A real-time simulation model of water quality with the impact of internal pollution for water source reservoir.

The water source reservoirs are the important urban water source in northern China. Although external pollution has been greatly improved, the internal pollutants in reservoirs continue to accumulate with the complex deposition and release processes, resulting in potential risks to water supply safety. To address the aforementioned issue, this paper proposed a simulation model of water quality named ECOlab EU1-WSR to simulate the spatio-temporal changes of water quality under the influence of internal pollution for the water source reservoirs. Based on the analysis of the water quality characteristics and the distribution of benthic vegetation in the reservoir, a three-dimensional hydrodynamic model was established based on MIKE3, the corresponding parameters and the related state variables were set, the ECOlab EU1-WSR model was established by secondly developing the original ECOlab EU1 template, and the real-time dynamic outputs of pollutant content in sediment were added to link the water quality index with sediment nutrition index for better revealing the impact of the internal pollution on the water quality. The performance of the model was evaluated by the case application on the water quality simulation of Daye reservoir and the optimization of the connection project between Daye reservoir and Xueye reservoir in Shandong Province China. The results showed that the model can accurately and simultaneously simulate the pollution in water and sediment by the comparative verification of hydrodynamics, water temperature, and water quality. Moreover, the model can effectively reflect the influence of the accumulation, deposition, and release of internal pollution on water quality by analyzing the correlation between the content of various pollution in water body and those in sediment, such as the total nitrogen and total phosphorus in the water body at the bottom of the water intake, were negatively correlated with the total nitrogen and total phosphorus in the sediments with correlation coefficients of 0.538 and 0.917, respectively. In addition, the optimal water inlet position and water flow rate of the connection project can be optimized and determined by using the model to effectively control water quality. The established model will be a useful tool for the design and management of a reservoir, the interconnection projects, and other water bodies by adaptively recoded.

A single-center analysis of lung transplantation outcomes in recipients aged 70 or older.

OBJECTIVES: As life expectancies continue to increase, a greater proportion of older patients will require lung transplants (LTs). However, there are no well-defined age cutoffs for which LT can be performed safely. At our high-volume LT center, we explored outcomes for LT recipients ≥70 years old versus <70 years old. METHODS: This is a retrospective single-center study of survival after LT among older recipients. Data were stratified by recipient age (≥70 years old versus <70 years old) and procedure type (single versus double lung transplant). Demographics and clinical variables were compared using Chi-square test and two sample t-test. Survival was assessed by Kaplan-Meier curves and compared by log-rank test with propensity score matching. RESULTS: 988 LTs were performed at our center over 10 years, including 289 LTs in patients ≥70 years old and 699 LTs in patients <70 years old. The recipient groups differed significantly by race (p < 0.0001), sex (p = 0.003), and disease etiology (p < 0.0001). Older patients were less likely to receive a double lung transplant compared to younger patients (p < 0.0001) and had lower rates of intraoperative cardiopulmonary bypass (p = 0.019) and shorter length of stay (p = 0.001). Both groups had overall high 1-year survival (85.8% versus 89.1%, respectively). Survival did not differ between groups after propensity matching (p = 0.15). CONCLUSIONS: Our data showed high survival for older and younger LT recipients. There were no statistically significant differences observed in survival between the groups after propensity matching, however, a trend in favour of younger patients was observed.

The Critical Blood-Sparing Effect of Tranexamic Acid (TXA) in Liposuction: A Systematic Review and Meta-Analysis.

Introduction: Tranexamic acid (TXA) has been used to improve bleeding outcomes in many surgical procedures. However, its blood-sparing effect in liposuction is not well established. Methods: A systematic literature search was performed using PubMed, Embase, Cumulated Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central, ClinicalTrials.gov, and WorldWideScience.org databases from their inception to October 8, 2021, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The authors focused on 3 main topics: 1) TXA, 2) liposuction, and 3) complications. We included articles evaluating the potential blood-sparing effects of TXA in liposuction. Studies were excluded if they were systematic review articles or protocol papers, animal studies, conference abstracts, survey studies, or non-English publications. Results: A total of 711 articles were identified, with 1 retrospective and 4 prospective (3 randomized) studies meeting our inclusion criteria. TXA was used in various forms: administered intravenously either on induction or after the procedure, mixed into the tumescent solution, or infiltrated into the liposuction sites after lipoaspiration. A significantly smaller reduction in hematocrit was noted in the TXA group compared with that in the non-TXA group (p<0.001) despite a significantly greater amount of lipoaspirate removed in the TXA group (p<0.001). Patients in non-TXA cohorts experienced adverse effects (such as seroma and need for transfusion) that were not seen in TXA cohorts. Conclusion: TXA use in patients undergoing liposuction seems to be associated with a beneficial blood-sparing effect, which may enhance safety in this population. Future studies should aim to determine the optimal route and dosing for TXA in liposuction. Evidence Based Medicine: Level IV.

Distinct functional neutrophil phenotypes in sepsis patients correlate with disease severity.

Purpose: Sepsis is a clinical syndrome defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a highly heterogeneous syndrome with distinct phenotypes that impact immune function and response to infection. To develop targeted therapeutics, immunophenotyping is needed to identify distinct functional phenotypes of immune cells. In this study, we utilized our Organ-on-Chip assay to categorize sepsis patients into distinct phenotypes using patient data, neutrophil functional analysis, and proteomics. Methods: Following informed consent, neutrophils and plasma were isolated from sepsis patients in the Temple University Hospital ICU (n=45) and healthy control donors (n=7). Human lung microvascular endothelial cells (HLMVEC) were cultured in the Organ-on-Chip and treated with buffer or cytomix ((TNF/IL-1ß/IFNγ). Neutrophil adhesion and migration across HLMVEC in the Organ-on-Chip were used to categorize functional neutrophil phenotypes. Quantitative label-free global proteomics was performed on neutrophils to identify differentially expressed proteins. Plasma levels of sepsis biomarkers and neutrophil extracellular traps (NETs) were determined by ELISA. Results: We identified three functional phenotypes in critically ill ICU sepsis patients based on ex vivo neutrophil adhesion and migration patterns. The phenotypes were classified as: Hyperimmune characterized by enhanced neutrophil adhesion and migration, Hypoimmune that was unresponsive to stimulation, and Hybrid with increased adhesion but blunted migration. These functional phenotypes were associated with distinct proteomic signatures and differentiated sepsis patients by important clinical parameters related to disease severity. The Hyperimmune group demonstrated higher oxygen requirements, increased mechanical ventilation, and longer ICU length of stay compared to the Hypoimmune and Hybrid groups. Patients with the Hyperimmune neutrophil phenotype had significantly increased circulating neutrophils and elevated plasma levels NETs. Conclusion: Neutrophils and NETs play a critical role in vascular barrier dysfunction in sepsis and elevated NETs may be a key biomarker identifying the Hyperimmune group. Our results establish significant associations between specific neutrophil functional phenotypes and disease severity and identify important functional parameters in sepsis pathophysiology that may provide a new approach to classify sepsis patients for specific therapeutic interventions.

Pelvic Vein Obstruction in Chronic Thromboembolic Pulmonary Hypertension: A Novel Association.

Background: Pelvic venous obstruction (PVO), defined as greater than 50% stenosis or occlusion of pelvic veins, is a known risk factor for deep vein thrombosis (DVT). DVT is a known risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), but the prevalence of PVO in CTEPH is unknown. Methods: This cross-sectional study at Temple University's tertiary referral center for Pulmonary Hypertension, Right Heart Failure, and CTEPH sought to identify the presence of PVO in patients with CTEPH who underwent cardiac catheterization, pulmonary angiography, and venography. Results: A total of 193 CTEPH patients were referred for pulmonary angiography, and among these, 148 underwent venography. PVO was identified in 65 (44%) patients. Lower extremity (LE) DVT was associated with PVO (p = 0.004). The severity of pulmonary hypertension was similar with and without PVO (mean pulmonary artery pressure 43.0 ± 10.3 mm Hg vs. 43.8 ± 12.4 mm Hg, p = 0.70), as was the need for pulmonary thromboendarterectomy (69.2% vs. 61.4%, p = 0.32). Conclusions: Pelvic vein obstruction is common and a novel clinical association in patients with CTEPH, particularly in patients with a history of LE DVT. PVO and its role in CTEPH warrants further study, including the potential role of revascularization to mitigate further risk.

Heart Transplant Human Leukocyte Antigen Matching in the Modern Era.

BACKGROUND: Although numerous reports have studied the consequences of human leukocyte antigen (HLA) mismatching in renal transplantation, there are limited and outdated data analyzing this association in thoracic organ transplantation. Therefore, our study reviewed the impact of HLA mismatching at both the total and the loci levels in the modern-era heart-transplant procedure on survival and chronic rejection outcomes. METHODS: We performed a retrospective analysis of adult patients after heart transplant by using the United Network for Organ Sharing database from January 2005-July 2021. Total HLA and HLA-A, HLA-B and HLA-DR mismatches were analyzed. Survival and cardiac allograft vasculopathy were the outcomes of interest during a 10-year follow-up period using Kaplan-Meier curves, log-rank tests and multivariable regression models. RESULTS: A total of 33,060 patients were included in this study. Recipients with a high degree of HLA mismatching had increased incidences of acute organ rejection. There were no significant differences in mortality rates among any of the total or loci level groups. Similarly, there were no significant differences between total HLA mismatch groups in time to first cardiac allograft vasculopathy, though mismatching at the HLA-DR locus was associated with an increased risk of cardiac allograft vasculopathy. CONCLUSION: Our analysis suggests that HLA mismatch is not a significant predictor of survival in the modern era. Overall, the clinical implications of this study provide reassuring data for the continued use of non-HLA-matched donors in an effort to increase the donor pool. If HLA matching is to be considered for heart transplant donor-recipient selection, matching at the HLA-DR locus should take priority due to its association with cardiac allograft vasculopathy.

Racial and ethnic disparities in inferior vena cava filter placement for deep vein thrombosis in the United States.

OBJECTIVE: We sought to determine whether racial and ethnic disparities existed in inferior vena cava (IVC) filter (IVCF) placement rates among Black and Latino patients for the treatment of acute proximal lower extremity (LE) deep vein thrombosis (DVT) in the United States from 2016 to 2019. METHODS: We performed a retrospective review of National Inpatient Sample data to identify adult patients with a primary discharge diagnosis of acute proximal LE DVT from January 2016 to December 2019, including self-reported patient race and ethnicity. IVCF placement rates were identified using International Classification of Diseases, 10th revision, codes. Weighted multivariable logistic regression was used to compare IVCF use by race and ethnicity. The regression model was adjusted for patient demographics (ie, sex, primary payer, quartile classification of household income), hospital information (ie, region, location, teaching status, bed size), weekend admission, and clinical characteristics (ie, modified Charlson comorbidity index, hypertension, atrial fibrillation, diabetes mellitus type 2, congestive heart failure, dyslipidemia, coronary artery disease, smoking, obesity, alcohol abuse, chronic kidney disease, pulmonary embolism, malignancy, contraindications to anticoagulation, including other major bleeding). RESULTS: Of 134,499 acute proximal LE DVT patients, 18,909 (14.1%) received an IVCF. Of the patients who received an IVCF, 12,733 were White (67.3%), 3563 were Black (18.8%), and 1679 were Latino (8.9%). IVCF placement decreased for all patient groups between 2016 and 2019. After adjusting for the U.S. population distribution, the IVCF placement rates were 11 to 12/100,000 persons for Black patients, 7 to 8/100,000 persons for White patients, and 4 to 5/100,000 persons for Latino patients. The difference in IVCF placement rates was statistically significant between patient groups (Black patients vs White patients, P < .05; Black patients vs Latino patients, P < .05; Latino patients vs White patients, P < .05). CONCLUSIONS: This nationwide study showed that Black patients have higher IVCF placement rates compared with White and Latino patients. Given the known long-term complications and uncertain benefits of IVCFs, coupled with the 2010 U.S. Food and Drug Administration safety warning regarding adverse patient events for these devices, proactive measures should be taken to address this disparity among the Black patient population to promote health equity. Future work should assess whether clinician bias might be perpetuating this disparity.

Association of vena cava filters and catheter-directed thrombolysis for deep vein thrombosis with hospital readmissions.

BACKGROUND: Acute deep vein thrombosis (DVT) affects >350,000 patients each year in the United States. Contemporary rehospitalization rates and predictors of acute DVT have not been well-characterized. We aimed to evaluate the all-cause 30-day readmission rate and its association with catheter-directed thrombolysis and vena cava filters in patients with proximal and caval DVT. METHODS: Patients with an index hospitalization for acute proximal lower extremity DVT were evaluated for unplanned readmission rates at 30 days using the Nationwide Readmission Database from 2016 to 2017. We used Cox proportional hazard model to determine the predictors of 30-day readmissions and their association with inferior vena cava (IVC) filter and CDT use. RESULTS: We identified 58,306 adult patients with an index hospitalization for acute proximal DVT. The unplanned 30-day rehospitalization rate was 14.7% (95% confidence interval [CI], 14.5-15.0%). There were 4995 patients (10.0%) who underwent CDT and 6085 (12.2%) who underwent IVC filter placement. In multivariable analysis, only CDT was associated with a lower hazard for rehospitalization (hazard ratio [HR], 0.77; 95% CI, 0.71-0.84; P < .001), whereas IVC filter placement (HR, 1.26; 95% CI, 1.19-1.34; P < .001), Charlson Comorbidity Index of >3 (HR, 1.47; 95% CI, 1.38-1.56; P < .001), malignancy (HR, 1.45; 95% CI, 1.34-1.57; P < .001), and length of stay >5 days (HR, 1.39; 95% CI, 1.33-1.46; P < .001), and acute kidney injury (HR, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with higher readmission rates. CONCLUSIONS: The 30-day unplanned rehospitalization rate continues to be high in patients with acute proximal DVT. CDT was associated with lower rehospitalization rates, whereas IVC filter placement was associated with increased rehospitalization rates.

Maternal Blood Lipid Biomarkers of Oligodendrocyte Pathology to Predict Fetal Alcohol Spectrum Disorders.

Introduction: Up to 9.9% of children have fetal alcohol spectrum disorders (FASD), the most frequent cause of intellectual disability in the US. FASD may involve abnormal brain development, including dysmyelination, suggesting abnormal development of oligodendrocytes (OLs), which make myelin and are rich in lipids. Indeed, low serum levels of omega-3 fatty acids (ω-3) have been reported in FASD. Free fatty acids bind to specific receptors (FFARs). We have isolated cell type-specific fetal brain-derived exosomes (FB-E) from maternal blood and sampled their contents to search for lipid-related biomarkers that predict FASD. Methods: Blood samples were collected from two groups of pregnant women: 1) those who consumed EtOH during pregnancy, and 2) non-EtOH using controls, under an IRB-approved protocol. Serum and OL-derived exosomes (OL-Es) were used to assay myelin basic protein (MBP) and FFAR by ELISA and droplet digital PCR (ddPCR), respectively. Results: FFAR and MBP proteins were downregulated in the EtOH group compared to controls, and this difference was greatest in OL-Es from maternal blood compared maternal serum. Conclusion: MBP and FFAR levels were reduced in OL-Es from EtOH-consuming pregnant women. The data suggest potential therapeutic targets to predict which children are at risk for developing FASD and reduce dysmyelination in developing.

Deciphering the True Immunologic Risk in Renal Transplantation in Patients With HIV.

Since 1995, rates of end-stage renal disease have risen dramatically in patients living with HIV infection. However, given the concern for higher rates of acute rejection in this patient population, the immunologic threat posed by HIV infection is a specter clinicians must continually confront. Living donor transplantation may negate this risk; this study aims to assess the benefit of living donor transplantation in this population and to ascertain the immunologic risk faced by patients who are HIV-infected. The 2021 UNOS database was queried, and all HIV-infected kidney transplant recipients since 1987 were identified. Recipients were stratified based on deceased (DDKT) vs living (LDKT) donor status. Overall survival, allograft survival, acute rejection, panel reactive antibody (PRA) percentage, and crossmatch positivity were compared between groups. One thousand two hundred twenty-six patients underwent DDKT, and 304 patients underwent LDKT. Living donor kidney transplantation demonstrated greater overall survival (P = .045) and graft survival (P < .001). However, no difference in acute rejection was noted between the cohorts, and no difference in overall or graft survival was evident based on PRA percentage. Crossmatch positive status did not negatively affect graft survival. Patients with HIV undergoing LDKT fared better than those undergoing DDKT. Nevertheless, patients at higher immunologic risk-elevated PRA% and crossmatch positivity-did not experience graft loss at a higher rate than patients at lower immunologic risk. These results were valid in both DDKT and LDKT cohorts. These findings suggest that infection with HIV does not overtly increase patients' immunologic risk, and concerns surrounding transplantation in this population may be overestimated.

A Shorter Door-In-Door-Out Time Is Associated with Improved Outcome in Large Vessel Occlusion Stroke.

Introduction: Endovascular thrombectomy (EVT) significantly improves outcomes in large vessel occlusion stroke (LVOS). When a patient with a LVOS arrives at a hospital that does not perform EVT, emergent transfer to an endovascular stroke center (ESC) is required. Our objective was to determine the association between door-in-door-out time (DIDO) and 90-day outcomes in patients undergoing EVT. Methods: We conducted an analysis of the Optimizing Prehospital Stroke Systems of Care-Reacting to Changing Paradigms (OPUS-REACH) registry of 2,400 LVOS patients treated at nine ESCs in the United States. We examined the association between DIDO times and 90-day outcomes as measured by the modified Rankin scale. Results: A total of 435 patients were included in the final analysis. The mean DIDO time for patients with good outcomes was 17 minute shorter than patients with poor outcomes (122 minutes [min] vs 139 min, P = 0.04). Absolute DIDO cutoff times of ≤60 min, ≤90 min, or ≤120 min were not associated with improved functional outcomes (46.4 vs 32.3%, P = 0.12; 38.6 vs 30.6%, P = 0.10; and 36.4 vs 28.9%, P = 0.10, respectively). This held true for patients with hyperacute strokes of less than four-hour onset. Lower baseline National Institutes of Health Stroke Scale (NIHSS) score (11.9 vs 18.2, P = <.001) and younger age (62.5 vs 74.9 years (P < .001) were associated with improved outcomes. On multiple regression analysis, age (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.45-2.02) and baseline NIHSS score (OR 1.67, 95% CI 1.42-1.98) were associated with improved outcomes while DIDO time was not associated with better outcome (OR 1.13, 95% CI 0.99-1.30). Conclusion: Although the DIDO time was shorter for patients with a good outcome, this was non-significant in multiple regression analysis. Receipt of intravenous thrombolysis and time to EVT were not associated with better outcomes, while male gender, lower age, arrival by private vehicle, and lower NIHSS score portended better outcomes. No absolute DIDO-time cutoff or modifiable factor was associated with improved outcomes for LVOS. This study underscores the need to streamline DIDO times but not to set an artificial DIDO time benchmark to meet.

Delay in hospital presentation is the main reason large vessel occlusion stroke patients do not receive intravenous thrombolysi.

Objectives: Intravenous thrombolysis (IVT) and endovascular therapy (EVT) are the mainstays of treatment for large vessel occlusion stroke (LVOS). Prior studies have examined why patients have not received IVT, the most cited reasons being last-known-well (LKW) to hospital arrival of >4.5 hours and minor/resolving stroke symptoms. Given that LVOS patients typically present moderate-to-severe neurologic deficits, these patients should be easier to identify and treat than patients with minor strokes. This investigation explores why IVT was not administered to a cohort of LVOS patients who underwent EVT. Methods: This is an analysis of the Optimizing the Use of Prehospital Stroke Systems of Care (OPUS-REACH) registry, which contains patients from 9 endovascular centers who underwent EVT between 2015 and 2020. The exposure of interest was the receipt of intravenous thrombolysis. Descriptive summary statistics are presented as means and SDs for continuous variables and as frequencies with percentages for categorical variables. Two-sample t tests were used to compare continuous variables and the chi-square test was used to compare categorical variables between those who received IVT and those who did not receive EVT. Results: Two thousand forty-three patients were included and 60% did not receive IVT. The most common reason for withholding IVT was LKW to arrival of >4.5 (57.2%). The second most common contraindication was oral anticoagulation (15.5%). On multivariable analysis, 2 factors were associated with not receiving IVT: increasing age (odds ratio [OR] 0.86; 95% confidence interval [CI] 0.78-0.93) and increasing time from LKW-to hospital arrival (OR 0.45 95% CI 0.46-0.49). Conclusion: Like prior studies, the most frequent reason for exclusion from IVT was a LKW to hospital presentation of >4.5 hours; the second reason was anticoagulation. Efforts must be made to increase awareness of the time-sensitive nature of IVT and evaluate the safety of IVT in patients on oral anticoagulants.

Increased-risk versus standard-risk donation in lung transplantation: A United Network of Organ Sharing analysis.

OBJECTIVES: Donors with characteristics that increase risk of hepatitis B virus, hepatitis C virus, and HIV transmission are deemed increased-risk donors (IRDs) per Public Health Service guidelines. Compared with organs from standard-risk donors (SRDs), IRD organs are more frequently declined. We sought to investigate the outcomes of IRD lung transplant recipients following the 2013 guideline change. METHODS: We retrospectively identified lung transplant recipients using the United Network of Organ Sharing registry (February 2014 to March 2020). Patients were divided into 2 cohorts, based on Centers for Disease Control and Prevention risk status of the donor: SRD or IRD. Demographics and clinical parameters were compared across groups. Survival was compared using Kaplan-Meier curves and log-rank tests. Cox proportional hazard model was performed to identify variables associated with survival outcome. RESULTS: We identified 13,205 lung transplant recipients, 9963 who received allografts from SRDs and 3242 who received allografts from IRDs. In both groups, most donors were White, male, and <30 years old. IRDs demonstrated greater rates of heavy alcohol, cigarette, and cocaine use. SRDs had greater rates of cancer, hypertension, previous myocardial infarction, and diabetes. Survival analysis demonstrated no significant difference in 90-day, 1-year, 3-year, or 5-year survival outcome between SRD and IRD recipients (P = .34, P = .67, P = .40, P = .52, respectively). Cox regression demonstrated that double-lung transplants were associated with 13% decreased mortality risk compared with single-lung (P = .0009). CONCLUSIONS: IRD and SRD recipients demonstrated equivalent survival outcomes. Our study suggests that IRDs offer a safe approach to expand the donor pool and increase availability of lungs for transplantation.

ER stress mediates Angiotensin II-augmented innate immunity memory and facilitates distinct susceptibilities of thoracic from abdominal aorta to aneurysm development.

To determine the roles of endoplasmic reticulum (ER) stress and trained immunity, we performed transcriptome analyses on the thoracic aorta (TA) and abdominal aorta (AA) from the angiotensin II (Ang II)-HFD-ApoE-KO aneurysm model and made significant findings: 1) Ang II bypassed HFD-induced metabolic reprogramming and induced stronger inflammation in AA than in TA; 2) Ang II and HFD upregulated 890 genes in AA versus TA and induced cytokine signaling; 3) Ang II AA and TA upregulated 73 and 68 cytokines, scRNA-Seq identified markers of macrophages and immune cells, cell death regulators, respectively; transdifferentiation markers of neuron, glial, and squamous epithelial cells were upregulated by Ang II-AA and TA; and pyroptosis signaling with IL-1ß and caspase-4 were more upregulated in Ang II-AA than in TA; 4) Six upregulated transcriptomes in patients with AAA, Ang II AA, Ang II TA, additional aneurysm models, PPE-AAA and BAPN-Ang II-AAA, were partially overlapped with 10 lists of new ER stress gene sets including 3 interaction protein lists of ER stress regulators ATF6, PERK, and IRE1, HPA ER localization genes, KEGG signal genes, XBP1 transcription targets, ATF4 (PERK) targets, ATF6 targets, thapsigargin ER stress genes, tunicamycin-ER stress genes, respectively; 5) Ang II-AA and TA upregulated ROS regulators, MitoCarta genes, trained immunity genes, and glycolysis genes; and 6) Gene KO transcriptomes indicated that ATF6 and PERK played more significant roles than IRE1 in promoting AAA and trained immunity whereas antioxidant NRF2 inhibited them. Our unprecedented ER-focused transcriptomic analyses have provided novel insights on the roles of ER as an immune organelle in sensing various DAMPs and initiating ER stress that triggers Ang II-accelerated trained immunity and differs susceptibilities of thoracic and abdominal aortas to diseases.

Exosomal Lipid Biomarkers of Oligodendrocyte Pathology to Predict Scoliosis in Children with Cerebral Palsy.

Introduction: Cerebral Palsy (CP), the most common cause of disability in children, is phenotypically heterogeneous. Approximately 20% of cases develop severe scoliosis. A pathological hallmark of CP is periventricular leukomalacia (PVL), which is due to dysmyelination, suggesting the possibility of a lipidomic abnormality. Risk factors for CP include perinatal hypoxia, prematurity, multiple gestation, ischemia, infection, and maternal alcohol consumption. There is evidence for low serum levels of omega-3 (ω-3) fatty acids in CP patients, and separately in idiopathic scoliosis. Many effects of free fatty acids (FFAs) are mediated via specific G protein-coupled free fatty acid receptors (FFARs), which play essential roles as nutritional and signaling molecules. FFAs, including ω-3, and their receptors are involved in the development and metabolism of oligodendrocytes (OLs), and are critical to myelination. Thus, the cases of CP that will develop severe scoliosis might be those in which there is a deficiency of ω-3, FFARs, or other lipidomic abnormality that is detectable early in the plasma. If so, we might be able to predict scoliosis and prevent it with dietary supplementation. Methods: Blood samples were collected from four groups of patients at the Philadelphia Shriners Children's Hospital (SCH-P): 1) patients with CP; 2) severe scoliosis (>40o); 3) CP plus scoliosis; and 4) non-impaired controls stratified by age (2-18 yrs), gender, and race/ethnicity, under an IRB-approved protocol. Serum proteins and RNA were purified, and OL-derived exosomes (OL-Es) isolated, using myelin basic protein (MBP) as a late OL marker. Protein was used for the detection of MBP and FFAR by enzyme-linked immunosorbent assays (ELISAs), and by flow cytometry. RNA was assayed by digital droplet polymerase chain reaction (ddPCR) for OL markers and FFAR expression. Results: FFAR and MBP proteins were downregulated in each of the three patient groups compared to controls, and this difference was greatest in both patients with CP plus scoliosis. Conclusion: Altogether, MBP and FFAR levels were reduced in OL-Es from both children with CP plus scoliosis. The lipid abnormalities specific to CP with scoliosis were concentrated in OLs. Our data might i) suggest therapeutic targets to reduce dysmyelination and scoliosis in CP, ii) predict which children are at risk for developing scoliosis, iii) lead to therapeutic trials of fatty acids for CP and other dysmyelinating neurological disorders.

Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates.

In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV infection. EBT-001 is an AAV9-based vector delivering SaCas9 and dual guide RNAs designed to target multiple regions of the SIV genome: the viral LTRs, and the Gag gene. The results presented here demonstrate that a single IV inoculation of EBT-001 at each of 3 dose levels (1.4 × 1012, 1.4 × 1013 and 1.4 × 1014 genome copies/kg) resulted in broad and functional biodistribution of AAV9-EBT-001 to known tissue reservoirs of SIV. No off-target effects or abnormal pathology were observed, and animals returned to their normal body weight after receiving EBT-001. Importantly, the macaques that received the 2 highest doses of EBT-001 showed improved absolute lymphocyte counts as compared to antiretroviral-treated controls. Taken together, these results demonstrate safety, biodistribution, and in vivo proviral DNA editing following IV administration of EBT-001, supporting the further development of CRISPR-based gene editing as a potential therapeutic approach for HIV in humans.

Incidence and Predictors of Acute Limb Ischemia in Patients With Acute Myocardial Infarction-Insight from National Readmission Database.

Acute limb ischemia (ALI) has been a rare complication of acute myocardial infarction (AMI), however, with the increasing use of mechanical circulatory devices it is seen more frequently. The incidence and predictors of ALI in patients with AMI in contemporary clinical practice are unknown. A retrospective review of patients with index hospitalization for AMI in the Nationwide Readmission Database from 2016 to 2019 was done. We evaluated the annual incidence of ALI and its impact on outcomes. We used multivariate logistic regression analysis to determine predictors of ALI. In 1,283,586 patients with AMI, 3,971 patients (0.31%) had ALI and 365 (0.03%) had limb amputation. The 3 major predictors of ALI were peripheral artery disease (odds ratio [OR] 11.91, 95% confidence interval [CI]: 10.78 to 13.51), intravascular microaxial left ventricular assist device (OR 4.39, 95% CI 3.86 to 5.00), and veno-arterial extracorporeal membrane oxygenation (OR 4.37, 95% CI 3.19 to 6.01). Intra-aortic balloon pump had a substantially lower predictive ability (OR 1.81, 95% CI 1.63 to 2.0, p <0.0001) than other forms of mechanical circulatory support. The mortality rate in patients with ALI was significantly higher than those without ALI (19.49% vs 4.85%, p <0.0001). Patients who developed ALI had higher rates of amputation (1.59% vs 0.02%, p <0.0001). This observational nationwide study showed that ALI is an important complication in patients with AMI and is more frequently seen in patients who have peripheral artery disease, and require a left ventricular assist device or venoarterial extracorporeal membrane oxygenation. This complication was also associated with significantly higher in-hospital mortality.

Transmitted/founder SHIV.D replicates in the brain, causes neuropathogenesis, and persists on combination antiretroviral therapy in rhesus macaques.

A biologically relevant non-human primate (NHP) model of HIV persistence in the central nervous system (CNS) is necessary. Most current NHP/SIV models of HIV infection fail to recapitulate viral persistence in the CNS without encephalitis or fail to employ viruses that authentically represent the ongoing HIV-1 pandemic. Here, we demonstrate viral replication in the brain and neuropathogenesis after combination antiretroviral therapy (ART) in rhesus macaques (RMs) using novel macrophage-tropic transmitted/founder (TF) simian-human immunodeficiency virus SHIV.D.191,859 (SHIV.D). Quantitative immunohistochemistry (IHC) and DNA/RNAscope in situ hybridization (ISH) were performed on three brain regions from six SHIV.D-infected RMs; two necropsied while viremic, two during analytical treatment interruptions, and two on suppressive ART. We demonstrated myeloid-mediated neuroinflammation, viral replication, and proviral DNA in the brain in all animals. These results demonstrate that TF SHIV.D models native HIV-1 CNS replication, pathogenesis, and persistence on ART in rhesus macaques.

Refined Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension: Initial Results of U.S. Regional Program.

Objectives: We sought to evaluate the efficacy and safety of refined balloon pulmonary angioplasty (BPA) in the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Background: BPA is rapidly evolving therapeutic option for patients with nonsurgical CTEPH. There are few US studies that have reported on the outcomes of this novel therapeutic option. Methods: This is a retrospective study of CTEPH patients that underwent BPA at Temple University Hospital. The primary efficacy endpoint was the change in pulmonary vascular resistance (PVR) after BPA as compared to baseline and the primary safety endpoint was the rate of hemoptysis within 24 hours. Secondary endpoints included death, WHO functional class, and 6-minute walk distance (6MWD). We used logistic regression to evaluate factors associated with a hemodynamic and functional response. Results: A total of 211 BPA sessions were performed on 77 patients (average 2.7 ± 1.7 sessions/patient). After BPA the mean PVR improved by 26% (P<0.001) while the mean 6MWD improved by 71.7 meters (P <0.001) and WHO functional class improved by one functional class (P <0.001). Ten sessions (4.7%) were complicated by hemoptysis. The independent factors associated with a improved functional and hemodynamic response included the pre-procedural use of riociguat, reduce baseline PA compliance and > 3 BPA sessions per patient. Conclusion: This single center study from the US showed that BPA with refined techniques in patients with CTEPH was safe and was associated with significant improvements in pulmonary hemodynamics and functional capacity.