Add publication-backed causal graph to Long COVID

references_cache/PMID_15710782.md

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+---
+reference_id: PMID:15710782
+title: Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders.
+authors:
+- Shibao C
+- Arzubiaga C
+- Roberts LJ 2nd
+- Raj S
+- Black B
+- Harris P
+- Biaggioni I
+journal: Hypertension
+year: '2005'
+doi: 10.1161/01.HYP.0000158259.68614.40
+content_type: abstract_only
+---
+
+# Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders.
+**Authors:** Shibao C, Arzubiaga C, Roberts LJ 2nd, Raj S, Black B, Harris P, Biaggioni I
+**Journal:** Hypertension (2005)
+**DOI:** [10.1161/01.HYP.0000158259.68614.40](https://doi.org/10.1161/01.HYP.0000158259.68614.40)
+
+## Content
+
+1. Hypertension. 2005 Mar;45(3):385-90. doi: 10.1161/01.HYP.0000158259.68614.40. 
+Epub 2005 Feb 14.
+
+Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders.
+
+Shibao C(1), Arzubiaga C, Roberts LJ 2nd, Raj S, Black B, Harris P, Biaggioni I.
+
+Author information:
+(1)Division of Clinical Pharmacology, Department of Medicine and Pharmacology, 
+and the Autonomic Dysfunction Center, Vanderbilt University School of Medicine, 
+Nashville, Tenn 37212, USA.
+
+Comment in
+    Hypertension. 2005 Mar;45(3):354-5. doi: 10.1161/01.HYP.0000158260.46156.b7.
+
+Postural tachycardia syndrome (POTS) is a disabling condition that commonly 
+affects otherwise normal young females. Because these patients can present with 
+a flushing disorder, we hypothesized that mast cell activation (MCA) can 
+contribute to its pathogenesis. Here we describe POTS patients with MCA 
+(MCA+POTS), diagnosed by episodes of flushing and abnormal increases in urine 
+methylhistamine, and compared them to POTS patients with episodic flushing but 
+normal urine methylhistamine and to normal healthy age-matched female controls. 
+MCA+POTS patients were characterized by episodes of flushing, shortness of 
+breath, headache, lightheadedness, excessive diuresis, and gastrointestinal 
+symptoms such as diarrhea, nausea, and vomiting. Triggering events include 
+long-term standing, exercise, premenstrual cycle, meals, and sexual intercourse. 
+In addition, patients were disabled by orthostatic intolerance and a 
+characteristic hyperadrenergic response to posture, with orthostatic tachycardia 
+(from 79+/-4 to 114+/-6 bpm), increased systolic blood pressure on standing 
+(from 117+/-5 to 126+/-7 mm Hg versus no change in POTS controls), increased 
+systolic blood pressure at the end of phase II of the Valsalva maneuver 
+(157+/-12 versus 117+/-9 in normal controls and 119+/-7 mm Hg in POTS; P=0.048), 
+and an exaggerated phase IV blood pressure overshoot (50+/-10 versus 17+/-3 mm 
+Hg in normal controls; P<0.05). In conclusion, MCA should be considered in 
+patients with POTS presenting with flushing. These patients often present with a 
+typical hyperadrenergic response, but beta-blockers should be used with great 
+caution, if at all, and treatment directed against mast cell mediators may be 
+required.
+
+DOI: 10.1161/01.HYP.0000158259.68614.40
+PMID: 15710782 [Indexed for MEDLINE]

references_cache/PMID_27816065.md

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+---
+reference_id: PMID:27816065
+title: "Insomnia and the risk of depression: a meta-analysis of prospective cohort studies."
+authors:
+- Li L
+- Wu C
+- Gan Y
+- Qu X
+- Lu Z
+journal: BMC Psychiatry
+year: '2016'
+doi: 10.1186/s12888-016-1075-3
+content_type: abstract_only
+---
+
+# Insomnia and the risk of depression: a meta-analysis of prospective cohort studies.
+**Authors:** Li L, Wu C, Gan Y, Qu X, Lu Z
+**Journal:** BMC Psychiatry (2016)
+**DOI:** [10.1186/s12888-016-1075-3](https://doi.org/10.1186/s12888-016-1075-3)
+
+## Content
+
+1. BMC Psychiatry. 2016 Nov 5;16(1):375. doi: 10.1186/s12888-016-1075-3.
+
+Insomnia and the risk of depression: a meta-analysis of prospective cohort 
+studies.
+
+Li L(1)(2), Wu C(1)(3), Gan Y(1), Qu X(4), Lu Z(5).
+
+Author information:
+(1)School of Public Health, Tongji Medical College, Huazhong University of 
+Science and Technology, No. 13 Hangkong Road, Wuhan, Hubei, 430030, China.
+(2)School of Economics and Management, Jiangxi Science and Technology Normal 
+University, Nanchang, Jiangxi, China.
+(3)School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, China.
+(4)School of Health Management, Hangzhou Normal University, Hangzhou, Zhejiang, 
+China.
+(5)School of Public Health, Tongji Medical College, Huazhong University of 
+Science and Technology, No. 13 Hangkong Road, Wuhan, Hubei, 430030, China. 
+zuxunlu@yahoo.com.
+
+BACKGROUND: Observational studies suggest that insomnia might be associated with 
+an increased risk of depression with inconsistent results. This study aimed at 
+conducting a meta-analysis of prospective cohort studies to evaluate the 
+association between insomnia and the risk of depression.
+METHODS: Relevant cohort studies were comprehensively searched from the PubMed, 
+Embase, Web of Science, and China National Knowledge Infrastructure databases 
+(up to October 2014) and from the reference lists of retrieved articles. A 
+random-effects model was used to calculate the pooled risk estimates and 95 % 
+confidence intervals (CIs). The I 2 statistic was used to assess the 
+heterogeneity and potential sources of heterogeneity were assessed with 
+meta-regression. The potential publication bias was explored by using funnel 
+plots, Egger's test, and Duval and Tweedie trim-and-fill methods.
+RESULTS: Thirty-four cohort studies involving 172,077 participants were included 
+in this meta-analysis with an average follow-up period of 60.4 months (ranging 
+from 3.5 to 408). Statistical analysis suggested a positive relationship between 
+insomnia and depression, the pooled RR was 2.27 (95 % CI: 1.89-2.71), and a high 
+heterogeneity was observed (I 2  = 92.6 %, P < 0.001). Visual inspection of the 
+funnel plot revealed some asymmetry. The Egger's test identified evidence of 
+substantial publication bias (P <0.05), but correction for this bias using 
+trim-and-fill method did not alter the combined risk estimates.
+CONCLUSIONS: This meta-analysis indicates that insomnia is significantly 
+associated with an increased risk of depression, which has implications for the 
+prevention of depression in non-depressed individuals with insomnia symptoms.
+
+DOI: 10.1186/s12888-016-1075-3
+PMCID: PMC5097837
+PMID: 27816065 [Indexed for MEDLINE]

references_cache/PMID_28668382.md

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+---
+reference_id: PMID:28668382
+title: "Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders?"
+authors:
+- van Horssen J
+- van Schaik P
+- Witte M
+journal: Neurosci Lett
+year: '2019'
+doi: 10.1016/j.neulet.2017.06.050
+content_type: abstract_only
+---
+
+# Inflammation and mitochondrial dysfunction: A vicious circle in neurodegenerative disorders?
+**Authors:** van Horssen J, van Schaik P, Witte M
+**Journal:** Neurosci Lett (2019)
+**DOI:** [10.1016/j.neulet.2017.06.050](https://doi.org/10.1016/j.neulet.2017.06.050)
+
+## Content
+
+1. Neurosci Lett. 2019 Sep 25;710:132931. doi: 10.1016/j.neulet.2017.06.050. Epub
+ 2017 Jun 28.
+
+Inflammation and mitochondrial dysfunction: A vicious circle in 
+neurodegenerative disorders?
+
+van Horssen J(1), van Schaik P(2), Witte M(2).
+
+Author information:
+(1)Dept. of Molecular Cell Biology and Immunology, VU University Medical Center, 
+Amsterdam, The Netherlands. Electronic address: j.vanhorssen@vumc.nl.
+(2)Dept. of Molecular Cell Biology and Immunology, VU University Medical Center, 
+Amsterdam, The Netherlands.
+
+Experimental evidence supports an intricate association between inflammation and 
+mitochondrial dysfunction as main contributors of neurological diseases. 
+Inflammatory mediators produced by activated microglia and infiltrated immune 
+cells trigger intracellular signalling cascades that can alter cellular 
+mitochondrial metabolism. Cytokines, particularly tumor necrosis factor-alpha, 
+impede mitochondrial oxidative phosphorylation and associated ATP production and 
+instigate mitochondrial reactive oxygen species production. This culminates in 
+mitochondrial membrane permeabilization, altered mitochondrial dynamics and 
+might ultimately result in cell death. When severely injured mitochondria are 
+not appropriately removed by mitophagy they can release their contents into the 
+cytosol and extracellular environment and thereby amplify the inflammatory 
+process. Here we provide a comprehensive overview on how inflammatory mediators 
+impair mitochondrial metabolism and discuss how defective mitochondria can 
+elicit and potentiate an inflammatory response.
+
+Copyright © 2017. Published by Elsevier B.V.
+
+DOI: 10.1016/j.neulet.2017.06.050
+PMID: 28668382 [Indexed for MEDLINE]

references_cache/PMID_30537570.md

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+---
+reference_id: PMID:30537570
+title: "Insomnia as a predictor of mental disorders: A systematic review and meta-analysis."
+authors:
+- Hertenstein E
+- Feige B
+- Gmeiner T
+- Kienzler C
+- Spiegelhalder K
+- Johann A
+- Jansson-Fröjmark M
+- Palagini L
+- Rücker G
+- Riemann D
+- Baglioni C
+journal: Sleep Med Rev
+year: '2019'
+doi: 10.1016/j.smrv.2018.10.006
+content_type: abstract_only
+---
+
+# Insomnia as a predictor of mental disorders: A systematic review and meta-analysis.
+**Authors:** Hertenstein E, Feige B, Gmeiner T, Kienzler C, Spiegelhalder K, Johann A, Jansson-Fröjmark M, Palagini L, Rücker G, Riemann D, Baglioni C
+**Journal:** Sleep Med Rev (2019)
+**DOI:** [10.1016/j.smrv.2018.10.006](https://doi.org/10.1016/j.smrv.2018.10.006)
+
+## Content
+
+1. Sleep Med Rev. 2019 Feb;43:96-105. doi: 10.1016/j.smrv.2018.10.006. Epub 2018 
+Nov 16.
+
+Insomnia as a predictor of mental disorders: A systematic review and 
+meta-analysis.
+
+Hertenstein E(1), Feige B(2), Gmeiner T(2), Kienzler C(2), Spiegelhalder K(2), 
+Johann A(2), Jansson-Fröjmark M(3), Palagini L(4), Rücker G(5), Riemann D(2), 
+Baglioni C(2).
+
+Author information:
+(1)University Psychiatric Services Bern (UPD), Bern, Switzerland. Electronic 
+address: elisabeth.hertenstein@upd.ch.
+(2)Department of Psychiatry and Psychotherapy, Medical Center - University of 
+Freiburg, Faculty of Medicine University of Freiburg, Germany.
+(3)Department of Psychology, Stockholm University, Sweden.
+(4)Department of Psychiatry, University of Pisa, Italy.
+(5)Institute for Medical Biometry and Statistics, Medical Center - University of 
+Freiburg, Faculty of Medicine University of Freiburg, Germany.
+
+Previous research has identified insomnia as a predictor for the onset of 
+depression. The aim of this meta-analysis is to investigate whether insomnia 
+also predicts the onset of other mental disorders. Longitudinal studies were 
+eligible for inclusion if they investigated insomnia at baseline (including 
+nighttime- and daytime-symptoms) as a predictor of the later onset of 
+psychopathology within a follow-up time-frame of at least 12 mo. Thirteen 
+primary studies were included. The results suggest that insomnia is a 
+significant predictor for the onset of depression (10 studies, OR 2.83, CI 
+1.55-5.17), anxiety (six studies, OR 3.23, CI 1.52-6.85), alcohol abuse (two 
+studies, OR 1.35, CI 1.08-1.67, and psychosis (one study, OR 1.28, CI 
+1.03-1.59). The overall risk of bias in the primary studies was moderate. This 
+meta-analysis provides evidence that insomnia increases the risk for 
+psychopathology. A future research agenda should include more prospective 
+studies using established diagnostic criteria, assessing insomnia at baseline 
+and including long-term follow-up intervals evaluating a wider range of mental 
+disorders. In addition, prospective long-term interventional studies 
+investigating the efficacy of insomnia treatment for the prevention of mental 
+disorders are called for.
+
+Copyright © 2018 Elsevier Ltd. All rights reserved.
+
+DOI: 10.1016/j.smrv.2018.10.006
+PMID: 30537570 [Indexed for MEDLINE]

references_cache/PMID_35295802.md

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+---
+reference_id: PMID:35295802
+title: "A Review: The Manifestations, Mechanisms, and Treatments of Musculoskeletal Pain in Patients With COVID-19."
+authors:
+- Wang L
+- Yang N
+- Yang J
+- Zhao S
+- Su C
+journal: Front Pain Res (Lausanne)
+year: '2022'
+doi: 10.3389/fpain.2022.826160
+content_type: abstract_only
+---
+
+# A Review: The Manifestations, Mechanisms, and Treatments of Musculoskeletal Pain in Patients With COVID-19.
+**Authors:** Wang L, Yang N, Yang J, Zhao S, Su C
+**Journal:** Front Pain Res (Lausanne) (2022)
+**DOI:** [10.3389/fpain.2022.826160](https://doi.org/10.3389/fpain.2022.826160)
+
+## Content
+
+1. Front Pain Res (Lausanne). 2022 Mar 10;3:826160. doi:
+10.3389/fpain.2022.826160.  eCollection 2022.
+
+A Review: The Manifestations, Mechanisms, and Treatments of Musculoskeletal Pain 
+in Patients With COVID-19.
+
+Wang L(1)(2), Yang N(1), Yang J(1), Zhao S(1), Su C(1).
+
+Author information:
+(1)Department of Anesthesiology, Hunan Cancer Hospital/The Affiliated Cancer 
+Hospital of Xiangya School of Medicine, Central South University, Changsha, 
+China.
+(2)Department of Medicine, University of South China, Hengyang, China.
+
+The outbreak of COVID-19 poses a serious threat to global health. 
+Musculoskeletal (MSK) pain is the most frequent symptom in patients with 
+COVID-19 besides fever and cough. There are limited studies addressing MSK 
+symptoms in patients with COVID-19. This review aims to provide an overview of 
+current studies related to MSK pain in patients with COVID-19, summarize the 
+possible mechanisms of myalgia, and describe the current management options. In 
+addition to acute respiratory manifestations, COVID-19 might also affect 
+neurological systems which include skeletal manifestations and muscular injury. 
+A possible mechanism of MSK pain and myalgia in COVID-19 may be related to the 
+distribution of angiotensin-converting enzyme 2 (ACE-2) and the occurrence of 
+cytokine storms. ACE-2 has been shown to be the receptor of Severe Acute 
+Respiratory Syndrome Coronavirus 2 (SARS-COV2). Moreover, studies have shown 
+that inflammatory cytokines could cause myalgia by inducing prostaglandin E2 
+(PGE2) production. In addition, it was also found that the plasma levels of IL2, 
+IL7, IL10, IL-6, TNFα, and e lymphopenia were higher in patients with COVID-19. 
+In general, the treatment of MSK pain in patients with COVID-19 falls into 
+pharmacological and non-pharmacological interventions. Various treatments of 
+each have its own merits. The role of vaccination is irreplaceable in the 
+efforts to prevent COVID-19 and mitigates its subsequent symptoms.
+
+Copyright © 2022 Wang, Yang, Yang, Zhao and Su.
+
+DOI: 10.3389/fpain.2022.826160
+PMCID: PMC8915767
+PMID: 35295802
+
+Conflict of interest statement: The authors declare that the research was 
+conducted in the absence of any commercial or financial relationships that could 
+be construed as a potential conflict of interest.

references_cache/PMID_35938771.md

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+---
+reference_id: PMID:35938771
+title: Mast cell activation syndrome and the link with long COVID.
+authors:
+- Arun S
+- Storan A
+- Myers B
+journal: Br J Hosp Med (Lond)
+year: '2022'
+doi: 10.12968/hmed.2022.0123
+content_type: abstract_only
+---
+
+# Mast cell activation syndrome and the link with long COVID.
+**Authors:** Arun S, Storan A, Myers B
+**Journal:** Br J Hosp Med (Lond) (2022)
+**DOI:** [10.12968/hmed.2022.0123](https://doi.org/10.12968/hmed.2022.0123)
+
+## Content
+
+1. Br J Hosp Med (Lond). 2022 Jul 2;83(7):1-10. doi: 10.12968/hmed.2022.0123.
+Epub  2022 Jul 26.
+
+Mast cell activation syndrome and the link with long COVID.
+
+Arun S(1)(2), Storan A(2)(3), Myers B(4).
+
+Author information:
+(1)Division of Biosciences, University College London, London, UK.
+(2)Mast Cell Action, Leamington Spa, UK.
+(3)Department of Science, Engineering, and Environment, The University of 
+Salford, Salford, UK.
+(4)Haematology Department, University Hospitals of Leicester, Leicester, UK.
+
+Mast cells are innate immune cells found in connective tissues throughout the 
+body, most prevalent at tissue-environment interfaces. They possess multiple 
+cell-surface receptors which react to various stimuli and, after activation, 
+release many mediators including histamine, heparin, cytokines, prostaglandins, 
+leukotrienes and proteases. In mast cell activation syndrome, excessive amounts 
+of inflammatory mediators are released in response to triggers such as foods, 
+fragrances, stress, exercise, medications or temperature changes. Diagnostic 
+markers may be difficult to assess because of their rapid degradation; these 
+include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and 
+serum tryptase (which is stable) in the UK. Self-management techniques, 
+medications and avoiding triggers may improve quality of life. Treatments 
+include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory 
+agents. 'Long COVID' describes post-COVID-19 syndrome when symptoms persist for 
+more than 12 weeks after initial infection with no alternative diagnosis. Both 
+mast cell activation syndrome and long COVID cause multiple symptoms. It is 
+theorised that COVID-19 infection could lead to exaggeration of existing 
+undiagnosed mast cell activation syndrome, or could activate normal mast cells 
+owing to the persistence of viral particles. Other similarities include the 
+relapse-remission cycle and improvements with similar treatments. Importantly, 
+however, aside from mast cell disorders, long COVID could potentially be 
+attributed to several other conditions.
+
+DOI: 10.12968/hmed.2022.0123
+PMID: 35938771 [Indexed for MEDLINE]