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1.
Pediatr Dermatol ; 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38632884

ABSTRACT

Prostaglandin E1 (PGE1) is a substance produced by the patent ductus arteriosus that keeps it open. PGE1 can be a lifesaving drug for infants born with ductus-dependent congenital heart disease (CHD) where there is a block of blood flow to the lungs or transposition of great arteries. We present a case of a 36-week, 2-day gestation neonate with CHD who developed bright erythematous annular and polycyclic patches on day 2 of PGE1 administration. When PGE1 dosing was decreased, the rash resolved on its own. Our case demonstrates that PGE1 treatment may not need to be interrupted.

2.
Article in English | MEDLINE | ID: mdl-38685466

ABSTRACT

OBJECTIVE: To assess a machine learning model's ability to predict the occurrence of life altering events (LAE) in hemiarch surgery and determine contributing patient characteristics and intraoperative factors. METHODS: In total, 602 patients who underwent hemiarch replacement at a high-volume, aortic center from 2009-2022 were included. Patients were randomly divided into training (80%) and testing (20%) sets with various eXtreme gradient boosting (XGBoost) candidate models constructed to predict the risk of experiencing LAE, including stroke, mortality, or new renal replacement therapy requirement. 64 input parameters from the index hospitalization were identified, including 24 demographic characteristics as well as 8 pre-operative and 32 intra-operative variables. A SHapley Additive exPlanation (SHAP) beeswarm plot was generated to identify and interpret the impact of individual features on the predictions of the final model. RESULTS: A LAE was noted in 15% (90/602) of patients who underwent hemiarch replacement, including urgent/emergent cases and dissections. The final XGBoost model demonstrated a cross-validation accuracy of 88% on the testing set and was well-calibrated as evidenced by a low Brier score of 0.12. The best performing model achieved an area under the receiver-operating characteristic curve of 0.76 and an area under the precision-recall curve of 0.55. The SHAP beeswarm plot provided insights into key features that significantly influenced model prediction. CONCLUSIONS: Machine learning demonstrated superior accuracy in predicting hemiarch patients that would experience a LAE. This model may help to guide patients and clinicians in stratifying risk on an individual basis, which may in turn influence clinical decision-making.

3.
J Surg Case Rep ; 2024(3): rjae114, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38463743

ABSTRACT

We present the case of a 3-week-old girl with LUMBAR syndrome, a rare condition involving segmental infantile hemangiomas (IH) in the lumbosacral region, myelopathy, and other congenital anomalies. The patient developed severe ulceration of a left buttock IH. Treatment included broad-spectrum antibiotics, debridement, and a laparoscopic temporary colostomy. Propranolol therapy, wound care, and fecal diversion led to successful healing of the ulceration. The report highlights the challenges of ulcerated IH in the perineal area due to exposure to urine and stool. The comprehensive approach resulted in positive outcomes, including the successful surgical treatment of spinal dysraphism, successful colostomy reversal, and developmental progress. This case contributes insight into the surgical management of severe perianal ulcerated IH associated with LUMBAR syndrome, highlighting the importance of a tailored surgical approach with a multidisciplinary framework.

4.
JAMA Netw Open ; 6(11): e2343402, 2023 Nov 01.
Article in English | MEDLINE | ID: mdl-37971742

ABSTRACT

Importance: The clinical characteristics and prognosis of patients with ST-segment elevation myocardial infarction (STEMI) with nonobstructive coronaries (MINOCA) are largely unknown. Objective: To assess differences in 5-year mortality in patients presenting with STEMI due to MINOCA and MINOCA mimickers as compared with obstructive disease. Design, Setting, and Participants: A retrospective analysis of a prospective registry-based cohort study of consecutive STEMI activations at 3 regional Midwest STEMI programs. STEMI without a culprit artery and elevated troponin levels were categorized as MINOCA (absence of coronary artery stenosis >50% and confirmed or suspected coronary artery plaque disruption, epicardial coronary spasm, or coronary embolism/thrombosis) or MINOCA mimickers (takotsubo cardiomyopathy, myocarditis, or nonischemic cardiomyopathy). Data were analyzed from March 2003 to December 2020. Main Outcomes and Measures: Adjusted Cox regression analysis was used to assess 5-year mortality risk in STEMI presenting with MINOCA and MINOCA mimickers in comparison with obstructive disease. Results: Among 8560 consecutive patients with STEMI, mean (SD) age was 62 (14) years, 30% were female (2609 participants), and 94% were non-Hispanic White (4358 participants). The cohort included 8151 patients with STEMI due to obstructive disease (95.2%), 120 patients with MINOCA (1.4%), and 289 patients with MINOCA mimickers (3.8%). Patients were followed up for a median (IQR) of 7.1 (3.6-10.7) years. Patients with MINOCA and MINOCA mimickers were less likely to be discharged with cardiac medications compared with obstructive disease. At 5-year follow-up, mortality in STEMI presenting with obstructive disease (1228 participants [16%]) was similar to MINOCA (20 participants [18%]; χ21 = 1.1; log-rank P = .29) and MINOCA mimickers (52 participants [18%]; χ21 = 2.3; log-rank P = .13). In adjusted Cox regression analysis compared with obstructive disease, the 5-year mortality hazard risk was 1.93 times higher in MINOCA (95% CI, 1.06-3.53) and similar in MINOCA mimickers (HR, 1.08; 95% CI, 0.79-1.49). Conclusions and Relevance: In this large multicenter cohort study of consecutive clinical patients with STEMI, presenting with MINOCA was associated with a higher risk of mortality than obstructive disease; the risk of mortality was similar in patients with MINOCA mimickers and obstructive disease. Further investigation is necessary to understand the pathophysiologic mechanisms involved in this high-risk STEMI population.


Subject(s)
Myocardial Infarction , ST Elevation Myocardial Infarction , Humans , Female , Middle Aged , Male , ST Elevation Myocardial Infarction/epidemiology , Myocardial Infarction/epidemiology , MINOCA , Retrospective Studies , Cohort Studies , Coronary Vessels , Coronary Angiography
5.
J Orthop Trauma ; 37(11S): S7-S11, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37828695

ABSTRACT

OBJECTIVES: Electronic patient-reported outcome measure (E-PROM) collection is a technological advancement that has the potential to facilitate PROM collection in orthopaedic trauma. The purpose of this study was to compare E-PROM versus in-person PROM collection. DESIGN: This is a retrospective comparative study. SETTING: Urban Level I trauma center. PATIENTS/PARTICIPANTS: One hundred and fifty consecutive operative orthopaedic trauma patients. INTERVENTION: The Percent of Normal single assessment numerical evaluation and patient-reported outcomes measurement information system physical function were collected through automated e-mails from an online patient-engagement platform (PatientIQ, Chicago, IL) 2-week, 6-week, 3-month, and 6-month postoperatively. The Percent of Normal was also administered to patients in clinic at the same time intervals. MAIN OUTCOME MEASUREMENTS: Completion of PROMs; Loss to follow-up. RESULTS: The median clinical follow-up time was 4 months (interquartile range: 1.3-6 months), and 42.7% (64/150) were lost to follow-up. Loss to follow-up was associated with a more disadvantaged area deprivation index [observed difference, 7.0, 95% confidence interval, 1.0 to 13.0; P = 0.01] and noncommercial/no insurance (observed difference 34.8%, confidence interval, 20.9%-45.5%; P < 0.0001). In-person PROM collection was more successful than E-PROM collection at all intervals [2-week (51.3% vs 20.7), 6-week (46.7% vs 20.0%), 3-month (50.0% vs 18.7%), and 6-month (38.0% vs 18.7%), P < 0.0001]. Patients who completed 3-month E-PROMs had longer clinical follow-up (5.2 vs. 3.0 months, P = 0.004) and a trend of being less likely to be lost to follow-up (28.6% vs 45.9%, P = 0.13). CONCLUSION: E-PROMs were less successful than in-person PROM collection in trauma patients at an urban safety net trauma center. LEVEL OF EVIDENCE: Diagnostic Level III.


Subject(s)
Orthopedics , Humans , Trauma Centers , Retrospective Studies , Patient Reported Outcome Measures
6.
Surgery ; 174(4): 1034-1040, 2023 10.
Article in English | MEDLINE | ID: mdl-37500409

ABSTRACT

BACKGROUND: Prehospital endotracheal intubation is a debated topic, and few studies have found it beneficial after trauma. A growing body of evidence suggests that prehospital endotracheal intubation is associated with increased morbidity and mortality. Our study was designed to compare patients with attempted prehospital endotracheal intubation to those intubated promptly upon emergency department arrival. METHODS: A retrospective review of a single-center trauma research data repository was utilized. Inclusion criteria included age ≥15 years, transport from the scene by ground ambulance, and undergoing prehospital endotracheal intubation attempts or intubation within 10 minutes of emergency department arrival without prior prehospital endotracheal intubation attempt. Propensity score matching was used to minimize differences in baseline characteristics between groups. Standard mean differences are also presented for pre- and post-matching datasets to evaluate for covariate balance. RESULTS: In total, 208 patients met the inclusion criteria. Of these, 95 patients (46%) underwent prehospital endotracheal intubation, which was successful in 47% of cases. A control group of 113 patients (54%) were intubated within 10 minutes of emergency department arrival. We performed propensity score matching between cohorts based on observed differences after univariate analysis and used standard mean differences to estimate covariate balance. After propensity score matching, patients who underwent prehospital endotracheal intubation experienced a longer time on scene as compared with those intubated in the emergency department (9 minutes [interquartile range 6-12] vs 6 minutes [interquartile range 5-9], P < .01) without difference in overall mortality (67% vs 65%, P = 1.00). Rapid sequence intubation was not used in the field; however, it was used for 58% of patients intubated within 10 minutes of emergency department arrival. After matched analysis, patients with a failed prehospital intubation attempt were equally likely to receive rapid sequence intubation during re-intubation in the emergency department as compared with those undergoing a first attempt (n = 13/28, 46% vs n = 28/63, 44%, P = 1.00, standard mean differences 0.04). Among patients with prehospital arrest (n = 98), prehospital endotracheal intubation was associated with shorter time to death (8 minutes [interquartile range 3-17] vs 14 minutes [interquartile range 8-45], P = .008) and longer total transport time (23 minutes [interquartile range 19-31] vs 19 minutes [interquartile range 16-24], P = .006), but there was no difference in observed mortality (n = 29/31, 94% vs n = 30/31, 97%, P = 1.00, standard mean differences = 0.15) after propensity score matching. CONCLUSION: Prehospital providers should prioritize expeditious transport over attempting prehospital endotracheal intubation, as prehospital endotracheal intubation is inconsistently successful, may delay definitive care, and appears to have no survival benefit.


Subject(s)
Emergency Medical Services , Humans , Adolescent , Emergency Service, Hospital , Retrospective Studies , Intubation, Intratracheal , Trauma Centers
7.
J Am Acad Orthop Surg ; 31(21): 1136-1142, 2023 Nov 01.
Article in English | MEDLINE | ID: mdl-37432990

ABSTRACT

INTRODUCTION: Collection of patient-reported outcome measures (PROMs) in orthopaedic patients at safety-net hospitals is challenging. The purpose of this study was to evaluate the success of electronic PROM (E-PROM) collection in this setting. METHODS: A retrospective review identified 207 consecutive orthopaedic patients undergoing 77 elective arthroplasty procedures and 130 trauma procedures. E-PROMs were collected through automated e-mails from an online patient engagement platform (PatientIQ) at 2 weeks, 6 weeks, and 3 months postoperatively. Patients with trauma received the percentage of normal Single Assessment Numerical Evaluation (SANE) and Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF). Arthroplasty patients received the Hip/Knee SANE, Hip/Knee Disability and Osteoarthritis Outcome Score-Joint Replacement (HOOS Jr/KOOS Jr), PROMIS Global Physical Health (PROMIS-G-PH), and Veterans RAND 12-Item (VR-12) Health Survey. RESULTS: Compared with patients with trauma, arthroplasty patients were older (median difference 18.0 years; 95% confidence interval [CI] 12.0-22.0; P < 0.0001), more likely to be Hispanic/Black (proportional difference 16.9%; CI 2.8-30.3%; P = 0.02), more likely to have noncommercial or no insurance (proportional difference 34.0%; CI 23.2-43.0%; P < 0.001), and did not differ in Area Deprivation Index or E-PROM completion at each time point. E-PROMs were completed at 2 weeks, 6 weeks, and 3 months by 25.1% (52 of 207), 24.6% (51 of 207), and 21.7% (45 of 207) of all patients, respectively. Trauma and arthroplasty patients had a similar rate of partial E-PROM completion. Patients who completed 3-month E-PROMs were less likely to be Hispanic/Black (PD -16.4%; CI -31.0 to -0.2%; P < 0.04); less likely to have noncommercial/no insurance (PD -20.0%; CI -35.5 to -4.5%; P = 0.01); and did not differ in age, sex, Area Deprivation Index, or procedure type. DISCUSSION: The low collection rate of E-PROMs from orthopaedic patients at safety-net hospitals should be weighed against their costs. E-PROM collection may exacerbate disparities in PROM collection among certain patient populations. LEVEL OF EVIDENCE: Diagnostic Level III.

8.
medRxiv ; 2023 Feb 07.
Article in English | MEDLINE | ID: mdl-36798420

ABSTRACT

Background: The prognosis of ST-segment elevation myocardial infarction with non-obstructive coronaries (STE-MINOCA) is largely unknown. Methods: The objective of this study is to evaluate the prevalence, characteristics, and 5-year mortality of patients with STE-MINOCA compared to STEMI with coronary artery obstruction (STEMI-Obstruction) using a multicenter cohort of consecutive STEMI patients at 3 regional Midwest STEMI programs from 2003 to 2020. STE-MINOCA was defined based on (1) coronary stenosis < 60% by visual estimation, (2) ischemia with elevated troponin, and (3) no alternative diagnosis. STE-MINOCA was further classified based on American Heart Association (AHA) definition as AHA STE-MINOCA and AHA STE-MINOCA Mimicker. Results: 8,566 STEMI patients, including 420 (4.9%) STE-MINOCA (26.9% AHA STE-MINOCA and 73.1% AHA STE-MINOCA Mimicker) were followed for a median of 7.1 years. Compared to STEMI-Obstruction, STE-MINOCA were younger, more often female, had fewer cardiovascular risk factors, and were less likely to be discharged on cardiac medications. At five years, mortality was higher in STE-MINOCA compared with STEMI-Obstruction (18% vs. 15%, p=0.033). In propensity score-matched analysis, STE-MINOCA had a 1.4-fold (95% CI: 1.04-1.89, p=0.028) higher risk of 5-year all-cause mortality compared with STEMI-Obstruction. Furthermore, 5-year mortality risk was significantly higher in AHA STE-MINOCA Mimicker (19% vs. 15%, p=0.043) but similar in AHA STE-MINOCA (17% vs. 15%, p=0.42) compared with STEMI-Obstruction. Conclusions: In this large multicenter STEMI cohort, nearly 5% of patients presented with STE-MINOCA. At five years, mortality approached 20% among patients with STE-MINOCA. Despite the lower risk profile, STE-MINOCA patients were at 40% higher risk of 5-year all-cause mortality compared with STEMI-Obstruction. Additionally, 5-year all-cause mortality risk was higher in AHA STE-MINOCA Mimicker but similar in AHA STE-MINOCA compared to STEMI-Obstruction.

9.
Eur J Pediatr ; 182(2): 581-590, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36394647

ABSTRACT

Acute kidney injury (AKI), fluid overload (FO), and mortality are common in pediatric patients supported by extracorporeal membrane oxygenation (ECMO). The aim of this study is to evaluate if using a fluid management algorithm reduced AKI and mortality in children supported by ECMO. We performed a retrospective study of pediatric patients aged birth to 25 years requiring ECMO at a quaternary level children's hospital from 2007 to 2019 In October 2017, a fluid management algorithm was implemented for protocolized fluid removal after deriving a daily fluid goal using a combination of diuretics and ultrafiltration. Daily algorithm compliance was defined as ≥ 12 h on the algorithm each day. The primary and secondary outcomes were AKI and mortality, respectively, and were assessed in the entire cohort and the sub-analysis of children from the era in which the algorithm was implemented. Two hundred and ninety-nine (median age 5.3 months; IQR: 0.2, 62.3; 45% male) children required ECMO (venoarterial in 85%). The fluid algorithm was applied in 74 patients. The overall AKI rate during ECMO was 38% (26% severe-stage 2/3). Both AKI incidence and mortality were significantly lower in patients managed on the algorithm (p = 0.02 and p = 0.05). After adjusting for confounders, utilization of the algorithm was associated with lower odds of AKI (aOR: 0.40, 95%CI: 0.21, 0.76; p = 0.005) but was not associated with a reduction in mortality. In the sub-analysis, algorithm compliance of 80-100% was associated with a 54% reduction in mortality (ref: < 60% compliant; aOR:0.46, 95%CI:0.22-1.00; p = 0.05).  Conclusion: Among the entire cohort, the use of a fluid management algorithm reduced the odds of AKI. Better compliance on the algorithm was associated with lower mortality. Multicenter studies that implement systematic fluid removal may represent an opportunity for improving ECMO-related outcomes. What is Known: • Acute kidney injury and fluid overload are associated with morbidity and mortality in children supported by extracorporeal membrane oxygenation. What is New: • A systematic and protocolized approach to fluid removal in children supported by extracorporeal membrane oxygenation reduces acute kidney injury incidence. • Greater adherence to a protocolized fluid removal algorithm is associated with a reduction in mortality.


Subject(s)
Acute Kidney Injury , Humans , Child , Male , Aged , Infant , Female , Retrospective Studies , Hospital Mortality , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Acute Kidney Injury/epidemiology , Incidence , Algorithms
10.
Am J Physiol Heart Circ Physiol ; 323(4): H818-H824, 2022 10 01.
Article in English | MEDLINE | ID: mdl-36083798

ABSTRACT

Microvascular obstruction (MVO) frequently develops after ST-elevation myocardial infarction (STEMI) and is associated with increased mortality and adverse left ventricular remodeling. We hypothesized that increased extravascular compressive forces in the myocardium that arise from the development of myocardial edema because of ischemia-reperfusion injury would contribute to the development of MVO. We measured MVO, infarct size, and left ventricular mass in patients with STEMI (n = 385) using cardiac MRI 2 to 3 days following successful percutaneous coronary intervention and stenting. MVO was found in 57% of patients with STEMI. The average infarct size was 45 ± 29 g. Patients with MVO had significantly greater infarct size and reduced left ventricular (LV) function (P < 0.01) compared with patients without MVO. Patients with MVO had significantly greater LV mass than patients without MVO and there was a linear increase in MVO with increasing LV mass (P < 0.001). Myocardial edema by T2-weighted imaging increased with increasing LV mass and patients with MVO had significantly greater myocardial edema than patients without MVO (P < 0.01). Patients with MVO had significantly greater left ventricular end-diastolic pressure (LVEDP) than patients without MVO (P < 0.05). In a cohort of patients with STEMI who underwent primary percutaneous intervention, we observed that MVO increased linearly with increasing LV mass and was associated with increased myocardial edema and higher LVEDP. These observations support the concept that extravascular compressive forces in the left ventricle may increase with increasing ischemic injury and contribute to the development of MVO.NEW & NOTEWORTHY Patients with STEMI (n = 385) had cardiac MRIs 2 to 3 days following reperfusion with primary PCI to determine the relationship between myocardial edema, LV mass, and MVO. We observed that MVO increased linearly with LV mass and that myocardial edema measured by T2-imaging also increased linearly with LV mass. Patients with MVO had greater edema and LVEDP than subjects without MVO. These findings suggest that myocardial edema which arises from ischemia-reperfusion injury may result in extravascular compression of the microcirculation manifested as MVO on cardiac MRI.


Subject(s)
Myocardial Infarction , Percutaneous Coronary Intervention , Reperfusion Injury , ST Elevation Myocardial Infarction , Coronary Circulation , Edema/diagnostic imaging , Humans , Microcirculation , Myocardial Infarction/complications , Myocardial Infarction/diagnostic imaging , Myocardium , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/methods , Reperfusion Injury/complications , ST Elevation Myocardial Infarction/complications , ST Elevation Myocardial Infarction/diagnostic imaging , Treatment Outcome
11.
Hosp Pediatr ; 12(10): 866-877, 2022 10 01.
Article in English | MEDLINE | ID: mdl-36102129

ABSTRACT

OBJECTIVE: The Nephrotoxic Injury Negated by Just-in-Time Action (NINJA) program is a multicenter, quality improvement initiative that identifies patients at risk for nephrotoxic medication-associated acute kidney injury (NTMx-AKI). The purpose of this study was to (1) evaluate the prevalence and types of NTMx exposures and (2) determine the prevalence of NTMx-AKI categorized by service. Exploratory analysis evaluated potential associations between hospital measures and NTMx-AKI. METHODS: This is a single-center, retrospective chart review of NTMx exposures from January 2019 to June 2020 in noncritically ill children. High NTMx exposures were defined as ≥3 simultaneous nephrotoxins or ≥3 days of either intravenous vancomycin or aminoglycoside. Prevalence of high NTMx and NTMx-AKI rate were normalized to 1000 patient days. A retrospective case-control analysis assessed for potential associations with development of NTMx-AKI. RESULTS: There were 609 NTMx exposures in 565 patients and 44 (7.2%) episodes of NTMx-AKI. The NTMx prevalence rate per 1000 patient days was highest among liver, neurosurgery, and gastroenterology services. The most commonly used NTMx were vancomycin, intravenous contrast, and nonsteroidal antiinflammatory drugs. The NTMx-AKI rate in exposed patients ranged from 0% to 14% across service lines. AKI was most often attributable to vancomycin. Univariable analyses suggest type and duration of NTMx exposure are associated with development of NTMx-AKI but not with severity. CONCLUSIONS: NTMx exposures and NTMx-AKI are variable across services. Partnerships with antimicrobial stewardship and multicenter studies are needed to modify NTMx-AKI risk. Ongoing surveillance is needed in patients who do not have normalization of creatinine before discharge.


Subject(s)
Acute Kidney Injury , Drug-Related Side Effects and Adverse Reactions , Acute Kidney Injury/chemically induced , Acute Kidney Injury/epidemiology , Aminoglycosides , Child , Creatinine , Humans , Retrospective Studies , Risk Factors , Vancomycin/adverse effects
12.
Pediatr Crit Care Med ; 23(12): e564-e573, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36066647

ABSTRACT

OBJECTIVES: Quality improvement initiatives to decrease rates of nephrotoxic medication exposure have reduced rates of acute kidney injury (AKI) in noncritically ill children. The objective of our study was to analyze the implementation of a similar program in critically ill children and to measure important balancing measures including opioid and benzodiazepine exposure. DESIGN: Prospective quality improvement study. SETTING: PICU at Children's Hospital Colorado between 2018 and 2020. PATIENTS: All children admitted to PICU. INTERVENTIONS: Quality improvement initiative called Nephrotoxic Injury Negated by Just-In-Time Action (NINJA). MEASUREMENT AND MAIN RESULTS: Eight thousand eight hundred thirty-three PICU patient admissions were included. Mean rates of nephrotoxic medication exposure/1,000 PICU patient days decreased from 46 to 26, whereas rates of nephrotoxic AKI/1,000 PICU patient days did not change. Nonsteroidal anti-inflammatory drug dispenses per 1,000 patient days were reduced from 521 to 456. Similarly, opioid and benzodiazepine exposures per 1,000 patient days were reduced from 812 to 524 and 441 to 227, respectively, during the study observation period. CONCLUSIONS: The NINJA intervention was efficaciously implemented in our single-center PICU. Nephrotoxic exposure is a modifiable factor that did not inadvertently increase exposure to opioids and benzodiazepines.


Subject(s)
Acute Kidney Injury , Analgesics, Opioid , Child , Humans , Infant , Prospective Studies , Analgesics, Opioid/adverse effects , Critical Illness/therapy , Acute Kidney Injury/chemically induced , Acute Kidney Injury/epidemiology , Benzodiazepines/adverse effects , Pain
13.
Int J Cardiol ; 366: 25-29, 2022 11 01.
Article in English | MEDLINE | ID: mdl-35817202

ABSTRACT

BACKGROUND: Microvascular obstruction (MVO) contributes significantly to adverse left-ventricular remodeling and mortality following ST-segment elevation myocardial infarction (STEMI). Because circadian processes contribute significantly to the timing and degree of ischemic injury in STEMI we hypothesized that the occurrence of MVO may also exhibit circadian behavior. METHODS AND RESULTS: A single center cohort trial of 336 STEMI patients (273 M 63 F) with their first STEMI who were reperfused with primary percutaneous coronary intervention (PCI) and referred for cardiac MRI prior to discharge. The time of onset of chest pain was recorded from the patients chart and used to stratify patients with MVO over a 24-h cycle to analyze for circadian behavior. Subjects with MVO (n = 200) had greater infarct size by cMRI (45 vs. 20 g; p < 0.001), had reduced ejection fraction (LVEF = 50 vs 45%; p = 0.008) and significantly greater LV end-diastolic (LVEDVI) and end-systolic (LVESVI) volume index compared to subject without MVO (n = 136). The frequency of patients with MVO was compared against the frequency of patients without MVO at each 1-h and 3-h period over a 24-h cycle. A clear peak in patients with MVO (MVO + / MVO -) was seen at the 0700 h interval where 26 out of 27 patients had MVO (p = 0.0038) although MVO mass was not increased. This observation remained significant at the 06-09 time interval when 3-h segments were analyzed. Through 2021, mortality in patients with MVO was significantly greater compared to patients without MVO (n = 20 vs. 5, p < 0.03). CONCLUSIONS: This analysis reveals for the first time a circadian dependence of the frequency of MVO in the setting of STEMI which could explain in part, the wide variation in MVO seen in STEMI patients with similar ischemic times and infarct size.


Subject(s)
Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Female , Humans , Magnetic Resonance Imaging , Male , Microcirculation , Percutaneous Coronary Intervention/methods , ST Elevation Myocardial Infarction/diagnostic imaging , ST Elevation Myocardial Infarction/etiology , ST Elevation Myocardial Infarction/surgery , Ventricular Remodeling
14.
Antiviral Res ; 188: 105038, 2021 04.
Article in English | MEDLINE | ID: mdl-33577806

ABSTRACT

As the second leading cause of death in the United States, cancer has a considerable impact on society, and one cellular process that is commonly dysregulated in many cancers is the post-translational modification of proteins by the Small Ubiquitin-like Modifier (SUMO; sumoylation). We documented that sumoylation processes are up-regulated in lymphoma tissues in the presence of Latent Membrane Protein-1 (LMP1), the principal oncoprotein of Epstein-Barr virus (EBV). LMP1-mediated dysregulation of cellular sumoylation processes contributes to oncogenesis, modulates innate immune responses, and aids the maintenance of viral latency. Manipulation of protein sumoylation has been proposed for anti-cancer and anti-viral therapies; however, known inhibitors of sumoylation do not only target sumoylation processes. Recently, a specific and selective small-molecule inhibitor of sumoylation (ML-792) was identified; however, nothing is known about the effect of ML-792 on LMP1-mediated dysregulation of cellular sumoylation or the EBV life-cycle. We hypothesized that ML-792 modulates viral replication and the oncogenic potential of EBV LMP1 by inhibiting protein sumoylation. Results showed that ML-792 inhibited sumoylation processes in multiple EBV-positive B cell lines and EBV-positive nasopharyngeal carcinoma cell lines but not in their EBV-negative counterparts. Focusing on its effect on B cells, ML-792 inhibited B-cell growth and promoted cell death at very low doses. ML-792 also modulated LMP1-induced cell migration and cell adhesion, which suggests the abrogation of the oncogenic potential of LMP1. Finally, while higher concentrations of ML-792 were sufficient to induce low levels EBV spontaneous reactivation, they decreased the production of new infectious virus following an induced reactivation and the infection of new cells, suggesting that ML-792 has anti-viral potential. Together, these findings suggest that ML-792 may be a potential therapeutic drug to treat EBV-associated lymphoid malignancies by targeting oncogenesis and the EBV life-cycle.


Subject(s)
Antiviral Agents/pharmacology , B-Lymphocytes/virology , Epithelial Cells/virology , Esters/pharmacology , Herpesvirus 4, Human/drug effects , Herpesvirus 4, Human/physiology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Sulfonic Acids/pharmacology , B-Lymphocytes/metabolism , Cell Adhesion/drug effects , Cell Death/drug effects , Cell Line , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation , Cell Survival/drug effects , Cell Transformation, Viral , Epithelial Cells/metabolism , Humans , Small Ubiquitin-Related Modifier Proteins/metabolism , Sumoylation/drug effects , Ubiquitination , Viral Matrix Proteins/metabolism , Virus Activation , Virus Latency , Virus Replication/drug effects
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