Drug treatments affecting ACE2 in COVID-19 infection: a systematic review protocol

BackgroundThe SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs that up- or down-regulate ACE2 expression are, therefore, of critical research interest as agents that might promote or reduce risk of COVID-19 infection in a susceptible population.AimTo collate evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2, and thus potentially affect COVID-19 infection.Design & settingSystematic review of studies published in MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), the Cochrane Library, and Web of Science from inception to 1 April 2020.MethodA systematic review will be conducted in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Inclusion criteria will be: (1) assesses the effect of drug exposure on ACE2 level of expression or activity; (2) the drug is included in the British National Formulary (BNF) and, therefore, available to prescribe in the UK; and (3) a control, placebo, or sham group is included as comparator. Exclusion criteria will be: (1) ACE2 measurement in utero; (2) ACE2 measurement in children aged <18 years; (3) drug not in the BNF; and (4) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool for animal studies.ResultsData will be reported in summary tables and narrative synthesis.ConclusionThis systematic review will identify drug therapies that may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.

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Drug treatments affecting ACE2 in COVID-19 infection: a systematic review protocol

10.1101/2020.05.25.20100438 ◽

2020 ◽

Author(s):

Hajira Dambha-Miller ◽

Ali Albasri ◽

Sam Hodgson ◽

Chris Wilcox ◽

Nazrul Islam ◽

...

Keyword(s):

Systematic Review ◽

Animal Studies ◽

Drug Exposure ◽

Risk Of Bias ◽

Cochrane Library ◽

Susceptible Population ◽

Drug Treatments ◽

Review Protocol ◽

The Uk ◽

The Cochrane Library

Abstract Background: The SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs which up- or down-regulate ACE2 expression are therefore of critical research interest as agents which might promote or reduce risk of COVID-19 infection in a susceptible population. Aim: To review evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2 and potentially affect COVID-19 infection. Design and setting: Systematic review of studies published in MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science from inception to April 1st 2020. Method: A systematic review will be conducted in line with PRISMA guidelines. Inclusion criteria will be: i) assess effect of drug exposure on ACE2 level; ii) drug is included in British National Formulary (BNF) and therefore available to prescribe in UK; iii) a control, placebo or sham group is included as comparator. Exclusion criteria will be: i) ACE2 measurement in utero; ii) ACE2 measurement in children under 18 years; iii) drug not in BNF; iv) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYRCLE risk of bias tool for animal studies. Results: Data will be reported in summary tables and narrative synthesis. Conclusion: This systematic review will identify drug therapies which may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.

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Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review

BMJ Open ◽

10.1136/bmjopen-2020-040644 ◽

2020 ◽

Vol 10 (9) ◽

pp. e040644

Author(s):

Hajira Dambha-Miller ◽

Ali Albasri ◽

Sam Hodgson ◽

Christopher R Wilcox ◽

Shareen Khan ◽

...

Keyword(s):

Systematic Review ◽

Web Of Science ◽

Angiotensin Receptor Blockers ◽

Risk Of Bias ◽

Cochrane Library ◽

Channel Blockers ◽

Human Lungs ◽

The Uk ◽

The Cochrane Library ◽

The Impact

ObjectiveTo review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease.DesignSystematic review.Data sourceMEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science.Study selectionAny design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression.Data extraction and synthesisMEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies.ResultsWe screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2).ConclusionsThere is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.

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Currently prescribed drugs in the UK that could up or downregulate ACE2 in COVID-19 disease: A systematic review

10.1101/2020.05.19.20106856 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hajira Dambha-Miller ◽

Ali Albasri ◽

Sam Hodgson ◽

Christopher R Wilcox ◽

Shareen Khan ◽

...

Keyword(s):

Systematic Review ◽

Angiotensin Converting Enzyme ◽

Web Of Science ◽

Risk Of Bias ◽

Cochrane Library ◽

Converting Enzyme ◽

Human Lungs ◽

The Uk ◽

The Cochrane Library ◽

The Impact

Objective: To review evidence on routinely prescribed drugs in the UK that could up or downregulate Angiotensin Converting Enzyme 2 (ACE2) and potentially affect COVID-19 disease Design: Systematic review Data source: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science Study selection: Any design with animal or human models examining a currently prescribed UK drug compared to a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. Data extraction and synthesis: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1st April 2020. Methodological quality was assessed using the SYRCLE's risk of bias tool for animal studies and Cochrane risk of bias tool for human studies. Results: We screened 3,360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and 102 were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were Angiotensin Receptor Blockers (ARBs) (n= 55) and Angiotensin-Converting Enzyme- Inhibitors (ACE-I) (n= 22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel-blockers (n=3) GLP-1 agonists (n=2) and NSAIDs (n=2). Conclusions: There is an abundance of academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty amongst patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in-vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.

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Warming Acupuncture in the Treatment of Cervical Spondylotic Radiculopathy: A Systematic Review and Meta-analysis

Acupuncture & Electro-Therapeutics Research ◽

10.3727/036012921x16273277361795 ◽

2021 ◽

Author(s):

Wang Zuqing ◽

Li Yan

Keyword(s):

Systematic Review ◽

Odds Ratio ◽

Meta Analysis ◽

Effective Rate ◽

Risk Of Bias ◽

Cochrane Library ◽

Efficacy And Safety ◽

Vas Score ◽

Cervical Spondylotic Radiculopathy ◽

The Cochrane Library

Background: Warming acupuncture (WA) is widely used in the management of Cervical spondylotic radiculopathy (CSR)in China and obtains desirable efficacy. Therefore, the aim of this study is to systematically assess the efficacy and safety whether using WA alone or combined with traditional Chinese medicine (TCM) therapy for the treatment of CSR. Methods: PubMed, EMBASE, Sinomed, the Cochrane Library, CNKI, VIP and Wangfang databases were searched from their inception through 30 September 2020. All the retrieved records were screened or excluded based on the criteria that were pre-established, and the results that meet the criteria were assessed by the Cochrane risk of bias tool and Meta-analysis was conducted by using RevMan5.3 software. Results: Fourteen RCTs (1021patients) were included in the meta-analysis. The effective rate of WA alone or combination with TCM therapy was analyzed in comparison with the treatment of regular therapy. The results indicated that compared with regular therapy, WA alone or in combination with TCM therapy increased clinical effective rate (Odds ratio (OR)=4.43,95%CI 2.85 to 6.90, P<0.01). Additionally decreased VAS score (mean difference (MD)=-1.21,95%CI -1.68 to -0.73, P<0.01), PPI (MD=-1.34, 95% CI -2.08 to -0.61) and PRI (MD=-0.55,95% CI -0.72 to -0.37, P<0.001). However, adverse events of WA were not specially reported in all studies. Conclusions: WA as the main treatment for CSR can improve the clinical effective rate and reduce the level of VAS score, PPI and PRI. Further research is needed to determine the effectiveness of WA for CSR treatment, rigorously and unambiguously.

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Effectiveness of Nutritional Education for Obese Older Adults With Frailty: A Systematic Review and Meta-Analysis

Innovation in Aging ◽

10.1093/geroni/igaa057.1291 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 401-401

Author(s):

Yue-Heng Yin ◽

Liu Yat Justina

Keyword(s):

Systematic Review ◽

Physical Function ◽

Meta Analysis ◽

Experimental Studies ◽

Well Being ◽

Risk Of Bias ◽

Cochrane Library ◽

Nutritional Education ◽

Hand Search ◽

Education Interventions

Abstract Obesity has been shown to intensify the decline of physical function and lead to frailty. Nutrition is an important method in managing obesity and frailty, while seldom reviews have ever explored the effects of nutritional education interventions. We conducted a systematic review (PROSPERO: CRD42019142403) to explore the effectiveness of nutritional education interventions in managing body composition and physio-psychosocial parameters related to frailty. Randomized controlled trials and quasi-experimental studies were searched in CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, PubMed and Scopus from 2001 to 2019. Hand search for the reference lists of included papers was conducted as well. We assessed the quality of included studies by Cochrane risk of bias tool. Meta-analyses and narrative synthesis were used to analyse the data. Two studies with low risk of bias were screened from 180 articles, which involved 177 older people with an average age of 69.69±4.08 years old. The results showed that nutritional education was significantly effective in reducing body weight and fat mass than exercises, and it was beneficial to enhancing physical function and psychosocial well-being. But the effects of nutritional education in increasing muscle strength were not better than exercises. The combined effects of nutritional education and exercises were superior than either exercises or nutritional education interventions solely in preventing the loss of lean mass and bone marrow density, and in improving physical function. Due to limited numbers of relevant studies, the strong evidence of effectiveness of nutritional education interventions on reversing frailty is still lacking.

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Mitochondrial transplantation therapy for ischemia reperfusion injury: a systematic review of animal and human studies

Journal of Translational Medicine ◽

10.1186/s12967-021-02878-3 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Kei Hayashida ◽

Ryosuke Takegawa ◽

Muhammad Shoaib ◽

Tomoaki Aoki ◽

Rishabh C. Choudhary ◽

...

Keyword(s):

Systematic Review ◽

Reperfusion Injury ◽

Animal Studies ◽

Ischemia Reperfusion Injury ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Meta Analysis ◽

Relevant Literature ◽

Human Studies ◽

Cochrane Library

Abstract Background Mitochondria are essential organelles that provide energy for cellular functions, participate in cellular signaling and growth, and facilitate cell death. Based on their multifactorial roles, mitochondria are also critical in the progression of critical illnesses. Transplantation of mitochondria has been reported as a potential promising approach to treat critical illnesses, particularly ischemia reperfusion injury (IRI). However, a systematic review of the relevant literature has not been conducted to date. Here, we systematically reviewed the animal and human studies relevant to IRI to summarize the evidence for mitochondrial transplantation. Methods We searched MEDLINE, the Cochrane library, and Embase and performed a systematic review of mitochondrial transplantation for IRI in both preclinical and clinical studies. We developed a search strategy using a combination of keywords and Medical Subject Heading/Emtree terms. Studies including cell-mediated transfer of mitochondria as a transfer method were excluded. Data were extracted to a tailored template, and data synthesis was descriptive because the data were not suitable for meta-analysis. Results Overall, we identified 20 animal studies and two human studies. Among animal studies, 14 (70%) studies focused on either brain or heart IRI. Both autograft and allograft mitochondrial transplantation were used in 17 (85%) animal studies. The designs of the animal studies were heterogeneous in terms of the route of administration, timing of transplantation, and dosage used. Twelve (60%) studies were performed in a blinded manner. All animal studies reported that mitochondrial transplantation markedly mitigated IRI in the target tissues, but there was variation in biological biomarkers and pathological changes. The human studies were conducted with a single-arm, unblinded design, in which autologous mitochondrial transplantation was applied to pediatric patients who required extracorporeal membrane oxygenation (ECMO) for IRI–associated myocardial dysfunction after cardiac surgery. Conclusion The evidence gathered from our systematic review supports the potential beneficial effects of mitochondrial transplantation after IRI, but its clinical translation remains limited. Further investigations are thus required to explore the mechanisms of action and patient outcomes in critical settings after mitochondrial transplantation. Systematic review registration The study was registered at UMIN under the registration number UMIN000043347.

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EXPRESS: Stroke risk following traumatic brain injury: systematic review and meta-analysis

International Journal of Stroke ◽

10.1177/17474930211004277 ◽

2021 ◽

pp. 174749302110042

Author(s):

Grace Mary Turner ◽

Christel McMullan ◽

Olalekan Lee Aiyegbusi ◽

Danai Bem ◽

Tom Marshall ◽

...

Keyword(s):

Systematic Review ◽

Stroke Risk ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Cochrane Library ◽

Control Group ◽

Large Sample Size ◽

Hazard Ratios ◽

Increased Risk ◽

The Cochrane Library

Aims To investigate the association between TBI and stroke risk. Summary of review We undertook a systematic review of MEDLINE, EMBASE, CINAHL, and The Cochrane Library from inception to 4th December 2020. We used random-effects meta-analysis to pool hazard ratios (HR) for studies which reported stroke risk post-TBI compared to controls. Searches identified 10,501 records; 58 full texts were assessed for eligibility and 18 met the inclusion criteria. The review included a large sample size of 2,606,379 participants from four countries. Six studies included a non-TBI control group, all found TBI patients had significantly increased risk of stroke compared to controls (pooled HR 1.86; 95% CI 1.46-2.37). Findings suggest stroke risk may be highest in the first four months post-TBI, but remains significant up to five years post-TBI. TBI appears to be associated with increased stroke risk regardless of severity or subtype of TBI. There was some evidence to suggest an association between reduced stroke risk post-TBI and Vitamin K antagonists and statins, but increased stroke risk with certain classes of antidepressants. Conclusion TBI is an independent risk factor for stroke, regardless of TBI severity or type. Post-TBI review and management of risk factors for stroke may be warranted.

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Prevalence of retinopathy in prediabetes: protocol for a systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2020-040997 ◽

2021 ◽

Vol 11 (1) ◽

pp. e040997

Author(s):

Varo Kirthi ◽

Paul Nderitu ◽

Uazman Alam ◽

Jennifer Evans ◽

Sarah Nevitt ◽

...

Keyword(s):

Systematic Review ◽

Diabetic Retinopathy ◽

Data Extraction ◽

Meta Analysis ◽

International Diabetes Federation ◽

Current Data ◽

Risk Of Bias ◽

Fundus Photography ◽

Primary Data ◽

Cochrane Library

IntroductionThere is growing evidence of a higher than expected prevalence of retinopathy in prediabetes. This paper presents the protocol of a systematic review and meta-analysis of retinopathy in prediabetes. The aim of the review is to estimate the prevalence of retinopathy in prediabetes and to summarise the current data.Methods and analysisThis protocol is developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. A comprehensive electronic bibliographic search will be conducted in MEDLINE, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Scholar and the Cochrane Library. Eligible studies will report prevalence data for retinopathy on fundus photography in adults with prediabetes. No time restrictions will be placed on the date of publication. Screening for eligible studies and data extraction will be conducted by two reviewers independently, using predefined inclusion criteria and prepiloted data extraction forms. Disagreements between the reviewers will be resolved by discussion, and if required, a third (senior) reviewer will arbitrate.The primary outcome is the prevalence of any standard features of diabetic retinopathy (DR) on fundus photography, as per International Clinical Diabetic Retinopathy Severity Scale (ICDRSS) classification. Secondary outcomes are the prevalence of (1) any retinal microvascular abnormalities on fundus photography that are not standard features of DR as per ICDRSS classification and (2) any macular microvascular abnormalities on fundus photography, including but not limited to the presence of macular exudates, microaneurysms and haemorrhages. Risk of bias for included studies will be assessed using a validated risk of bias tool for prevalence studies. Pooled estimates for the prespecified outcomes of interest will be calculated using random effects meta-analytic techniques. Heterogeneity will be assessed using the I2 statistic.Ethics and disseminationEthical approval is not required as this is a protocol for a systematic review and no primary data are to be collected. Findings will be disseminated through peer-reviewed publications and presentations at national and international meetings including Diabetes UK, European Association for the Study of Diabetes, American Diabetes Association and International Diabetes Federation conferences.PROSPERO registration numberCRD42020184820.

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Effectiveness of Antalgic Therapies in Patients with Vertebral Bone Metastasis: A Protocol for a Systematic Review and Meta-Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18083991 ◽

2021 ◽

Vol 18 (8) ◽

pp. 3991

Author(s):

Antonio Jose Martin-Perez ◽

María Fernández-González ◽

Paula Postigo-Martin ◽

Marc Sampedro Pilegaard ◽

Carolina Fernández-Lao ◽

...

Keyword(s):

Systematic Review ◽

Bone Metastasis ◽

Data Extraction ◽

Meta Analysis ◽

Risk Of Bias ◽

Cochrane Library ◽

Pharmacological Intervention ◽

Vertebral Metastasis ◽

Randomized Controlled Clinical Trials

There is no systematic review that has identified existing studies evaluating the pharmacological and non-pharmacological intervention for pain management in patients with bone metastasis. To fill this gap in the literature, this systematic review with meta-analysis aims to evaluate the effectiveness of different antalgic therapies (pharmacological and non-pharmacological) in the improvement of pain of these patients. To this end, this protocol has been written according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) and registered in PROSPERO (CRD42020135762). A systematic search will be carried out in four international databases: Medline (Via PubMed), Web of Science, Cochrane Library and SCOPUS, to select the randomized controlled clinical trials. The Risk of Bias Tool developed by Cochrane will be used to assess the risk of bias and the quality of the identified studies. A narrative synthesis will be used to describe and compare the studies, and after the data extraction, random effects model and a subgroup analyses will be performed according to the type of intervention, if possible. This protocol aims to generate a systematic review that compiles and synthesizes the best and most recent evidence on the treatment of pain derived from vertebral metastasis.

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Adjuvant Transarterial Chemoembolization Following Curative-Intent Hepatectomy Versus Hepatectomy Alone for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Cancers ◽

10.3390/cancers13122984 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2984

Author(s):

Stepan M. Esagian ◽

Christos D. Kakos ◽

Emmanouil Giorgakis ◽

Lyle Burdine ◽

J. Camilo Barreto ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Systematic Review ◽

Randomized Controlled Trials ◽

Transarterial Chemoembolization ◽

Meta Analysis ◽

Risk Of Bias ◽

Cochrane Library ◽

Controlled Trials ◽

Curative Intent ◽

Randomized Controlled

The role of adjuvant transarterial chemoembolization (TACE) for patients with resectable hepatocellular carcinoma (HCC) undergoing hepatectomy is currently unclear. We performed a systematic review of the literature using the MEDLINE, Embase, and Cochrane Library databases. Random-effects meta-analysis was carried out to compare the overall survival (OS) and recurrence-free survival (RFS) of patients with resectable HCC undergoing hepatectomy followed by adjuvant TACE vs. hepatectomy alone in randomized controlled trials (RCTs). The risk of bias was assessed using the Risk of Bias 2.0 tool. Meta-regression analyses were performed to explore the effect of hepatitis B viral status, microvascular invasion, type of resection (anatomic vs. parenchymal-sparing), and tumor size on the outcomes. Ten eligible RCTs, reporting on 1216 patients in total, were identified. The combination of hepatectomy and adjuvant TACE was associated with superior OS (hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.52 to 0.85; p < 0.001) and RFS (HR: 0.70, 95% CI: 0.56 to 0.88; p < 0.001) compared to hepatectomy alone. There were significant concerns regarding the risk of bias in most of the included studies. Overall, adjuvant TACE may be associated with an oncologic benefit in select HCC patients. However, the applicability of these findings may be limited to Eastern Asian populations, due to the geographically restricted sample. High-quality multinational RCTs, as well as predictive tools to optimize patient selection, are necessary before adjuvant TACE can be routinely implemented into standard practice. PROSPERO Registration ID: CRD42021245758.

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