary artery extracardiac conduit implantation (IP-ECC). The cohort undergoing a Single-Stage Fontan, which is the more complex procedure, exhibited greater deviation from baseline measurements than did the cohort undergoing the IP-ECC for lactate, bicarbonate, and creatinine. The cohort undergoing the IP-ECC showed no significant deviation from baseline for any parameters, potentially indicating a better safety margin than expected when compared with the Single-Stage Fontan. Together, these results indicate the clinical value of arterial and venous whole blood measurements in perioperative management of sheep and can provide a reference for clinicians managing sheep after significant cardiovascular procedures.

Characteristics of Long-Term Survivors With EGFR-Mutant Metastatic NSCLC.

Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively). Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.

Tissue engineered vascular grafts are resistant to the formation of dystrophic calcification.

Advancements in congenital heart surgery have heightened the importance of durable biomaterials for adult survivors. Dystrophic calcification poses a significant risk to the long-term viability of prosthetic biomaterials in these procedures. Herein, we describe the natural history of calcification in the most frequently used vascular conduits, expanded polytetrafluoroethylene grafts. Through a retrospective clinical study and an ovine model, we compare the degree of calcification between tissue-engineered vascular grafts and polytetrafluoroethylene grafts. Results indicate superior durability in tissue-engineered vascular grafts, displaying reduced late-term calcification in both clinical studies (p < 0.001) and animal models (p < 0.0001). Further assessments of graft compliance reveal that tissue-engineered vascular grafts maintain greater compliance (p < 0.0001) and distensibility (p < 0.001) than polytetrafluoroethylene grafts. These properties improve graft hemodynamic performance, as validated through computational fluid dynamics simulations. We demonstrate the promise of tissue engineered vascular grafts, remaining compliant and distensible while resisting long-term calcification, to enhance the long-term success of congenital heart surgeries.

Fabrication Methods and Chronic In Vivo Validation of Mechanically Adaptive Microfluidic Intracortical Devices.

Intracortical neural probes are both a powerful tool in basic neuroscience studies of brain function and a critical component of brain computer interfaces (BCIs) designed to restore function to paralyzed patients. Intracortical neural probes can be used both to detect neural activity at single unit resolution and to stimulate small populations of neurons with high resolution. Unfortunately, intracortical neural probes tend to fail at chronic timepoints in large part due to the neuroinflammatory response that follows implantation and persistent dwelling in the cortex. Many promising approaches are under development to circumvent the inflammatory response, including the development of less inflammatory materials/device designs and the delivery of antioxidant or anti-inflammatory therapies. Here, we report on our recent efforts to integrate the neuroprotective effects of both a dynamically softening polymer substrate designed to minimize tissue strain and localized drug delivery at the intracortical neural probe/tissue interface through the incorporation of microfluidic channels within the probe. The fabrication process and device design were both optimized with respect to the resulting device mechanical properties, stability, and microfluidic functionality. The optimized devices were successfully able to deliver an antioxidant solution throughout a six-week in vivo rat study. Histological data indicated that a multi-outlet design was most effective at reducing markers of inflammation. The ability to reduce inflammation through a combined approach of drug delivery and soft materials as a platform technology allows future studies to explore additional therapeutics to further enhance intracortical neural probes performance and longevity for clinical applications.

Effect of Genetic and Dietary Perturbation of Glycine Metabolism on Atherosclerosis in Humans and Mice.

Objective: Epidemiological and genetic studies have reported inverse associations between circulating glycine levels and risk of coronary artery disease (CAD). However, these findings have not been consistently observed in all studies. We sought to evaluate the causal relationship between circulating glycine levels and atherosclerosis using large-scale genetic analyses in humans and dietary supplementation experiments in mice. Methods: Serum glycine levels were evaluated for association with prevalent and incident CAD in the UK Biobank. A multi-ancestry genome-wide association study (GWAS) meta-analysis was carried out to identify genetic determinants for circulating glycine levels, which were then used to evaluate the causal relationship between glycine and risk of CAD by Mendelian randomization (MR). A glycine feeding study was carried out with atherosclerosis-prone apolipoprotein E deficient (ApoE-/-) mice to determine the effects of increased circulating glycine levels on amino acid metabolism, metabolic traits, and aortic lesion formation. Results: Among 105,718 subjects from the UK Biobank, elevated serum glycine levels were associated with significantly reduced risk of prevalent CAD (Quintile 5 vs. Quintile 1 OR=0.76, 95% CI 0.67-0.87; P<0.0001) and incident CAD (Quintile 5 vs. Quintile 1 HR=0.70, 95% CI 0.65-0.77; P<0.0001) in models adjusted for age, sex, ethnicity, anti-hypertensive and lipid-lowering medications, blood pressure, kidney function, and diabetes. A meta-analysis of 13 GWAS datasets (total n=230,947) identified 61 loci for circulating glycine levels, of which 26 were novel. MR analyses provided modest evidence that genetically elevated glycine levels were causally associated with reduced systolic blood pressure and risk of type 2 diabetes, but did provide evidence for an association with risk of CAD. Furthermore, glycine-supplementation in ApoE-/- mice did not alter cardiometabolic traits, inflammatory biomarkers, or development of atherosclerotic lesions. Conclusions: Circulating glycine levels were inversely associated with risk of prevalent and incident CAD in a large population-based cohort. While substantially expanding the genetic architecture of circulating glycine levels, MR analyses and in vivo feeding studies in humans and mice, respectively, did not provide evidence that the clinical association of this amino acid with CAD represents a causal relationship, despite being associated with two correlated risk factors.

Computational analysis of serum-derived extracellular vesicle miRNAs in juvenile sheep model of single stage Fontan procedure.

Patients with single ventricle heart defects requires a series of staged open-heart procedures, termed Fontan palliation. However, while lifesaving, these operations are associated with significant morbidity and early mortality. The attendant complications are thought to arise in response to the abnormal hemodynamics induced by Fontan palliation, although the pathophysiology underlying these physicochemical changes in cardiovascular and other organs remain unknown. Here, we investigated the microRNA (miRNA) content in serum and serum-derived extracellular vesicles (EVs) by sequencing small RNAs from a physiologically relevant sheep model of the Fontan operation. The differential expression analysis identified the enriched miRNA clusters in (1) serum vs. serum-derived EVs and (2) pre-Fontan EVs vs. post-Fontan EVs. Metascape analysis showed that the overexpressed subset of EV miRNAs by Fontan procedure target liver-specific cells, underscoring a potentially important pathway involved in the liver dysfunction that occurs as a consequence of Fontan palliation. We also found that post-Fontan EV miRNAs were associated with senescence and cell death, whereas pre-Fontan EV miRNAs were associated with stem cell maintenance and epithelial-to-mesenchymal transition. This study shows great potential to identify novel circulating EV biomarkers from Fontan sheep serum that may be used for the diagnosis, prognosis, and therapeutics for patients that have undergone Fontan palliation.

Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface.

(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain-machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application.

Establishment of a COVID-19 Recovery Unit in a Veterans Affairs Post-Acute Facility.

Coronavirus disease 2019 (COVID-19) is now an epidemic of global proportion, with major adverse impacts on older adults, persons with chronic diseases, and especially residents of long-term care facilities. This health catastrophe has challenged healthcare facilities' capacity to deliver care to not only COVID-19 patients but all patients who need hospital care. We report on a novel approach of utilizing long-term care beds at a Department of Veterans Affairs healthcare facility for managing recovering COVID-19 patients. J Am Geriatr Soc 68:2163-2166, 2020.

Acute interstitial nephritis, a potential predictor of response to immune checkpoint inhibitors in renal cell carcinoma.

Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab have improved outcomes in metastatic renal cell carcinoma (mRCC) patients, but they are also associated with immune-related adverse events (irAEs). As observed in melanoma, we hypothesized that patients experiencing an autoimmune reaction directed against the tissue of origin may be more likely to benefit from ICI. Specifically, we asked whether patients with immune-related acute interstitial nephritis (irAIN) exhibited improved outcomes. Using Kidney Cancer Explorer (KCE), a data portal and i2b2-based central database for clinical, pathological and experimental genetic data, we systematically identified all patients with mRCC at UT Southwestern Medical Center (UTSW) from 2014-2018 who received at least one dose of ICI. More recent cases were identified through a provider query. We extracted creatinine (Cr) values at baseline and over the entirety of each patient ICI treatment course using KCE. Patients with ≥ 1.5-fold Cr increase over baseline were investigated. The likelihood of irAIN was determined based on the work-up (biopsy, if available), or by clinical criteria (timing of kidney injury, exclusion of other etiologies, treatment with immunosuppressants and response). We identified 177 mRCC patients who received at least one dose of ICI, 36 of whom had ≥ 1.5-fold increase in Cr over baseline while on treatment. Of those, two had biopsy-proven irAIN and one was clinically diagnosed, resulting in an incidence of 1.7%. One additional biopsy-proven case past 2018 was identified through a provider query, for a total of four patients. Two received combination nivolumab and ipilimumab in the first line, whereas the remaining received nivolumab after first line therapy. irAIN onset ranged from 1.5 to 12 months. All four patients stopped ICI with recovery of renal function, at least partially, three after receiving systemic steroids. Notably, all four patients had a deep response. In conclusion, irAIN is a rare event, but it may portend a higher likelihood of response. One possible explanation is antigenic overlap between normal renal tubular cells and tumor cells.

Heat shock response and groEL sequence of Bartonella henselae and Bartonella quintana.

Transmission of Bartonella species from ectoparasites to the mammalian host involves adaptation to thermal and other forms of stress. In order to better understand this process, the heat shock response of Bartonella henselae and Bartonella quintana was studied. Cellular proteins synthesized after shift to higher temperatures were intrinsically labelled with [25S]methionine and analysed by gel electrophoresis and fluorography. The apparent molecular masses of three of the major heat shock proteins produced by the two Bartonella species were virtually identical, migrating at 70, 60 and 10 kDa. A fourth major heat shock protein was larger in B. quintana (20 kDa) than in B. henselae (17 kDa). The maximum heat shock response in B. quintana and B. henselae was observed at 39 degrees C and 42 degrees C, respectively. The groEL genes of both Bartonella species were amplified, sequenced and compared to other known groEL genes. The phylogenetic tree based on the groEL alignment places B. quintana and B. henselae in a monophyletic group with Bartonella bacilliformis. The deduced amino acid sequences of Bartonella GroEL homologues contain signature sequences that are uniquely shared by members of the Gram-negative alpha-purple subdivision of bacteria, which live within eukaryotic cells. Recombinant His6-GroEL fusion proteins were expressed in Escherichia coli to generate specific rabbit antisera. The GroEL antisera were used to confirm the identity of the 60 kDa Bartonella heat shock protein. These studies provide a foundation for evaluating the role of the heat shock response in the pathogenesis of Bartonella infection.