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Article: The role of the circadian rhythms in critical illness with a focus on acute pancreatitis.

Waddell, Heather / Stevenson, Tyler J / Mole, Damian J

2023 Volume 9, Issue 4, Page(s) e15335

Abstract: Circadian rhythms are responsible for governing various physiological processes, including hormone secretion, immune responses, metabolism, and the sleep/wake cycle. In critical illnesses such as acute pancreatitis (AP), circadian rhythms can become ... ...

Abstract	Circadian rhythms are responsible for governing various physiological processes, including hormone secretion, immune responses, metabolism, and the sleep/wake cycle. In critical illnesses such as acute pancreatitis (AP), circadian rhythms can become dysregulated due to disease. Evidence suggests that time of onset of disease, coupled with peripheral inflammation brought about by AP will impact on the circadian rhythms generated in the central pacemaker and peripheral tissues. Cells of the innate and adaptive immune system are governed by circadian rhythms and the diurnal pattern of expression can be disrupted during disease. Peak circadian immune cell release and gene expression can coincide with AP onset, that may increase pancreatic injury, tissue damage and the potential for systemic inflammation and multiple organ failure to develop. Here, we provide an overview of the role of circadian rhythms in AP and the underpinning inflammatory mechanisms to contextualise ongoing research into the chronobiology and chronotherapeutics of AP.
Language	English
Publishing date	2023-04-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e15335
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Article ; Online: The role of the circadian rhythms in critical illness with a focus on acute pancreatitis

Waddell, Heather / Stevenson, Tyler John / Mole, Damian J.

Heliyon. 2023 Apr., v. 9, no. 4 p.e15335-

2023

Abstract	Circadian rhythms are responsible for governing various physiological processes, including hormone secretion, immune responses, metabolism, and the sleep/wake cycle. In critical illnesses such as acute pancreatitis (AP), circadian rhythms can become dysregulated due to disease. Evidence suggests that time of onset of disease, coupled with peripheral inflammation brought about by AP will impact on the circadian rhythms generated in the central pacemaker and peripheral tissues. Cells of the innate and adaptive immune system are governed by circadian rhythms and the diurnal pattern of expression can be disrupted during disease. Peak circadian immune cell release and gene expression can coincide with AP onset, that may increase pancreatic injury, tissue damage and the potential for systemic inflammation and multiple organ failure to develop. Here, we provide an overview of the role of circadian rhythms in AP and the underpinning inflammatory mechanisms to contextualise ongoing research into the chronobiology and chronotherapeutics of AP.
Keywords	adaptive immunity ; diurnal variation ; gene expression ; hormone secretion ; inflammation ; metabolism ; pancreatitis ; sleep ; Acute pancreatitis ; Circadian rhythms ; Critical illness ; Immune response ; Immune cells
Language	English
Dates of publication	2023-04
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e15335
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Article ; Online: Increased risk of type 3c diabetes mellitus after acute pancreatitis warrants a personalized approach including diabetes screening.

Walker, Alexander / O'Kelly, James / Graham, Catriona / Nowell, Sian / Kidd, Doug / Mole, Damian J

BJS open

2022 Volume 6, Issue 6

Abstract: Background: Acute pancreatitis (AP) is a frequent cause of hospitalization with long-term health consequences, including type 3c diabetes mellitus (DM). The incidence and risk factors for new-onset morbidities after AP need to be clarified to inform a ... ...

Abstract	Background: Acute pancreatitis (AP) is a frequent cause of hospitalization with long-term health consequences, including type 3c diabetes mellitus (DM). The incidence and risk factors for new-onset morbidities after AP need to be clarified to inform a personalized medicine approach. Methods: Using a longitudinal electronic healthcare record-linkage analysis, all patients admitted to hospital in Scotland with a first episode of AP between 1 April 2009 and 31 March 2012 and followed for a minimum of 5 years after their index AP admission were identified. All new-onset morbidity with specific focus on type 3c DM were analysed and, using time-split multiple regression. Results: A total of 2047 patients were included. AP requiring critical care was followed by 2 years of heightened risk (HR 5.24) of developing type 3c DM, increased risk of new-onset cardiac disease (HR 1.61), and renal disease (HR 2.96). The additional risk conferred by critical care AP had a negative interaction with time, whereas additional risk associated with male sex and a non-gallstone aetiology was long lasting. Conclusion: Based on these findings, a personalized approach to include type 3c DM screening for a minimum of 2 years for individuals who required critical care when hospitalized with AP is recommended.
MeSH term(s)	Humans ; Male ; Pancreatitis/diagnosis ; Pancreatitis/etiology ; Pancreatitis/therapy ; Acute Disease ; Risk Factors ; Incidence ; Diabetes Mellitus/epidemiology ; Diabetes Mellitus/diagnosis ; Diabetes Mellitus/etiology
Language	English
Publishing date	2022-12-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2474-9842
ISSN (online)	2474-9842
DOI	10.1093/bjsopen/zrac148
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Article ; Online: The top 10 research priorities for pancreatitis: findings from a James Lind Alliance priority setting partnership.

Mitra, Vikramjit / Munnelly, Stacey / Grammatikopoulos, Tassos / Mole, Damian / Hopper, Andrew / Ryan, Barbara / Phillips, Mary / Tarpey, Maryrose / Leeds, John

The lancet. Gastroenterology & hepatology

2023 Volume 8, Issue 9, Page(s) 780–782

MeSH term(s)	Humans ; Biomedical Research ; Pancreatitis/therapy
Language	English
Publishing date	2023-06-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2468-1253
ISSN (online)	2468-1253
DOI	10.1016/S2468-1253(23)00151-6
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Article ; Online: Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase Inhibition During Sepsis Dampens the Early Systemic Inflammatory Response.

Hayes, Alastair J / Mole, Damian J

Critical care medicine

2016 Volume 44, Issue 8, Page(s) 1628–1629

MeSH term(s)	Extracellular Signal-Regulated MAP Kinases ; Humans ; Phosphorylation ; Sepsis ; p38 Mitogen-Activated Protein Kinases
Chemical Substances	Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2016-07-18
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	197890-1
ISSN	1530-0293 ; 0090-3493
ISSN (online)	1530-0293
ISSN	0090-3493
DOI	10.1097/CCM.0000000000001752
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Article ; Online: Pre-, peri- and post-operative factors for the development of pancreatic fistula after pancreatic surgery.

Søreide, Kjetil / Healey, Andrew J / Mole, Damian J / Parks, Rowan W

HPB : the official journal of the International Hepato Pancreato Biliary Association

2019 Volume 21, Issue 12, Page(s) 1621–1631

Abstract: Background: The most hazardous complication to pancreatic surgery is the development of a post-operative pancreatic fistula (POPF). Appropriate understanding of the underlying pathophysiology, risk factors and perioperative mechanisms may allow for ... ...

Abstract	Background: The most hazardous complication to pancreatic surgery is the development of a post-operative pancreatic fistula (POPF). Appropriate understanding of the underlying pathophysiology, risk factors and perioperative mechanisms may allow for better management and use of preventive measures. Methods: Systematic literature search using the English PubMed literature up to April 2019, with emphasis on the past 5 years. Results: Several risk scores have been developed but none are perfect in predicting POPF risk. A conceptual framework of factors that contribute to the pathophysiology of pancreatic fistulae is still developing but incomplete. Recognized factors include those related to the patient, the pathology and the perioperative care. Interventions such as use of drains, stents and various drugs to mediate risk is still debated. Emerging data suggest that both the microbiome and the inflammation in the post-operative phase may play important roles in risk for POPF. Available risk scores allow for stratification of risk and mitigation strategies tailored to reduce this. However, accurate estimation of risk remains a challenge and mechanisms are only partially understood. Conclusions: The pathophysiology of POPF remains poorly understood. Current models only partially explain risks or associated mechanisms. Novel areas of investigation need to be explored for better prediction.
MeSH term(s)	Humans ; Pancreas/surgery ; Pancreatic Fistula/etiology ; Postoperative Complications ; Risk Assessment ; Risk Factors ; Severity of Illness Index
Language	English
Publishing date	2019-07-27
Publishing country	England
Document type	Journal Article ; Systematic Review
ZDB-ID	2131251-5
ISSN	1477-2574 ; 1365-182X
ISSN (online)	1477-2574
ISSN	1365-182X
DOI	10.1016/j.hpb.2019.06.004
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Article: The Role of the Multiparametric MRI LiverMultiScan

Chouari, Tarak / Merali, Nabeel / La Costa, Francesca / Santol, Jonas / Chapman, Shelley / Horton, Alex / Aroori, Somaiah / Connell, John / Rockall, Timothy A / Mole, Damian / Starlinger, Patrick / Welsh, Fenella / Rees, Myrddin / Frampton, Adam E

Cancers

2023 Volume 15, Issue 19

Abstract: Liver biopsy remains the gold standard for the histological assessment of the liver. With clear disadvantages and the rise in the incidences of liver disease, the role of neoadjuvant chemotherapy in colorectal liver metastasis (CRLM) and an explosion of ... ...

Abstract	Liver biopsy remains the gold standard for the histological assessment of the liver. With clear disadvantages and the rise in the incidences of liver disease, the role of neoadjuvant chemotherapy in colorectal liver metastasis (CRLM) and an explosion of surgical management options available, non-invasive serological and imaging markers of liver histopathology have never been more pertinent in order to assess liver health and stratify patients considered for surgical intervention. Liver MRI is a leading modality in the assessment of hepatic malignancy. Recent technological advancements in multiparametric MRI software such as the LiverMultiScan
Language	English
Publishing date	2023-10-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15194863
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Article ; Online: Timing of Cholecystectomy After Moderate and Severe Acute Biliary Pancreatitis.

Di Martino, Marcello / Ielpo, Benedetto / Pata, Francesco / Pellino, Gianluca / Di Saverio, Salomone / Catena, Fausto / De Simone, Belinda / Coccolini, Federico / Sartelli, Massimo / Damaskos, Dimitrios / Mole, Damian / Murzi, Valentina / Leppaniemi, Ari / Pisanu, Adolfo / Podda, Mauro

JAMA surgery

2023 Volume 158, Issue 10, Page(s) e233660

Abstract: Importance: Considering the lack of equipoise regarding the timing of cholecystectomy in patients with moderately severe and severe acute biliary pancreatitis (ABP), it is critical to assess this issue.: Objective: To assess the outcomes of early ... ...

Abstract	Importance: Considering the lack of equipoise regarding the timing of cholecystectomy in patients with moderately severe and severe acute biliary pancreatitis (ABP), it is critical to assess this issue. Objective: To assess the outcomes of early cholecystectomy (EC) in patients with moderately severe and severe ABP. Design, settings, and participants: This cohort study retrospectively analyzed real-life data from the MANCTRA-1 (Compliance With Evidence-Based Clinical Guidelines in the Management of Acute Biliary Pancreatitis) data set, assessing 5304 consecutive patients hospitalized between January 1, 2019, and December 31, 2020, for ABP from 42 countries. A total of 3696 patients who were hospitalized for ABP and underwent cholecystectomy were included in the analysis; of these, 1202 underwent EC, defined as a cholecystectomy performed within 14 days of admission. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality and morbidity. Data analysis was performed from January to February 2023. Main outcomes: Mortality and morbidity after EC. Results: Of the 3696 patients (mean [SD] age, 58.5 [17.8] years; 1907 [51.5%] female) included in the analysis, 1202 (32.5%) underwent EC and 2494 (67.5%) underwent delayed cholecystectomy (DC). Overall, EC presented an increased risk of postoperative mortality (1.4% vs 0.1%, P < .001) and morbidity (7.7% vs 3.7%, P < .001) compared with DC. On the multivariable analysis, moderately severe and severe ABP were associated with increased mortality (odds ratio [OR], 361.46; 95% CI, 2.28-57 212.31; P = .02) and morbidity (OR, 2.64; 95% CI, 1.35-5.19; P = .005). In patients with moderately severe and severe ABP (n = 108), EC was associated with an increased risk of mortality (16 [15.6%] vs 0 [0%], P < .001), morbidity (30 [30.3%] vs 57 [5.5%], P < .001), bile leakage (2 [2.4%] vs 4 [0.4%], P = .02), and infections (12 [14.6%] vs 4 [0.4%], P < .001) compared with patients with mild ABP who underwent EC. In patients with moderately severe and severe ABP (n = 108), EC was associated with higher mortality (16 [15.6%] vs 2 [1.2%], P < .001), morbidity (30 [30.3%] vs 17 [10.3%], P < .001), and infections (12 [14.6%] vs 2 [1.3%], P < .001) compared with patients with moderately severe and severe ABP who underwent DC. On the multivariable analysis, the patient's age (OR, 1.12; 95% CI, 1.02-1.36; P = .03) and American Society of Anesthesiologists score (OR, 5.91; 95% CI, 1.06-32.78; P = .04) were associated with mortality; severe complications of ABP were associated with increased mortality (OR, 50.04; 95% CI, 2.37-1058.01; P = .01) and morbidity (OR, 33.64; 95% CI, 3.19-354.73; P = .003). Conclusions and relevance: This cohort study's findings suggest that EC should be considered carefully in patients with moderately severe and severe ABP, as it was associated with increased postoperative mortality and morbidity. However, older and more fragile patients manifesting severe complications related to ABP should most likely not be considered for EC.
MeSH term(s)	Humans ; Female ; Middle Aged ; Male ; Cohort Studies ; Retrospective Studies ; Gallstones/surgery ; Cholecystectomy/adverse effects ; Pancreatitis/etiology ; Acute Disease
Language	English
Publishing date	2023-10-11
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2701841-6
ISSN	2168-6262 ; 2168-6254
ISSN (online)	2168-6262
ISSN	2168-6254
DOI	10.1001/jamasurg.2023.3660
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Article ; Online: Survival and new-onset morbidity after critical care admission for acute pancreatitis in Scotland: a national electronic healthcare record linkage cohort study.

Ventre, Chiara / Nowell, Sian / Graham, Catriona / Kidd, Doug / Skouras, Christos / Mole, Damian J

BMJ open

2018 Volume 8, Issue 12, Page(s) e023853

Abstract: Introduction: Severe acute pancreatitis (AP) requiring critical care admission (ccAP) impacts negatively on long-term survival.: Objective: To document organ-specific new morbidity and identify risk factors associated with premature mortality after ... ...

Abstract	Introduction: Severe acute pancreatitis (AP) requiring critical care admission (ccAP) impacts negatively on long-term survival. Objective: To document organ-specific new morbidity and identify risk factors associated with premature mortality after an episode of ccAP. Design: Cohort study. Setting: Electronic healthcare registries in Scotland. Participants: The ccAP cohort included 1471 patients admitted to critical care with AP between 1 January 2008 and 31 December 2010 followed up until 31 December 2014. The population cohort included 3450 individuals from the general population of Scotland frequency-matched for age, sex and social deprivation. Methods: Record linkage of routinely collected electronic health data with population matching. Primary and secondary outcome measures: Patient demographics, comorbidity (Charlson Comorbidity Index), acute physiology, organ support and other critical care data were linked to records of mortality (death certificate data) and new-onset morbidity. Kaplan-Meier and Cox regression analyses were used to identify risk factors associated with mortality. Results: 310 patients with AP died during the index admission. Outcomes were not ascertained for five patients, and the deprivation quintile was not known for six patients. 340 of 1150 patients in the resulting postdischarge ccAP cohort died during the follow-up period. Greater comorbidity measured by the Charlson score, prior to ccAP, negatively influenced survival in the hospital and after discharge. The odds of developing new-onset diabetes mellitus after ccAP compared with the general population were 10.70 (95% CI 5.74 to 19.94). A new diagnosis of myocardial infarction, stroke, heart failure, liver disease, peptic ulcer, renal failure, cancer, peripheral vascular disease and lung disease was more frequent in the ccAP cohort than in the general population. Conclusions: The persistent deleterious impact of severe AP on long-term outcome and survival is multifactorial in origin, influenced by pre-existing patient characteristics and acute episode features. Further mechanistic and epidemiological investigation is warranted.
MeSH term(s)	Acute Disease ; Adult ; Aged ; Aged, 80 and over ; Cause of Death ; Cohort Studies ; Critical Care/methods ; Databases, Factual ; Female ; Hospital Mortality/trends ; Humans ; Intensive Care Units/statistics & numerical data ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Morbidity/trends ; Pancreatitis/diagnosis ; Pancreatitis/mortality ; Pancreatitis/therapy ; Patient Admission/statistics & numerical data ; Prognosis ; Proportional Hazards Models ; Recurrence ; Registries ; Retrospective Studies ; Scotland/epidemiology ; Survival Analysis
Language	English
Publishing date	2018-12-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2599832-8
ISSN	2044-6055 ; 2044-6055
ISSN (online)	2044-6055
ISSN	2044-6055
DOI	10.1136/bmjopen-2018-023853
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Article ; Online: Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis.

Cell reports

2023 Volume 42, Issue 8, Page(s) 112763

Abstract: Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine ... ...

Abstract	Kynurenine monooxygenase (KMO) blockade protects against multiple organ failure caused by acute pancreatitis (AP), but the link between KMO and systemic inflammation has eluded discovery until now. Here, we show that the KMO product 3-hydroxykynurenine primes innate immune signaling to exacerbate systemic inflammation during experimental AP. We find a tissue-specific role for KMO, where mice lacking Kmo solely in hepatocytes have elevated plasma 3-hydroxykynurenine levels that prime inflammatory gene transcription. 3-Hydroxykynurenine synergizes with interleukin-1β to cause cellular apoptosis. Critically, mice with elevated 3-hydroxykynurenine succumb fatally earlier and more readily to experimental AP. Therapeutically, blockade with the highly selective KMO inhibitor GSK898 rescues the phenotype, reducing 3-hydroxykynurenine and protecting against critical illness and death. Together, our findings establish KMO and 3-hydroxykynurenine as regulators of inflammation and the innate immune response to sterile inflammation. During critical illness, excess morbidity and death from multiple organ failure can be rescued by systemic KMO blockade.
MeSH term(s)	Mice ; Animals ; Kynurenine ; Pancreatitis ; Critical Illness ; Multiple Organ Failure ; Acute Disease ; Mice, Knockout ; Inflammation ; Kynurenine 3-Monooxygenase/genetics
Chemical Substances	Kynurenine (343-65-7) ; Kynurenine 3-Monooxygenase (EC 1.14.13.9)
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112763
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