Neurological and neuropsychiatric symptoms that persist or develop three months after the onset of COVID-19 pose a significant threat to the global healthcare system. These symptoms are yet to be ...synthesized and quantified via meta-analysis.
To determine the prevalence of neurological and neuropsychiatric symptoms reported 12 weeks (3 months) or more after acute COVID-19 onset in adults.
A systematic search of PubMed, EMBASE, Web of Science, Google Scholar and Scopus was conducted for studies published between January 1st, 2020 and August 1st, 2021. The systematic review was guided by Preferred Reporting Items for Systematic Review and Meta-Analyses.
Studies were included if the length of follow-up satisfied the National Institute for Healthcare Excellence (NICE) definition of post-COVID-19 syndrome (symptoms that develop or persist ≥3 months after the onset of COVID-19). Additional criteria included the reporting of neurological or neuropsychiatric symptoms in individuals with COVID-19.
Two authors independently extracted data on patient characteristics, hospital and/or ICU admission, acute-phase COVID-19 symptoms, length of follow-up, and neurological and neuropsychiatric symptoms.
The primary outcome was the prevalence of neurological and neuropsychiatric symptoms reported ≥3 months post onset of COVID-19. We also compared post-COVID-19 syndrome in hospitalised vs. non-hospitalised patients, with vs. without ICU admission during the acute phase of infection, and with mid-term (3 to 6 months) and long-term (>6 months) follow-up.
Of 1458 articles, 18 studies, encompassing a total of 10,530 patients, were analysed. Overall prevalence for neurological post-COVID-19 symptoms were: fatigue (37%, 95% CI: 25%–48%), brain fog (32%, 10%–54%), memory issues (28%, 22%–35%), attention disorder (22%, 7%–36%), myalgia (17%, 9%–25%), anosmia (12%, 8%–16%), dysgeusia (10%, 6%–14%) and headache (15%, 4%–26%). Neuropsychiatric conditions included sleep disturbances (31%, 19%–42%), anxiety (23%, 14%–32%) and depression (17%, 10%–24%). Neuropsychiatric symptoms substantially increased in prevalence between mid- and long-term follow-up. Compared to non-hospitalised patients, patients hospitalised for acute COVID-19 had reduced frequency of anosmia, anxiety, depression, dysgeusia, fatigue, headache, myalgia, and sleep disturbance at three (or more) months post-infection. Cohorts with >20% of patients admitted to the ICU during acute COVID-19 experienced higher prevalence of fatigue, anxiety, depression, and sleep disturbances than cohorts with <20% of ICU admission.
Fatigue, cognitive dysfunction (brain fog, memory issues, attention disorder) and sleep disturbances appear to be key features of post-COVID-19 syndrome. Psychiatric manifestations (sleep disturbances, anxiety, and depression) are common and increase significantly in prevalence over time. Randomised controlled trials are necessary to develop intervention strategy to reduce disease burden.
•Question: How commonly are neurological and neuropsychiatric symptoms reported three months or more after acute COVID-19 onset in adults?•Findings: In a meta-analysis of 18 studies encompassing 10,530 patients (hospitalised and non-hospitalised), overall prevalence for neurological symptoms three months after COVID-19 onset was: fatigue (37%), brain fog (32%), memory issues (28%), attention disorder (22%), myalgia (17%), anosmia (12%), dysgeusia (10%), and headache (15%). The prevalence of neuropsychiatric symptoms was sleep disturbances (31%), anxiety (23%), and depression (17%).•Meaning: Given the high prevalence of neurological and neuropsychiatric post-COVID-19 syndrome, randomised controlled trials are necessary to develop intervention strategy to reduce disease burden.
The spread of coronavirus disease 2019 (COVID-19) continues to grow exponentially in most countries, posing an unprecedented burden on the healthcare sector and the world economy. Previous ...respiratory virus outbreaks, such as severe acute respiratory syndrome (SARS), pandemic H1N1 and Middle East respiratory syndrome (MERS), have provided significant insights into preparation and provision of intensive care support including extracorporeal membrane oxygenation (ECMO). Many patients have already been supported with ECMO during the current COVID-19 pandemic, and it is likely that many more may receive ECMO support, although, at this point, the role of ECMO in COVID-19-related cardiopulmonary failure is unclear. Here, we review the experience with the use of ECMO in the past respiratory virus outbreaks and discuss potential role for ECMO in COVID-19.
Acute kidney injury (AKI) is a frequent and severe complication of both COVID-19-related acute respiratory distress syndrome (ARDS) and non-COVID-19-related ARDS. The COVID-19 Critical Care ...Consortium (CCCC) has generated a global data set on the demographics, management and outcomes of critically ill COVID-19 patients. The LUNG-SAFE study was an international prospective cohort study of patients with severe respiratory failure, including ARDS, which pre-dated the pandemic.
The incidence, demographic profile, management and outcomes of early AKI in patients undergoing invasive mechanical ventilation for COVID-19-related ARDS were described and compared with AKI in a non-COVID-19-related ARDS cohort.
Of 18,964 patients in the CCCC data set, 1699 patients with COVID-19-related ARDS required invasive ventilation and had relevant outcome data. Of these, 110 (6.5%) had stage 1, 94 (5.5%) had stage 2, 151 (8.9%) had stage 3 AKI, while 1214 (79.1%) had no AKI within 48 h of initiating invasive mechanical ventilation. Patients developing AKI were older and more likely to have hypertension or chronic cardiac disease. There were geo-economic differences in the incidence of AKI, with lower incidence of stage 3 AKI in European high-income countries and a higher incidence in patients from middle-income countries. Both 28-day and 90-day mortality risk was increased for patients with stage 2 (HR 2.00, p < 0.001) and stage 3 AKI (HR 1.95, p < 0.001). Compared to non-COVID-19 ARDS, the incidence of shock was reduced with lower cardiovascular SOFA score across all patient groups, while hospital mortality was worse in all groups no AKI (30 vs 50%), Stage 1 (38 vs 58%), Stage 2 (56 vs 74%), and Stage 3 (52 vs 72%), p < 0.001. The time profile of onset of AKI also differed, with 56% of all AKI occurring in the first 48 h in patients with COVID-19 ARDS compared to 89% in the non-COVID-19 ARDS population.
AKI is a common and serious complication of COVID-19, with a high mortality rate, which differs by geo-economic location. Important differences exist in the profile of AKI in COVID-19 versus non-COVID-19 ARDS in terms of their haemodynamic profile, time of onset and clinical outcomes.
Discovered in the 1990s, protease activated receptors(1) (PARs) are membrane-spanning cell surface proteins that belong to the G protein coupled receptor (GPCR) family. A defining feature of these ...receptors is their irreversible activation by proteases; mainly serine. Proteolytic agonists remove the PAR extracellular amino terminal pro-domain to expose a new amino terminus, or tethered ligand, that binds intramolecularly to induce intracellular signal transduction via a number of molecular pathways that regulate a variety of cellular responses. By these mechanisms PARs function as cell surface sensors of extracellular and cell surface associated proteases, contributing extensively to regulation of homeostasis, as well as to dysfunctional responses required for progression of a number of diseases. This review examines common and distinguishing structural features of PARs, mechanisms of receptor activation, trafficking and signal termination, and discusses the physiological and pathological roles of these receptors and emerging approaches for modulating PAR-mediated signaling in disease.
Expression of the protease sensing receptor, protease activated receptor-2 (PAR2), is elevated in a variety of cancers and has been promoted as a potential therapeutic target. With the development of ...potent antagonists for this receptor, we hypothesised that they could be used to treat renal cell carcinoma (RCC). The expression of PAR2 was, therefore, examined in human RCC tissues and selected RCC cell lines. Histologically confirmed cases of RCC, together with paired non-involved kidney tissue, were used to produce a tissue microarray (TMA) and to extract total tissue RNA. Immunohistochemistry and qPCR were then used to assess PAR2 expression. In culture, RCC cell lines versus primary human kidney tubular epithelial cells (HTEC) were used to assess PAR2 expression by qPCR, immunocytochemistry and an intracellular calcium mobilization assay. The TMA revealed an 85% decrease in PAR2 expression in tumour tissue compared with normal kidney tissue. Likewise, qPCR showed a striking reduction in PAR2 mRNA in RCC compared with normal kidney. All RCC cell lines showed lower levels of PAR2 expression than HTEC. In conclusion, we found that PAR2 was reduced in RCC compared with normal kidney and is unlikely to be a target of interest in the treatment of this type of cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Evidence of cerebrovascular complications in COVID-19 requiring venovenous extracorporeal membrane oxygenation (ECMO) is limited. Our study aims to characterize the prevalence and risk factors of ...stroke secondary to COVID-19 in patients on venovenous ECMO.
We analyzed prospectively collected observational data, using univariable and multivariable survival modeling to identify risk factors for stroke. Cox proportional hazards and Fine-Gray models were used, with death and discharge treated as competing risks.
Three hundred eighty institutions in 53 countries in the COVID-19 Critical Care Consortium (COVID Critical) registry.
Adult COVID-19 patients who were supported by venovenous ECMO.
None.
Five hundred ninety-five patients (median age interquartile range, 51 yr 42-59 yr; male: 70.8%) had venovenous ECMO support. Forty-three patients (7.2%) suffered strokes, 83.7% of which were hemorrhagic. In multivariable survival analysis, obesity (adjusted hazard ratio aHR, 2.19; 95% CI, 1.05-4.59) and use of vasopressors before ECMO (aHR, 2.37; 95% CI, 1.08-5.22) were associated with an increased risk of stroke. Forty-eight-hour post-ECMO Pa co2 -pre-ECMO Pa co2 /pre-ECMO Pa co2 (relative ΔPa co2 ) of negative 26% and 48-hour post-ECMO Pa o2 -pre-ECMO Pa o2 /pre-ECMO Pa o2 (relative ΔPa o2 ) of positive 24% at 48 hours of ECMO initiation were observed in stroke patients in comparison to relative ΔPa co2 of negative 17% and relative ΔPa o2 of positive 7% in the nonstroke group. Patients with acute stroke had a 79% in-hospital mortality compared with 45% mortality for stroke-free patients.
Our study highlights the association of obesity and pre-ECMO vasopressor use with the development of stroke in COVID-19 patients on venovenous ECMO. Also, the importance of relative decrease in Pa co2 and moderate hyperoxia within 48 hours after ECMO initiation were additional risk factors.
Mammalian survival depends on metabolizing nutrients, storing energy, and combating infection. Complement activation in blood triggers energy‐depleting immune responses to fight infections. Here we ...identify surprising energy‐conserving roles for complement proteins C5a and C3a and their receptors, C5aR and C3aR, roles that are contraindicated in complement biology. Rats fed a high‐carbohydrate high‐fat diet developed obesity, visceral adiposity, adipose inflammation, glucose/insulin intolerance, and cardiovascular dysfunction that correlated with increased plasma C3a, adipose C5aR, and C3aR. These in vivo changes were dramatically attenuated by receptor‐selective antagonists of either C5aR (5 mg/kg/d p.o.) or C3aR (30 mg/kg/d p.o.), which both reduced proinflammatory adipokines and altered expression of inflammatory genes in adipose tissue. In vitro C5a and C3a (100 nM) exhibited novel insulin‐like effects on 3T3‐L1 adipocytes, promoting energy conservation by increasing glucose and fatty acid uptake while inhibiting cAMP signaling and lipolysis, and induced PGE2 release from macrophages, effects all blocked by each respective antagonist (10 μM). These studies reveal important new links between complement signaling and metabolism, highlight new complement functions on adipocytes and in adipose tissue, demonstrate how aberrant immune responses may exacerbate obesity and metabolic dysfunction, and show that targeting C3aR or C5aR with antagonists is a new strategy for treating metabolic dysfunction.—Lim, J., Iyer, A., Suen, J. Y., Seow, V., Reid, R. C., Brown, L., Fairlie, D. P. C5aR and C3aR antagonists each inhibit diet‐induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. FASEB J. 27, 822–831 (2013). www.fasebj.org
...while the proinflammatory role of IL-6 in fueling harmful CRS is established, the role of IL-6 in ARDS pathophysiology, in which IL-6 may have also anti-inflammatory and anti-apoptotic activity 8, ...is not yet fully elucidated. ...it remains to be determined whether IL-6 is simply a biomarker of lung injury or has a causative role in ARDS pathogenesis, and what is the harmful IL-6 threshold that justifies beginning of treatment. ...COVID-19 ARDS is an etiological subphenotype of ARDS, and results on this cohort should not be generalized to the entire ARDS population. ...in most previous COVID-19 studies, it is difficult to determine the ARDS phase (exudative/inflammatory, proliferative, fibrotic) in which IL-6 inhibitors have been administered, leaving best timing for treatment still to be determined. ...IL-6 inhibitors have historically been used in chronic inflammatory diseases.
Background and Purpose
Specific cellular functions mediated by GPCRs are often associated with signalling through a particular G protein or β‐arrestin. Here, we examine signalling through a GPCR, ...protease‐activated receptor 2 (PAR2), in a high‐grade serous ovarian cancer cell line (OV90).
Experimental Approach
Human ovarian cancer tissues (n = 1,200) and nine human ovarian cancer cell lines were assessed for PAR2 expression. PAR2 signalling mechanisms leading to cell migration and invasion were dissected using cellular assays, western blots, CRISPR‐Cas9 gene knockouts, pharmacological inhibitors of PAR2 and downstream signalling proteins in OV90 cancer cells.
Key Results
PAR2 was significantly overexpressed in clinical ovarian cancer tissues and in OV90 ovarian cancer cells. PAR2 agonists, an endogenous protease (trypsin) and a synthetic peptide (2f‐LIGRL‐NH2), induced migration and invasion of OV90 ovarian cancer cells through activating a combination of Gαq/11, Gα12/13 and β‐arrestin1/2, but not Gαs or Gαi. This novel cooperative rather than parallel signalling resulted in downstream serial activation of Src kinases, then transactivation of epidermal growth factor receptor (EGFR), followed by downstream MEK–ERK1/2–FOS/MYC/STAT3–COX2 signalling. Either a PAR2 antagonist (I‐191), CRISPR‐Cas9 gene knockouts (PAR2 or Gα proteins or β‐arrestin1/2), or inhibitors of each downstream protein attenuated human ovarian cancer cell motility.
Conclusion and Implications
This study highlights a novel shared signalling cascade, requiring each of Gαq/11, Gα12/13 and β‐arrestin1/2 for PAR2‐induced ovarian cancer cell migration and invasion. This mechanism controlling a cellular function is unusual in not being linked to a specific individual G protein or β‐arrestin‐mediated signalling pathway.
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