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1.
The neurological insights of the emerging coronaviruses.
Msigwa, SS, Wang, Y, Li, Y, Cheng, X
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2020;:1-7
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Abstract
Emerging Viral diseases are incredibly infectious and proficient in inducing pandemics. Unlike the previous emerging coronaviruses (ECoVs) which neurological complexities were uncommon, with neurological features exhibition at 14-25 days post-onset, yet with critical outcomes exhibiting >50% mortality in central nervous (CNS) presenting pathologies. The COVID 19 neurological consequences occur more frequently even in mild cases, presenting with CNS involvement in up to 25%, musculoskeletal and peripheral manifestation (PNM). Through preceding ECoVs case reports, the PNM not linked to fatal outcomes, however, required, repeated neuro-imaging as notable CT and MRI changes appeared as late as 21 days while the likelihood of Cerebrospinal fluid to test positive for ECoV was 25%, only in the CNS presenting cases. Owing to 44-60% myalgia presentation, risk of the high inflammatory state, and coagulation cascade abnormalities reported in ECoVs, testing for C-reactive protein, serum creatine kinase, and D-dimer level is mandatory. Presently, there is no antiviral medication or vaccination for the ECoVs, early induction of antiviral drugs remains the backbone of management. Neurologically, the therapeutic dosages of anticoagulants are linked to the high incidence of thrombotic complexities, while methylprednisolone is associated with myopathy. Future studies expected to apply more neuro-imaging techniques for CNS exploration and further explore the pathogenesis of the COVID 19 myalgia, anosmia/ageusia reported in the majority of the initial cases.
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The Knowns and Unknowns of Contemporary Statin Therapy for Familial Hypercholesterolemia.
Pang, J, Chan, DC, Watts, GF
Current atherosclerosis reports. 2020;(11):64
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PURPOSE OF REVIEW Statins are first-line therapy for lowering low-density lipoprotein (LDL) cholesterol in familial hypercholesterolemia (FH), particularly in heterozygous patients. We review advances and new questions on the use of statins in FH. RECENT FINDINGS Cumulative evidence from registry data and sub-analyses of clinical trials mandates the value of statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in FH. Statins are safe in children and adolescents with FH, with longer term cardiovascular benefits. The potentially toxic effects of statins in pregnancy need to be considered, but no association has been reported in prospective cohort studies with birth defects. There is no rationale for discontinuation of statins in elderly FH unless indicated by adverse events. FH is undertreated, with > 80% of statin-treated FH patients failing to attain LDL cholesterol treatment targets. This may relate to adherence, tolerability, and genetic differences in statin responsiveness. Statin treatment from childhood may reduce the need for stringent cholesterol targets. Combination of statins with ezetimibe and PCSK9 inhibitors significantly improves the efficacy of treatment. Whether statin use could improve the clinical course of FH patients with COVID-19 and other respiratory infections remains an unsolved issue for future research. Statins are the mainstay for primary and secondary prevention of ASCVD in FH. Sustained long-term optimal statin treatment from an early age can effectively prevent ASCVD over decades of life. Despite their widespread use, statins merit further investigation in FH.
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Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial.
Desilles, JP, Gregoire, C, Le Cossec, C, Lambert, J, Mophawe, O, Losser, MR, Lambiotte, F, Le Tacon, S, Cantier, M, Engrand, N, et al
Trials. 2020;(1):548
Abstract
OBJECTIVES Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated. This Letter serves as a summary of the key elements of the full protocol.
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Containing COVID-19 by Matching Messages on Social Distancing to Emergent Mindsets-The Case of North America.
Bellissimo, N, Gabay, G, Gere, A, Kucab, M, Moskowitz, H
International journal of environmental research and public health. 2020;(21)
Abstract
Public compliance with social distancing is key to containing COVID-19, yet there is a lack of knowledge on which communication 'messages' drive compliance. Respondents (224 Canadians and Americans) rated combinations of messages about compliance, systematically varied by an experimental design. Independent variables were perceived risk; the agent communicating the policy; specific social distancing practices; and methods to enforce compliance. Response patterns to each message suggest three mindset segments in each country reflecting how a person thinks. Two mindsets, the same in Canada and the US, were 'tell me exactly what to do,' and 'pandemic onlookers.' The third was 'bow to authority' in Canada, and 'tell me how' in the US. Each mindset showed different messages strongly driving compliance. To effectively use messaging about compliance, policy makers may assign any person or group in the population to the appropriate mindset segment by using a Personal Viewpoint Identifier that we developed.
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Review on the potential action mechanisms of Chinese medicines in treating Coronavirus Disease 2019 (COVID-19).
Huang, YF, Bai, C, He, F, Xie, Y, Zhou, H
Pharmacological research. 2020;:104939
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The Coronavirus Disease 2019 (COVID-19) has been declared as a global pandemic, but specific medicines and vaccines are still being developed. In China, interventional therapies with traditional Chinese medicine for COVID-19 have achieved significant clinical efficacies, but the underlying pharmacological mechanisms are still unclear. This article reviewed the etiology of COVID-19 and clinical efficacy. Both network pharmacological study and literature search were used to demonstrate the possible action mechanisms of Chinese medicines in treating COVID-19. We found that Chinese medicines played the role of antivirus, anti-inflammation and immunoregulation, and target organs protection in the management of COVID-19 by multiple components acting on multiple targets at multiple pathways. AEC2 and 3CL protein could be the direct targets for inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Quercetin, kaempferol, luteolin, isorhamnetin, baicalein, naringenin, and wogonin could be the main active ingredients of Chinese medicines for the management of COVID-19 by targeting on AEC2 and 3CL protein and inhibiting inflammatory mediators, regulating immunity, and eliminating free radicals through COX-2, CASP3, IL-6, MAPK1, MAPK14, MAPK8, and REAL in the signaling pathways of IL-17, arachidonic acid, HIF-1, NF-κB, Ras, and TNF. This study may provide meaningful and useful information on further research to investigate the action mechanisms of Chinese medicines against SARS-CoV-2 and also provide a basis for sharing the "China scheme" for COVID-19 treatment.
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Relevant Nutrition Therapy in COVID-19 and the Constraints on Its Delivery by a Unique Disease Process.
Patel, JJ, Martindale, RG, McClave, SA
Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2020;(5):792-799
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Worldwide, as of July 2020, >13.2 million people have been infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The spectrum of coronavirus disease 2019 (COVID-19) ranges from mild illness to critical illness in 5% of cases. The population infected with SARS-CoV-2 requiring an intensive care unit admission often requires nutrition therapy as part of supportive care. Although the various societal guidelines for critical care nutrition meet most needs for the patient with COVID-19, numerous factors, which impact the application of those guideline recommendations, need to be considered. Since the SARS-CoV-2 virus is highly contagious, several key principles should be considered when caring for all patients with COVID-19 to ensure the safety of all healthcare personnel involved. Management strategies should cluster care, making all attempts to bundle patient care to limit exposure. Healthcare providers should be protected, and the spread of SARS-CoV-2 should be limited by minimizing procedures and other interventions that lead to aerosolization, avoiding droplet exposure through hand hygiene and use of personal protective equipment (PPE). PPE should be preserved by decreasing the number of individuals providing direct patient care and by limiting the number of patient interactions. Enteral nutrition (EN) is tolerated by the majority of patients with COVID-19, but a relatively low threshold for conversion to parenteral nutrition should be maintained if increased exposure to the virus is required to continue EN. This article offers relevant and practical recommendations on how to optimize nutrition therapy in critically ill patients with COVID-19.
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Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial.
Miller, J, Bruen, C, Schnaus, M, Zhang, J, Ali, S, Lind, A, Stoecker, Z, Stauderman, K, Hebbar, S
Critical care (London, England). 2020;(1):502
Abstract
BACKGROUND Calcium release-activated calcium (CRAC) channel inhibitors stabilize the pulmonary endothelium and block proinflammatory cytokine release, potentially mitigating respiratory complications observed in patients with COVID-19. This study aimed to investigate the safety and efficacy of Auxora, a novel, intravenously administered CRAC channel inhibitor, in adults with severe or critical COVID-19 pneumonia. METHODS A randomized, controlled, open-label study of Auxora was conducted in adults with severe or critical COVID-19 pneumonia. Patients were randomized 2:1 to receive three doses of once-daily Auxora versus standard of care (SOC) alone. The primary objective was to assess the safety and tolerability of Auxora. Following FDA guidance, study enrollment was halted early to allow for transition to a randomized, blinded, placebo-controlled study. RESULTS In total, 17 patients with severe and three with critical COVID-19 pneumonia were randomized to Auxora and nine with severe and one with critical COVID-19 pneumonia to SOC. Similar proportions of patients receiving Auxora and SOC experienced ≥ 1 adverse event (75% versus 80%, respectively). Fewer patients receiving Auxora experienced serious adverse events versus SOC (30% versus 50%, respectively). Two patients (10%) receiving Auxora and two (20%) receiving SOC died during the 30 days after randomization. Among patients with severe COVID-19 pneumonia, the median time to recovery with Auxora was 5 days versus 12 days with SOC; the recovery rate ratio was 1.87 (95% CI, 0.72, 4.89). Invasive mechanical ventilation was needed in 18% of patients with severe COVID-19 pneumonia receiving Auxora versus 50% receiving SOC (absolute risk reduction = 32%; 95% CI, - 0.07, 0.71). Outcomes measured by an 8-point ordinal scale were significantly improved for patients receiving Auxora, especially for patients with a baseline PaO2/FiO2 = 101-200. CONCLUSIONS Auxora demonstrated a favorable safety profile in patients with severe or critical COVID-19 pneumonia and improved outcomes in patients with severe COVID-19 pneumonia. These results, however, are limited by the open-label study design and small patient population resulting from the early cessation of enrollment in response to regulatory guidance. The impact of Auxora on respiratory complications in patients with severe COVID-19 pneumonia will be further assessed in a planned randomized, blinded, placebo-controlled study. TRIAL REGISTRATION ClinicalTrials.gov, NCT04345614 . Submitted on 7 April 2020.
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Exposome and Immunity Training: How Pathogen Exposure Order Influences Innate Immune Cell Lineage Commitment and Function.
Adams, K, Weber, KS, Johnson, SM
International journal of molecular sciences. 2020;(22)
Abstract
Immune memory is a defining characteristic of adaptive immunity, but recent work has shown that the activation of innate immunity can also improve responsiveness in subsequent exposures. This has been coined "trained immunity" and diverges with the perception that the innate immune system is primitive, non-specific, and reacts to novel and recurrent antigen exposures similarly. The "exposome" is the cumulative exposures (diet, exercise, environmental exposure, vaccination, genetics, etc.) an individual has experienced and provides a mechanism for the establishment of immune training or immunotolerance. It is becoming increasingly clear that trained immunity constitutes a delicate balance between the dose, duration, and order of exposures. Upon innate stimuli, trained immunity or tolerance is shaped by epigenetic and metabolic changes that alter hematopoietic stem cell lineage commitment and responses to infection. Due to the immunomodulatory role of the exposome, understanding innate immune training is critical for understanding why some individuals exhibit protective phenotypes while closely related individuals may experience immunotolerant effects (e.g., the order of exposure can result in completely divergent immune responses). Research on the exposome and trained immunity may be leveraged to identify key factors for improving vaccination development, altering inflammatory disease development, and introducing potential new prophylactic treatments, especially for diseases such as COVID-19, which is currently a major health issue for the world. Furthermore, continued exposome research may prevent many deleterious effects caused by immunotolerance that frequently result in host morbidity or mortality.
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Vitamin C for COVID-19: A living systematic review.
Baladia, E, Pizarro, AB, Ortiz-Muñoz, L, Rada, G
Medwave. 2020;(6):e7978
Abstract
OBJECTIVE This living systematic review aims to provide a timely, rigorous, and continuously updated summary of the available evidence on the role of vitamin C in treating patients with COVID-19. DATA SOURCES We conducted searches in PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature, and in a centralized repository in L·OVE (Living OVerview of Evidence). In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it comprises and has been customized to group all COVID-19 evidence in one place. All the searches covered the period until April 29, 2020 (one day before submission). STUDY SELECTION AND METHODS We adapted an already published standard protocol for multiple parallel systematic reviews. We searched for randomized trials evaluating the effect, in patients with COVID-19, of vitamin C versus placebo or no treatment. Anticipating the lack of randomized trials directly addressing this question, we also searched for trials evaluating MERS-CoV and SARS-CoV, and non-randomized studies in COVID-19. Two reviewers independently screened each study for eligibility. A living, web-based version of this review will be openly available during the COVID-19 pandemic, and we will resubmit it to the journal whenever there are substantial updates. RESULTS We screened 95 records, but no study was considered eligible. We identified 20 ongoing studies, including 13 randomized trials evaluating vitamin C in COVID-19. CONCLUSIONS We did not find any studies that met our inclusion criteria, and hence there is no evidence to support or refute the use of vitamin C in the treatment of patients with COVID-19. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon. PROSPERO REGISTRATION NUMBER CRD42020181216.
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Endoscopy in inflammatory bowel diseases during the COVID-19 pandemic and post-pandemic period.
Iacucci, M, Cannatelli, R, Labarile, N, Mao, R, Panaccione, R, Danese, S, Kochhar, GS, Ghosh, S, Shen, B
The lancet. Gastroenterology & hepatology. 2020;(6):598-606
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Abstract
The coronavirus disease 2019 (COVID-19) pandemic is changing the management of many chronic diseases, including that of patients with inflammatory bowel diseases (IBD). In particular, the performance of routine endoscopy is temporarily suspended, and only emergency endoscopy is allowed in many countries where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread. We highlight different scenarios in which endoscopy should still be performed urgently in patients with IBD, as well as recommendations regarding the use of personal protective equipment. We suggest a pathway for performing safe endoscopy and discuss the potential risks of postponing endoscopy in IBD. Finally, we propose a post-pandemic plan for access to endoscopy.