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Article: Zoster Sine Herpete Masquerading as Central Nervous System Vasculitis.

Lau, Arthur / Essien, Eno-Obong / Tan, Irene J

2020 Volume 12, Issue 3, Page(s) e7231

Abstract: Central nervous system (CNS) vasculopathy caused by varicella zoster virus (VZV) is a rare condition. Rarer still is the development of CNS vasculopathy in the absence of a typical zoster rash, a phenomenon known as zoster sine herpete. We report a case ... ...

Abstract	Central nervous system (CNS) vasculopathy caused by varicella zoster virus (VZV) is a rare condition. Rarer still is the development of CNS vasculopathy in the absence of a typical zoster rash, a phenomenon known as zoster sine herpete. We report a case of a 34-year-old male with HIV, non-compliant with highly active antiretroviral therapy (HAART), who presented with left-sided temporal headaches and numbness without rash. The patient had a complicated one-month hospital stay when he was initially diagnosed with mycobacterium avium complex (MAC) tuberculosis infection and treated with isoniazid, rifabutin, ethambutol, and azithromycin. Additionally, he was thought to have immune reconstitution inflammatory syndrome (IRIS) and was given steroids. Unfortunately, he presented one day post-discharge with lethargy, aphasia, and dysphagia and was found to have acute/subacute infarcts affecting multiple areas of the brain. CT angiogram (CTA) of the brain showed evidence of multifocal areas of mild to moderate stenosis throughout the intracranial arterial circulation. The patient underwent conventional angiography, which showed segmental arterial constrictions with post-stenotic dilatation consistent with vasculitis. Cerebrospinal fluid (CSF) studies eventually returned positive for VZV by polymerase chain reaction (PCR), confirming a diagnosis of VZV-induced CNS vasculopathy, or more specifically, CNS vasculopathy due to zoster sine herpete. The patient was treated with high-dose steroids as well as IV acyclovir with improvement in his symptoms. He was discharged with advice for a close follow-up with the infectious disease (ID) department. Our case highlights the importance of maintaining a high index of suspicion for varicella infection masquerading as CNS vasculitis, particularly in the absence of classic blistering shingles rash. Early detection may prevent neurological sequelae of the infection, including stroke, dissection, or neuropathy.
Language	English
Publishing date	2020-03-10
Publishing country	United States
Document type	Case Reports
ZDB-ID	2747273-5
ISSN	2168-8184
ISSN	2168-8184
DOI	10.7759/cureus.7231
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Pulmonary Embolism.

Essien, Eno-Obong / Rali, Parth / Mathai, Stephen C

The Medical clinics of North America

2019 Volume 103, Issue 3, Page(s) 549–564

Abstract: Venous thromboembolism (VTE) includes pulmonary embolism (PE) and deep vein thrombosis. PE is the third most common cause of cardiovascular death worldwide after stroke and heart attack. Management of PE has evolved recently with the availability of ... ...

Abstract	Venous thromboembolism (VTE) includes pulmonary embolism (PE) and deep vein thrombosis. PE is the third most common cause of cardiovascular death worldwide after stroke and heart attack. Management of PE has evolved recently with the availability of local thrombolysis; mechanical extraction devices; hemodynamic support devices, like extracorporeal membrane oxygenation; and surgical embolectomy. There has been development of multidisciplinary PE response teams nationwide to optimize the care of patients with VTE. This review describes the epidemiology of PE, discusses diagnostic strategies and current and emerging treatments for VTE, and considers post-PE follow-up care.
MeSH term(s)	Humans ; Pulmonary Embolism/diagnosis ; Pulmonary Embolism/etiology ; Pulmonary Embolism/physiopathology ; Pulmonary Embolism/therapy ; Venous Thromboembolism/complications
Language	English
Publishing date	2019-03-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	215710-x
ISSN	1557-9859 ; 0025-7125
ISSN (online)	1557-9859
ISSN	0025-7125
DOI	10.1016/j.mcna.2018.12.013
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Article ; Online: Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

Omo-Lamai, Serena / Zamora, Marco E / Patel, Manthan N / Wu, Jichuan / Nong, Jia / Wang, Zhicheng / Peshkova, Alina / Majumder, Aparajeeta / Melamed, Jilian R / Chase, Liam S / Essien, Eno-Obong / Weissman, Drew / Muzykantov, Vladimir R / Marcos-Contreras, Oscar A / Myerson, Jacob W / Brenner, Jacob S

Advanced materials (Deerfield Beach, Fla.)

2024 , Page(s) e2312026

Abstract: Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up or down-regulate any protein of interest. LNPs have mostly been targeted to specific cell types or organs by ... ...

Abstract	Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up or down-regulate any protein of interest. LNPs have mostly been targeted to specific cell types or organs by physicochemical targeting in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. Here lung-tropic LNPs are examined, whose organ tropism derives from containing either a cationic or ionizable lipid conferring a positive zeta potential. Surprisingly, these LNPs are found to induce massive thrombosis. Such thrombosis is shown in the lungs and other organs, and it is shown that it is greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles, and even by lung-tropic ionizable lipids that do not have a permanent cationic charge. The mechanism depends on the LNPs binding to and then changing the conformation of fibrinogen, which then activates platelets and thrombin. Based on these mechanisms, multiple solutions are engineered that enable positively charged LNPs to target the lungs while ameliorating thrombosis. The findings illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms.
Language	English
Publishing date	2024-02-23
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1474949-X
ISSN	1521-4095 ; 0935-9648
ISSN (online)	1521-4095
ISSN	0935-9648
DOI	10.1002/adma.202312026
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Article ; Online: Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases.

Ferguson, Laura T / Ma, Xiaonan / Myerson, Jacob W / Wu, Jichuan / Glassman, Patrick M / Zamora, Marco E / Hood, Elizabeth D / Zaleski, Michael / Shen, Mengwen / Essien, Eno-Obong / Shuvaev, Vladimir V / Brenner, Jacob S

Advanced nanobiomed research

2023 Volume 3, Issue 3, Page(s) 2200106

Abstract: Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from ... ...

Abstract	Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano-scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied. Direct instillation of liposomes in murine lung increases nintedanib's total lung delivery over time by 8000-fold and lung half life by tenfold, compared to oral nintedanib. Counterintuitively, it is shown that pulmonary surfactant neither lyses nor aggregates the liposomes. Instead, each lung compartment (alveolar fluid, alveolar leukocytes, and parenchyma) elutes liposomes over 24 h, likely serving as "drug depots." After deposition in the surfactant layer, liposomes are transferred over 3-6 h to alveolar leukocytes (which take up a surprisingly minor 1-5% of total lung dose instilled) in a nonsaturable fashion. Further, all cell layers of the lung parenchyma take up liposomes. These and other mechanisms elucidated here should guide engineering of future inhaled nanomedicine for alveolar diseases.
Language	English
Publishing date	2023-01-27
Publishing country	Germany
Document type	Journal Article
ZDB-ID	3009938-9
ISSN	2699-9307 ; 2699-9307
ISSN (online)	2699-9307
ISSN	2699-9307
DOI	10.1002/anbr.202200106
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Article: Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

Omo-Lamai, Serena / Zamora, Marco E / Patel, Manthan N / Wu, Jichuan / Nong, Jia / Wang, Zhicheng / Peshkova, Alina / Chase, Liam S / Essien, Eno-Obong / Muzykantov, Vladimir / Marcos-Contreras, Oscar / Myerson, Jacob W / Brenner, Jacob S

bioRxiv : the preprint server for biology

2023

Abstract: Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up- or down-regulate any protein of interest. LNPs have been targeted to specific cell types or organs by physicochemical ... ...

Abstract	Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up- or down-regulate any protein of interest. LNPs have been targeted to specific cell types or organs by physicochemical targeting, in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. In a popular approach, physicochemical targeting is accomplished by formulating with charged lipids. Negatively charged lipids localize LNPs to the spleen, and positively charged lipids to the lungs. Here we found that lung-tropic LNPs employing cationic lipids induce massive thrombosis. We demonstrate that thrombosis is induced in the lungs and other organs, and greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles. The mechanism depends on the LNPs binding to fibrinogen and inducing platelet and thrombin activation. Based on these mechanisms, we engineered multiple solutions which enable positively charged LNPs to target the lungs while not inducing thrombosis. Our findings implicate thrombosis as a major barrier that blood erects against LNPs with cationic components and illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms.
Language	English
Publishing date	2023-07-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.21.550080
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Physiologic Features of Brain Death.

Essien, Eno-Obong / Fioretti, Kristina / Scalea, Thomas M / Stein, Deborah M

The American surgeon

2017 Volume 83, Issue 8, Page(s) 850–854

Abstract: Brain death is known to be associated with physiologic derangements but their incidence is poorly described. Knowledge of the changes that occur during brain death is important for management of the potential organ donor. Thus, we sought to characterize ... ...

Abstract	Brain death is known to be associated with physiologic derangements but their incidence is poorly described. Knowledge of the changes that occur during brain death is important for management of the potential organ donor. Thus, we sought to characterize the pathophysiology that occurs during brain death in patients with traumatic injuries. All brain-dead patients over a 10-year period were identified from the trauma registry at a level 1 urban trauma center. Patient demographics, injury characteristics, and clinical data for defining organ dysfunction were reviewed for the 24 hours surrounding brain-death declaration. Three hundred and seventy-three patients were identified. Mean age was 37 years (±17.2). Seventy-five per cent were male. Major mechanism of injury was blunt trauma in 66 per cent. Median injury severity score was 34 (IQR 25-43) with a median head abbreviated injury scale score of 5. The most common physiological disturbance was hypotension with 91 per cent of subjects requiring vasopressors. Thrombocytopenia and acidosis both had an incidence of 79 per cent. The next most common disturbances were hypothermia and moderate-to-severe respiratory dysfunction in 62 per cent. Myocardial injury was seen in 91 per cent but only 5.7 per cent of patients manifested severe cardiac dysfunction with an ejection fraction of <35. Diabetes insipidus was diagnosed in 50 per cent of patients. Interestingly, coagulopathy was noted in only 61.3 per cent, and hyperglycemia was seen in 36 per cent despite widespread belief that these occur universally during brain death. This is the first and largest study to characterize the incidence of pathophysiological disturbances following brain death in humans. Appropriate management of these dysfunctions is important for support of potential brain-dead organ donors.
MeSH term(s)	Adult ; Brain Death/physiopathology ; Cause of Death ; Female ; Humans ; Male ; Retrospective Studies
Language	English
Publishing date	2017-07-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	202465-2
ISSN	1555-9823 ; 0003-1348
ISSN (online)	1555-9823
ISSN	0003-1348
DOI	10.1177/000313481708300835
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Article ; Online: A Comparison of Anticoagulation Strategies in Veno-venous Extracorporeal Membrane Oxygenation.

Shah, Aakash / Pasrija, Chetan / Kronfli, Anthony / Essien, Eno-Obong / Zhou, Ya / Brigante, Francis / Bittle, Gregory / Menaker, Jay / Herr, Daniel / Mazzeffi, Michael A / Deatrick, Kristopher B / Kon, Zachary N

ASAIO journal (American Society for Artificial Internal Organs : 1992)

2021 Volume 68, Issue 5, Page(s) 738–743

Abstract: Bleeding remains a major source of morbidity associated with veno-venous extracorporeal membrane oxygenation (VV-ECMO). Moreover, there remains significant controversy, and a paucity of data regarding the ideal anticoagulation strategy for VV-ECMO ... ...

Abstract	Bleeding remains a major source of morbidity associated with veno-venous extracorporeal membrane oxygenation (VV-ECMO). Moreover, there remains significant controversy, and a paucity of data regarding the ideal anticoagulation strategy for VV-ECMO patients. All patients undergoing isolated, peripheral VV-ECMO between January 2009 and December 2014 at our institution were retrospectively reviewed. Patients (n = 123) were stratified into one of three sequential eras of anticoagulation strategies: activated clotting time (ACT: 160-180 seconds, n = 53), high-partial thromboplastin time (H-PTT: 60-80 seconds, n = 25), and low-PTT (L-PTT: 45-55 seconds, n = 25) with high-flow (>4 L/min). Pre-ECMO APACHE II scores, SOFA scores, and Murray scores were not significantly different between the groups. Patients in the L-PTT group required less red blood cell units on ECMO than the ACT or H-PTT group (2.1 vs. 1.3 vs. 0.9; p < 0.001) and patients in the H-PTT and L-PTT group required less fresh frozen plasma than the ACT group (0.33 vs. 0 vs. 0; p = 0.006). Overall, major bleeding events were significantly lower in the L-PTT group than in the ACT and H-PTT groups. There was no difference in thrombotic events. In this single-institution experience, a L-PTT, high-flow strategy on VV-ECMO was associated with fewer bleeding and no difference in thrombotic events than an ACT or H-PTT strategy.
MeSH term(s)	Anticoagulants/adverse effects ; Blood Coagulation ; Extracorporeal Membrane Oxygenation/adverse effects ; Hemorrhage/etiology ; Hemorrhage/therapy ; Humans ; Retrospective Studies ; Thrombosis/etiology ; Thrombosis/prevention & control
Chemical Substances	Anticoagulants
Language	English
Publishing date	2021-08-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	759982-1
ISSN	1538-943X ; 0162-1432 ; 1058-2916
ISSN (online)	1538-943X
ISSN	0162-1432 ; 1058-2916
DOI	10.1097/MAT.0000000000001560
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Article: Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Omo-Lamai, Serena / Wang, Yufei / Patel, Manthan N / Essien, Eno-Obong / Shen, Mengwen / Majumdar, Aparajeeta / Espy, Carolann / Wu, Jichuan / Channer, Breana / Tobin, Michael / Murali, Shruthi / Papp, Tyler E / Maheshwari, Rhea / Wang, Liuqian / Chase, Liam S / Zamora, Marco E / Arral, Mariah L / Marcos-Contreras, Oscar A / Myerson, Jacob W /

Hunter, Christopher A / Tsourkas, Andrew / Muzykantov, Vladimir / Brodsky, Igor / Shin, Sunny / Whitehead, Kathryn A / Gaskill, Peter / Discher, Dennis / Parhiz, Hamideh / Brenner, Jacob S

bioRxiv : the preprint server for biology

2024

Abstract: Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe ... ...

Abstract	Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both
Language	English
Publishing date	2024-04-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.16.589801
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Article ; Online: Organ Dysfunction and Failure Following Brain Death Do Not Preclude Successful Donation.

Essien, Eno-Obong I / Parimi, Nehu / Gutwald-Miller, Jennifer / Nutter, Tyree / Scalea, Thomas M / Stein, Deborah M

World journal of surgery

2017 Volume 41, Issue 11, Page(s) 2933–2939

Abstract: Background: Organ dysfunction is common after neurologic determination of death (NDD) but before organ collection. Reliable markers for graft success following transplant of these organs would be useful. We sought to determine the relationship between ... ...

Abstract	Background: Organ dysfunction is common after neurologic determination of death (NDD) but before organ collection. Reliable markers for graft success following transplant of these organs would be useful. We sought to determine the relationship between the donor after neurologic determination of death (DNDD) pathophysiology and successful organ donation. Methods: Donor information was obtained through the local organ procurement organization. Donor demographics and clinical data points for cardiovascular, renal, respiratory, hepatic, hematological and neuroendocrine systems were reviewed 12 h before and 12 h after neurologic determination of death was declared. The worst values were utilized for analysis and generation of the organ-specific Sequential Organ Failure Assessment (SOFA) scores. SOFA scores were calculated and used to quantify the degree of organ dysfunction. The NDD non-donors for a specific organ were used as a comparison control group. The control group refers to DNDD patients whose specific organs were not transplanted. Lack of use was mostly due to discard by the transplant team as a result of unsuitability of the organ caused by deterioration or possible donor-specific pathology. Results: One hundred and five organ donors were analyzed. Mean age was 35.0 (± 13.6), 78.1% male, median GCS 3, interquartile range (IQR) 3-4 and median injury severity score 32 (IQR 25-43). Of the successful donors, organ-specific severe dysfunction (SOFA 3 or 4) occurred in 96, 27.5 and 3.3% of cardiac, lung and liver donors, respectively. There was no significant difference between the levels of organ dysfunction in donors versus non-donors except lung donors, in which the median lowest partial pressure of arterial oxygen-to-fraction of inspired oxygen (P/F) ratio in the non-donor was 194 (IQR 121.8-308.3) compared to the median lowest P/F ratio in the donor which was 287 (IQR 180-383.5), p = 0.02. In the recipients, graft failure 6 months after transplantation was reported in one kidney recipient (0.74%) (peak donor creatinine = 1 mg/dL) and in five pancreas recipients (11.4%). The median peak glucose of the pancreas donors in failed recipients was 178 mg/dL (IQR 157-213), whereas in the functioning recipients, the median glucose of their donors was not different (185 mg/dL, IQR 157-216), p = 0.394. Conclusion: Current measures of organ failure and dysfunction do not predict the success of organ donation. Successful donor management in the face of severe organ dysfunction and failure can result in lives saved.
Language	English
Publishing date	2017-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	224043-9
ISSN	1432-2323 ; 0364-2313
ISSN (online)	1432-2323
ISSN	0364-2313
DOI	10.1007/s00268-017-4089-1
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Article ; Online: Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape without Side Effects

Omo-Lamai, Serena / Wang, Yufei / Patel, Manthan N / Essien, Eno-obong / Shen, Mengwen / Majumder, Aparajeeta / Espy, Carolann / Wu, Jichuan / Channer, Breana / Tobin, Michael P / Murali, Shruthi / Papp, Tyler E / Maheshwari, Rhea / Wang, Liuqian / Chase, Liam S / Zamora, Marco E / Arral, Mariah L / Marcos-Contreras, Oscar A / Myerson, Jacob W /

Hunter, Christopher A / Tsourkas, Andrew / Muzykantov, Vladimir / Brodsky, Igor E / Shin, Sunny / Whitehead, Kathryn A / Gaskill, Peter / Discher, Dennis / Parhiz, Hamideh / Brenner, Jacob S

bioRxiv

Abstract	Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs9 hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo. We show that rapidly biodegradable ionizable lipids can preferentially create endosomal holes that are smaller in size and reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Ionizable lipids producing such ESCRT-recruiting endosomal holes can produce high expression from cargo mRNA with minimal inflammation. Finally, we show that both routes to non-inflammatory LNPs, either galectin inhibition or ESCRT-recruiting ionizable lipids, are compatible with therapeutic mRNAs that ameliorate inflammation in disease models. LNPs without galectin inhibition or biodegradable ionizable lipids lead to severe exacerbation of inflammation in these models. In summary, endosomal escape induces endosomal membrane damage that can lead to inflammation. However, the inflammation can be controlled by inhibiting galectins (large hole detectors) or by using biodegradable lipids, which create smaller holes that are reparable by the ESCRT pathway. These strategies should lead to generally safer LNPs that can be used to treat inflammatory diseases.
Keywords	covid19
Language	English
Publishing date	2024-04-18
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.04.16.589801
Database	COVID19

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