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Article ; Online: When Two Pandemics Meet: Why Is Obesity Associated with Increased COVID-19 Mortality?

Lockhart, Sam M / O'Rahilly, Stephen

Med (New York, N.Y.)

2020 Volume 1, Issue 1, Page(s) 33–42

Abstract: A growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of COVID-19, including death. By combining emerging knowledge of the pathological processes involved in COVID-19 with insights into the ... ...

Abstract	A growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of COVID-19, including death. By combining emerging knowledge of the pathological processes involved in COVID-19 with insights into the mechanisms underlying the adverse health consequences of obesity, we present some hypotheses regarding the deleterious impact of obesity on the course of COVID-19. These hypotheses are testable and could guide therapeutic and preventive interventions. As obesity is now almost ubiquitous and no vaccine for COVID-19 is currently available, even a modest reduction in the impact of obesity on mortality and morbidity from this viral infection could have profound consequences for public health.
MeSH term(s)	COVID-19/epidemiology ; Humans ; Obesity/epidemiology ; Pandemics ; Public Health ; SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2666-6340
ISSN (online)	2666-6340
DOI	10.1016/j.medj.2020.06.005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: When Two Pandemics Meet

Lockhart, Sam M. / O’Rahilly, Stephen

Med ; ISSN 2666-6340

Why Is Obesity Associated with Increased COVID-19 Mortality?

2020

Keywords	covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
DOI	10.1016/j.medj.2020.06.005
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The transcriptional coregulator CITED2 suppresses expression of IRS-2 and impairs insulin signaling in endothelial cells.

Kunkemoeller, Britta / Chen, Kuangyang / Lockhart, Sam M / Wang, Xuanchun / Rask-Madsen, Christian

American journal of physiology. Endocrinology and metabolism

2021 Volume 321, Issue 2, Page(s) E252–E259

Abstract: Endothelial cell insulin resistance contributes to the development of vascular complications in diabetes. Hypoxia-inducible factors (HIFs) modulate insulin sensitivity, and we have previously shown that a negative regulator of HIF activity, CREB-binding ... ...

Abstract	Endothelial cell insulin resistance contributes to the development of vascular complications in diabetes. Hypoxia-inducible factors (HIFs) modulate insulin sensitivity, and we have previously shown that a negative regulator of HIF activity, CREB-binding protein/p300 (CBP/p300) interacting transactivator-2 (CITED2), is increased in the vasculature of people with type 2 diabetes. Therefore, we examined whether CITED2 regulates endothelial insulin sensitivity. In endothelial cells isolated from mice with a "floxed" mutation in the
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Endothelial Cells/metabolism ; Gene Expression Regulation ; Insulin/metabolism ; Insulin Receptor Substrate Proteins/metabolism ; Mice ; Repressor Proteins/metabolism ; Signal Transduction ; Trans-Activators/metabolism
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; Cited2 protein, mouse ; Insulin ; Insulin Receptor Substrate Proteins ; Irs2 protein, mouse ; Repressor Proteins ; Trans-Activators ; endothelial PAS domain-containing protein 1 (1B37H0967P)
Language	English
Publishing date	2021-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00435.2020
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: When Two Pandemics Meet: Why Is Obesity Associated with Increased COVID-19 Mortality?

Lockhart, Sam M / O039, / Rahilly, Stephen

Abstract	A growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of COVID-19, including death. By combining emerging knowledge of the pathological processes involved in COVID-19 with insights into the mechanisms underlying the adverse health consequences of obesity, we present some hypotheses regarding the deleterious impact of obesity on the course of COVID-19. These hypotheses are testable and could guide therapeutic and preventive interventions. As obesity is now almost ubiquitous and no vaccine for COVID-19 is currently available, even a modest reduction in the impact of obesity on mortality and morbidity from this viral infection could have profound consequences for public health.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #628996
Database	COVID19

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Article ; Online: When Two Pandemics Meet

Lockhart, Sam M / O'Rahilly, Stephen

Why Is Obesity Associated with Increased COVID-19 Mortality?

2020

Abstract: A growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of COVID-19 including death. By combining emerging knowledge of the pathological processes involved in COVID-19 with insights into the ... ...

Abstract	A growing body of evidence indicates that obesity is strongly and independently associated with adverse outcomes of COVID-19 including death. By combining emerging knowledge of the pathological processes involved in COVID-19 with insights into the mechanisms underlying the adverse health consequences of obesity, we present some hypotheses regarding the deleterious impact of obesity on the course of COVID-19. These hypotheses are testable and could guide therapeutic and preventive interventions. As obesity is now almost ubiquitous and no vaccine for COVID-19 is currently available, even a modest reduction in the impact of obesity on mortality and morbidity from this viral infection could have profound consequences for public health.
Keywords	covid19
Language	English
Publishing date	2020-06-29
Publisher	Elsevier
Publishing country	uk
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Usefulness of Heat Map Explanations for Deep-Learning-Based Electrocardiogram Analysis.

Storås, Andrea M / Andersen, Ole Emil / Lockhart, Sam / Thielemann, Roman / Gnesin, Filip / Thambawita, Vajira / Hicks, Steven A / Kanters, Jørgen K / Strümke, Inga / Halvorsen, Pål / Riegler, Michael A

Diagnostics (Basel, Switzerland)

2023 Volume 13, Issue 14

Abstract: Deep neural networks are complex machine learning models that have shown promising results in analyzing high-dimensional data such as those collected from medical examinations. Such models have the potential to provide fast and accurate medical diagnoses. ...

Abstract	Deep neural networks are complex machine learning models that have shown promising results in analyzing high-dimensional data such as those collected from medical examinations. Such models have the potential to provide fast and accurate medical diagnoses. However, the high complexity makes deep neural networks and their predictions difficult to understand. Providing model explanations can be a way of increasing the understanding of "black box" models and building trust. In this work, we applied transfer learning to develop a deep neural network to predict sex from electrocardiograms. Using the visual explanation method Grad-CAM, heat maps were generated from the model in order to understand how it makes predictions. To evaluate the usefulness of the heat maps and determine if the heat maps identified electrocardiogram features that could be recognized to discriminate sex, medical doctors provided feedback. Based on the feedback, we concluded that, in our setting, this mode of explainable artificial intelligence does not provide meaningful information to medical doctors and is not useful in the clinic. Our results indicate that improved explanation techniques that are tailored to medical data should be developed before deep neural networks can be applied in the clinic for diagnostic purposes.
Language	English
Publishing date	2023-07-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics13142345
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Article ; Online: Identification of cancer chemotherapy regimens and patient cohorts in administrative claims: challenges, opportunities, and a proposed algorithm.

Lockhart, Catherine M / McDermott, Cara L / Mendelsohn, Aaron B / Marshall, James / McBride, Ali / Yee, Gary / Li, Minghui Sam / Jamal-Allial, Aziza / Djibo, Djeneba Audrey / Vazquez Benitez, Gabriela / DeFor, Terese A / Pawloski, Pamala A

Journal of medical economics

2023 Volume 26, Issue 1, Page(s) 403–410

Abstract: Background: Real-world evidence is a valuable source of information in healthcare. This study describes the challenges and successes during algorithm development to identify cancer cohorts and multi-agent chemotherapy regimens from claims data to ... ...

Abstract	Background: Real-world evidence is a valuable source of information in healthcare. This study describes the challenges and successes during algorithm development to identify cancer cohorts and multi-agent chemotherapy regimens from claims data to perform a comparative effectiveness analysis of granulocyte colony stimulating factor (G-CSF) use. Methods: Using the Biologics and Biosimilars Collective Intelligence Consortium's Distributed Research Network, we iteratively developed and tested a de novo algorithm to accurately identify patients by cancer diagnosis, then extract chemotherapy and G-CSF administrations for a retrospective study of prophylactic G-CSF. Results: After identifying patients with cancer and subsequent chemotherapy exposures, we observed only 12% of patients with cancer received chemotherapy, which is fewer than expected based on prior analyses. Therefore, we reversed the initial inclusion criteria to identify chemotherapy receipt, then prior cancer diagnosis, which increased the number of patients from 2,814 to 3,645, or 68% of patients receiving chemotherapy had diagnoses of interest. Additionally, we excluded patients with cancer diagnoses that differed from those of interest in the 183 days before the index date of G-CSF receipt, including early-stage cancers without G-CSF or chemotherapy exposure. By removing this criterion, we retained 77 patients who were previously excluded. Finally, we incorporated a 5-day window to identify all chemotherapy drugs administered (excluding oral prednisone and methotrexate, as these medications may be used for other non-malignant conditions) as patients may fill oral prescriptions days to weeks prior to infusion. This increased the number of patients with chemotherapy exposures of interest to 6,010. The final cohort of included patients, based on G-CSF exposure, increased from 420 from the initial algorithm to 886 using the final algorithm. Conclusions: Medications used for multiple indications, sensitivity and specificity of administrative codes, and relative timing of medication exposure must all be evaluated to identify patient cohorts receiving chemotherapy from claims data.
MeSH term(s)	Humans ; Retrospective Studies ; Biosimilar Pharmaceuticals ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Neoplasms/drug therapy ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Chemical Substances	Biosimilar Pharmaceuticals ; Granulocyte Colony-Stimulating Factor (143011-72-7)
Language	English
Publishing date	2023-03-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2270945-9
ISSN	1941-837X ; 1369-6998
ISSN (online)	1941-837X
ISSN	1369-6998
DOI	10.1080/13696998.2023.2187196
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Article ; Online: Author Correction: Proteogenomic links to human metabolic diseases.

Koprulu, Mine / Carrasco-Zanini, Julia / Wheeler, Eleanor / Lockhart, Sam / Kerrison, Nicola D / Wareham, Nicholas J / Pietzner, Maik / Langenberg, Claudia

Nature metabolism

2023 Volume 5, Issue 4, Page(s) 710

Language	English
Publishing date	2023-03-13
Publishing country	Germany
Document type	Published Erratum
ISSN	2522-5812
ISSN (online)	2522-5812
DOI	10.1038/s42255-023-00785-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Proteogenomic links to human metabolic diseases.

Koprulu, Mine / Carrasco-Zanini, Julia / Wheeler, Eleanor / Lockhart, Sam / Kerrison, Nicola D / Wareham, Nicholas J / Pietzner, Maik / Langenberg, Claudia

Nature metabolism

2023 Volume 5, Issue 3, Page(s) 516–528

Abstract: Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify new disease processes. Here, we conducted a cis-focused proteogenomic analysis of 2,923 plasma proteins measured in 1,180 individuals ... ...

Abstract	Studying the plasma proteome as the intermediate layer between the genome and the phenome has the potential to identify new disease processes. Here, we conducted a cis-focused proteogenomic analysis of 2,923 plasma proteins measured in 1,180 individuals using antibody-based assays. We (1) identify 256 unreported protein quantitative trait loci (pQTL); (2) demonstrate shared genetic regulation of 224 cis-pQTLs with 575 specific health outcomes, revealing examples for notable metabolic diseases (such as gastrin-releasing peptide as a potential therapeutic target for type 2 diabetes); (3) improve causal gene assignment at 40% (n = 192) of overlapping risk loci; and (4) observe convergence of phenotypic consequences of cis-pQTLs and rare loss-of-function gene burden for 12 proteins, such as TIMD4 for lipoprotein metabolism. Our findings demonstrate the value of integrating complementary proteomic technologies with genomics even at moderate scale to identify new mediators of metabolic diseases with the potential for therapeutic interventions.
MeSH term(s)	Humans ; Proteogenomics ; Proteomics ; Diabetes Mellitus, Type 2/genetics ; Quantitative Trait Loci ; Blood Proteins/genetics
Chemical Substances	Blood Proteins
Language	English
Publishing date	2023-02-23
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2522-5812
ISSN (online)	2522-5812
DOI	10.1038/s42255-023-00753-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Olfactory dysfunction in the 3xTg-AD model of Alzheimer's disease.

Mitrano, Darlene A / Houle, Sam E / Pearce, Patrick / Quintanilla, Ricardo M / Lockhart, Blakely K / Genovese, Benjamin C / Schendzielos, Rachel A / Croushore, Emma E / Dymond, Ethan M / Bogenpohl, James W / Grau, Harold J / Webb, Lisa Smith

IBRO neuroscience reports

2021 Volume 10, Page(s) 51–61

Abstract: Alzheimer's disease (AD) is an incurable neurodegenerative disease in which the risk of development increases with age. People with AD are plagued with deficits in their cognition, memory, and basic social skills. Many of these deficits are believed to ... ...

Abstract	Alzheimer's disease (AD) is an incurable neurodegenerative disease in which the risk of development increases with age. People with AD are plagued with deficits in their cognition, memory, and basic social skills. Many of these deficits are believed to be caused by the formation of amyloid-β plaques and neurofibrillary tangles in regions of the brain associated with memory, such as the hippocampus. However, one of the early, preclinical symptoms of AD is the loss of olfactory detection and discrimination. To determine if a mouse model of AD expresses the same olfactory dysfunction seen in human AD, 3xTg-AD mice were given a buried food test and, unlike previous studies, compared to their background and parental strains. Results showed that over 52 weeks, the 3xTg-AD mice took significantly longer to find the buried food than the control strains. The olfactory bulbs of the 3xTg-AD mice were removed, sliced, and stained using Congo red for histological analysis. Amyloid deposits were observed predominantly in the granule layer of the olfactory bulb beginning at 13 weeks of age in 3xTg-AD mice, but not in the control strains of mice. Further examination of the buried food test data revealed that 3xTg-AD females had a significantly longer latency to detect the buried food than males beginning at 26 weeks of age. Overall, this study provides further validation of the 3xTg-AD mouse model of AD and supports the idea that simple olfactory testing could be part of the diagnostic process for human AD.
Language	English
Publishing date	2021-01-08
Publishing country	Netherlands
Document type	Journal Article
ISSN	2667-2421
ISSN (online)	2667-2421
DOI	10.1016/j.ibneur.2020.12.004
Database	MEDical Literature Analysis and Retrieval System OnLINE

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