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Prenatal Predictors of Survival, Pulmonary Hypertension, and ECMO in Isolated CDH Undergoing Expectant Management, A Systematic Review and Meta-analysis
Get PDFBackground and Hypothesis: Congenital diaphragmatic hernia (CDH) is a severe developmental defect affecting 1-4 per 10,000 births, characterized by left/right-sided defect, or mixed with herniation of abdominal contents into thorax, with resultant lung hypoplasia and persistent pulmonary hypertension (PHTN). The study investigates prenatal predictors of survival to hospital discharge, PHTN and the need for ECMO in fetuses with isolated CDH undergoing prenatal expectant management.
Project Methods: We performed a systematic literature review on prenatal diagnostic tests in fetuses with isolated CDH undergoing expectant management. Primary outcomes included survival-to-hospital discharge, persistent PHTN within 28 days, and ECMO need. Newcastle Ottawa Scale assessed quality of studies. Meta-analysis performed when two or more studies reported on the same test. Subgroup analysis performed according to CDH side.
Results: 161 full-text articles between 2000-2022 were assed for eligibility; 48 met inclusion criteria. 45 reported on survival, 12 on ECMO need, 8 on PHTN; quality of studies was moderate. Studies included were retrospective (81%) or prospective (19%) regarding fetuses undergoing expectant management (77%), or mixed tracheal occlusion and expectant management (20%). Most studies included mixed (41%) or left-sided (47%) CDH. Survival predicted by TFLV, o/e-TFLV, o/e-TFLV <30%, LiTR, o/e-LHR, o/e-LHR <25%, percentage herniated liver, MSA, stomach position in mid-chest, and liver up. ECMO need predicted by o/e-TFLV, o/e-LHR, and PPLV. These results were confirmed through subgroup analysis of only left-sided lesions. PHTN was predicted by presence of intrathoracic liver (OR-1.96, 95%CI 1.14,3.37, I2-0%); this was not significant after left-sided subgroup analysis.
Conclusion and Potential Impact: In fetuses with CDH, FLV and presence/percentage of intrathoracic liver predict survival. FLV measurements predict ECMO need. Presence of intrathoracic liver may predict persistent PHTN; further studies are needed. Accurate prognostication of CDH severity would aid patient triage, resource mobilization, and identification of high-risk CDH infants in need of advanced treatment including ECMO or identification of candidates for fetal intervention procedures
Sex-Based Differences in LPS-induced Rapid Myocardial Dysfunction
Get PDFBackground: Previous studies have indicated better myocardial responses with preserved cardiac function in female animals compared to males after LPS challenge; however, the mechanisms remain incompletely understood. Our published studies have revealed that TNFa substantially increased in heart tissue and serum following LPS. Females experienced less cardiac dysfunction than males during equivalent dose of TNFa infusion. Therefore, sex-related disparities in myocardial impairment could be due to an indirect/secondary outcome from LPS-induced inflammatory cytokines, like TNFa. To dissect the potential mechanism underlying myocardial reactions between males and females, we aim to determine any sex differences in LPS-caused direct effects on cardiac function using coronary infusion of LPS.
Methods: Isolated hearts from aged-matched adult male and female mice were subjected to LPS infusion via Langendorff after >20-min equilibration (Eq), with left ventricular developed pressure (LVDP) continuously recorded. Dose responsive experiments with LPS at 2.5, 5.0, and 7.5 mg/kg of body weight were performed in male hearts. Significant depression of LVDP (>20% drop) after LPS infusion was considered rapid response to LPS. Female estrous cycle was determined via vaginal smear.
Results: Male hearts infused with 5.0 and 7.5 mg/kg of LPS demonstrated significant depression of LV function. Males also experienced worse outcomes of LV function than females following 5.0 mg/kg of LPS infusion. A trend of earlier response to LPS occurred in male hearts compared to females. However, there were no significant differences in cardiac function between female groups in different estrous phases.
Conclusion and Potential Impact: Our data demonstrates that male hearts exhibit higher sensitivity to LPS-induced rapid cardiac dysfunction compared to females, but estrogen may have little influence on LPS-induced rapid functional depression. The insight from our data can be used to better understand the differences between male and female outcomes to cardiac pathologies and insult
Ethanol Induces Blood Brain Barrier Dysfunction in Healthy and Familial Alzheimer’s Blood Brain Barrier Models
Get PDFBackground/Objective:
The blood brain barrier (BBB) is a highly selective semipermeable membrane between the blood and brain. Active efflux transporters such as PGP, MRP-1, and BCRP and localized tight junction proteins ensure barrier integrity. Interestingly, both alcohol consumption and Alzheimer’s disease (AD) suppress barrier functions independently. Furthermore, alcohol use can lead to or worsened neurodegenerative disorders, including AD. In this study, human stem-cell derived healthy and AD BBB models with near in vivo properties are used to investigate the effects of alcohol on critical BBB properties such as barrier tightness and efflux transporter activity.
Methods:
Induced pluripotent stem cells (iPSCs) from healthy (IMR90) and Familial Alzheimer’s (APP, PSEN1, PSEN2) cell lines were differentiated into brain microvascular endothelial cells (BMECs). BMECs were treated with varying ethanol concentrations (5, 25, 50, and 100 mM) for one hour. Following ethanol treatment several barrier properties were assessed: trans-endothelial electrical resistance (TEER), sodium fluorescein permeability, tight junction localization, and efflux transporter activity.
Results:
Moderate to severe ethanol concentrations (25 mM and 50 mM) reduced TEER and delocalized tight junctions in healthy and AD-derived BMECs, indicating a disruption in barrier integrity. AD-derived BMEC cell lines also show an increased susceptibility to ethanol-induced barrier dysregulation at lower concentrations of ethanol (5 mM). Interestingly, our preliminary data shows that ethanol exposure seems to reduce BCRP efflux transporter activity in APP and PSEN1 AD cell lines.
Conclusion and Scientific Impact and Implications:
This study is novel in elucidating the enhanced disruption of BBB properties in familial AD-derived BMEC cell lines following ethanol exposure and provides insight into the potential harm of alcohol consumption in the development and/or exacerbation of BBB dysfunction in Alzheimer’s disease. Further studies will also unveil the possibility of ethanol-induced reduction of BCRP efflux transporter activity in APP and PSEN1 AD
Percutaneous Liver Biopsy Adverse Events in Stable Fontan Patients
Get PDFBackground:In patients who have undergone a Fontan operation, altered cardiac circulation can lead to several organ pathologies, including Fontan-associated liver disease. Transjugular liver biopsies are the standard for assessing liver disease in these patients, however data for a percutaneous approach in these patients is limited. Percutaneous liver biopsies are the preferred method in the general population. The objective of this study was to compare the rate of adverse events for percutaneous liver biopsies in Fontan patients to the general pediatric population.
Methods:A retrospective chart review was conducted on percutaneous liver biopsy patients over a five-year period. For each patient, a 90-day period post-biopsy was investigated to look for any indications of adverse events (pain, hemorrhage) and related work-up (imaging, hospital admission), scoring the severity of these events based on SIR adverse event classification. Patients were stratified based on if they underwent a cardiac catheterization procedure immediately prior to biopsy or not.
Results:A total of 412 biopsies were reviewed, 367 without cardiac catheterization and 45 with catheterization. Across the entire population, 38 adverse events were found, giving an overall adverse event rate of 9.2%. Comparing populations, non-catheterized patients were found to have an adverse event rate of 9.0%, with a minor rate of 7.2% and a major rate of 1.8%. The catheterized group had an adverse event rate of 11.1%, with a minor rate of 8.8% and a major rate of 2.3%. There were no lethal events. These rates align with reported literature.
Conclusion and Potential Impact:There was no significant difference in adverse event rates between Fontan patients and the general population after a percutaneous liver biopsy. This information can guide clinical decisions, as these biopsies are cheaper, less invasive, and do not expose patients to ionizing radiation
Comparison of Sinus Flora Using Various Next-Generation Sequencing Techniques Versus Standard Culturing
Get PDFBackground:Next generation sequencing methods are being developed to help diagnose infectious diseases at the point of care and to help resolve discrepant results. These new methods hope to replace longer, more tedious sequencing methods such as Sanger/shotgun sequencing and less sensitive culture results to provide a clinical diagnosis and start appropriate treatment sooner. In lieu of dated techniques, with next generation sequencing the physician could analyze samples in their clinic with relative ease and receive a sensitive diagnosis in a fraction of the time.
Objective:To compare percent agreement between standard culturing results of swabbed sinus samples on blood and chocolate agar to BIOFIRE® FILMARRAY® results, and use Oxford Nanopore and 16s illumina sequencing results to resolve discrepancies.
Study design:Swabs were taken of the nasal sinuses of 21 patients and flash frozen. Some of these swabs (15/21) were sequenced with 16s illumina sequencing. All these swabs were put into a saline solution and plated on blood and chocolate agar plates as a 1:100 loop dipped into the solution and as the original swab. These solutions were sequenced through the BIOFIRE® FILMARRAY® Torch System on a pneumonia and blood culture (BCID2) panel and through the Oxford Nanopore® MinION Mk1C® system.
Results:The pneumonia panel had 36% agreement with blood agar and 52% agreement with chocolate agar plates. Using the top 3 genus results, either Nanopore or 16s illumina sequencing resolved 92% of discrepancies between the pneumonia panel and blood agar and 90% of discrepancies between the pneumonia panel and chocolate agar plates. The blood culture panel had 43% agreement with blood agar and 57% agreement with chocolate agar plates. Nanopore or 16s illumina sequencing resolved 92% of discrepancies between the blood panel and blood agar and 89% of discrepancies between the blood panel and chocolate agar
Investigating Post-Operative Refractive Outcomes in Patients Undergoing Cataract Surgery to Assess the Potential Impact of a Concurrent Diagnosis of Dry Eye Disease (DED)
No full textCataract surgery is one of the most performed surgical procedures in the world. A cataract is defined as opaqueness in the interior of the ocular lens2. The exact etiology of cataracts is multifactorial ranging from environmental conditions to biochemical changes induced by aging3. The Intraocular lens (IOL) power calculation is an essential part of the pre-operative planning for cataract surgery as it determines the specific IOL that should be utilized for a patient. Keratometry measurements are required for this IOL power calculation, however, DED has been shown to cause inaccurate keratometry measurements4,5. We hypothesize that patients with DED undergoing cataract surgery will have a larger deviation from the predicted spherical equivalent (SE) post-operatively.
Patients who were over the age of 18 and underwent cataract surgery were included. Patients who had a diagnosis of glaucoma, Herpes Simplex Keratitis, punctual plugs, undergone Laser-Assisted in Situ Keratomileusis (LASIK) surgery, Radial Keratometry, or any form of corneal scarring were excluded from this study as they can negatively impact keratometry measurements.
The DED sample had a statistically significant larger SE deviation from the predicted SE compared to the healthy sample (p=0.037). The DED sample also had a statistically significant larger percentage of patients with an SE deviation of 0.50 D or greater (p=0.002). Finally, the DED had a statistically significant older age than the healthy group (p=0.028).
The significant difference in age between the healthy sample and the DED sample confirms the significant correlation between age and prevalence of DED the literature has described6. The statistically significant increased post-operative SE deviation from predicted SE within the DED sample can be the result of the increased variability in the tear film associated with DED. This can lead to inaccurate keratometry measurements, thus leading to incorrect IOL power calculations
Exploring the Influence of tGLI-1 on Temozolomide Resistance in Glioblastomas: Unraveling Novel Therapeutic Targets
Get PDFBackground/Objective:Temozolomide (TMZ) is a standard chemotherapy treatment for patients with glioblastoma (GBM), but its effectiveness is limited, with only 50% of patients initially responding and developing resistance over time. Glioma stem cells (GSCs) have been implicated in TMZ resistance, particularly the mesenchymal subtype. The truncated form of GLI1, known as tGLI1, is highly expressed in mesenchymal GSCs and has been associated with poor patient outcomes in GBM. However, the role of tGLI1 in TMZ resistance remains unknown.
Methods:The GBM cell line, U87MG, was utilized for this study. The IC50 of TMZ was determined using a cell viability assay. After successful transfection with vector, GLI1, and tGLI1, the cells were treated with the IC50 of TMZ to assess changes in cell viability between the groups.
Results:The IC50 of TMZ is 290.1 μM, as averaged between replicate assays. Thus far, the results showed that tGLI1-expressing cells exhibited significantly higher cell viability (average: 39.09%) compared to Vector (average: 26.78%) and GLI1 (average: 27.11%). However, the tGLI1 group displayed higher variability in cell viability results, as evidenced by a larger standard deviation (0.2758) and standard error (0.1592) compared to vector (SD: 0.0325, SE: 0.0188) and GLI1 (SD: 0.1354, SE: 0.0781). The One-Way ANOVA, followed by Tukey\u27s Multiple Comparison Test, results showed no statistically significant differences in cell viability between the groups.
Conclusion/Impact:The increased cell viability observed in tGLI1-expressing cells suggests a potential association between tGLI1 and TMZ resistance, warranting additional research to fully comprehend its impact on GBM treatment response. Further investigation and replication studies are needed to establish the robustness of these results. This knowledge may contribute to the development oftargeted therapies aimed at inhibiting tGLI1 or its downstream signaling pathways, potentiallyimproving the response to TMZ and patient outcomes
