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European Journal of Clinical... Nov 2022Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG.
METHODS
Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022.
RESULTS
Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I = 95.09%; p < .001) in 139 volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions.
CONCLUSIONS
In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.
Topics: Apolipoprotein B-48; Apolipoprotein C-III; Cholesterol, LDL; Humans; Hyperlipidemias; Hypertriglyceridemia; Oligonucleotides; Oligonucleotides, Antisense; RNA, Messenger; Randomized Controlled Trials as Topic; Triglycerides
PubMed: 35851450
DOI: 10.1111/eci.13841 -
PloS One 2022Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic... (Meta-Analysis)
Meta-Analysis
Although advanced age and presence of comorbidities significantly impact the variation observed in the clinical symptoms of COVID-19, it has been suggested that genetic variants may also be involved in the disease. Thus, the aim of this study was to perform a systematic review with meta-analysis of the literature to identify genetic polymorphisms that are likely to contribute to COVID-19 pathogenesis. Pubmed, Embase and GWAS Catalog repositories were systematically searched to retrieve articles that investigated associations between polymorphisms and COVID-19. For polymorphisms analyzed in 3 or more studies, pooled OR with 95% CI were calculated using random or fixed effect models in the Stata Software. Sixty-four eligible articles were included in this review. In total, 8 polymorphisms in 7 candidate genes and 74 alleles of the HLA loci were analyzed in 3 or more studies. The HLA-A*30 and CCR5 rs333Del alleles were associated with protection against COVID-19 infection, while the APOE rs429358C allele was associated with risk for this disease. Regarding COVID-19 severity, the HLA-A*33, ACE1 Ins, and TMPRSS2 rs12329760T alleles were associated with protection against severe forms, while the HLA-B*38, HLA-C*6, and ApoE rs429358C alleles were associated with risk for severe forms of COVID-19. In conclusion, polymorphisms in the ApoE, ACE1, TMPRSS2, CCR5, and HLA loci appear to be involved in the susceptibility to and/or severity of COVID-19.
Topics: Apolipoproteins E; COVID-19; Genetic Predisposition to Disease; HLA-A Antigens; Humans; Polymorphism, Genetic
PubMed: 35793369
DOI: 10.1371/journal.pone.0270627 -
Frontiers in Psychiatry 2022Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The...
Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The identification of specific genetic factors and their biological pathways underpinning resilient functioning can help in the identification of common key factors, but heterogeneities in the operationalisation of resilience have hampered advances. We conducted a systematic review of genetic variants associated with resilience to enable the identification of general resilience mechanisms. We adopted broad inclusion criteria for the definition of resilience to capture both human and animal model studies, which use a wide range of resilience definitions and measure very different outcomes. Analyzing 158 studies, we found 71 candidate genes associated with resilience. OPRM1 (Opioid receptor mu 1), NPY (neuropeptide Y), CACNA1C (calcium voltage-gated channel subunit alpha1 C), DCC (deleted in colorectal carcinoma), and FKBP5 (FKBP prolyl isomerase 5) had both animal and human variants associated with resilience, supporting the idea of shared biological pathways. Further, for OPRM1, OXTR (oxytocin receptor), CRHR1 (corticotropin-releasing hormone receptor 1), COMT (catechol-O-methyltransferase), BDNF (brain-derived neurotrophic factor), APOE (apolipoprotein E), and SLC6A4 (solute carrier family 6 member 4), the same allele was associated with resilience across divergent resilience definitions, which suggests these genes may therefore provide a starting point for further research examining commonality in resilience pathways.
PubMed: 35669264
DOI: 10.3389/fpsyt.2022.840120 -
Frontiers in Aging Neuroscience 2022With the development of medicine, our research on Alzheimer's disease (AD) has been further deepened, but the mechanism of its occurrence and development has not been...
With the development of medicine, our research on Alzheimer's disease (AD) has been further deepened, but the mechanism of its occurrence and development has not been fully revealed, and there is currently no effective treatment method. Several studies have shown that apolipoprotein AI (ApoA-I) can affect the occurrence and development of Alzheimer's disease by binding to amyloid β (Aβ). However, the association between circulating levels of ApoA-I and AD remains controversial. We conducted a meta-analysis of 18 studies published between 1992 and 2017 to determine whether the ApoA-I levels in the blood and cerebrospinal fluid (CSF) are abnormal in AD. Literatures were searched in PubMed, EMBASE and Web of Science databases without language limitations. A pooled subject sample including 1,077 AD patients and 1,271 healthy controls (HCs) was available to assess circulating ApoA-I levels; 747 AD patients and 680 HCs were included for ApoA-I levels in serum; 246 AD patients and 456 HCs were included for ApoA-I levels in plasma; 201 AD patients and 447 HCs were included for ApoA-I levels in CSF. It was found that serum and plasma levels of ApoA-I were significantly reduced in AD patients compared with HCs {[standardized mean difference (SMD) = -1.16; 95% confidence interval (CI) (-1.72, -0.59); = 0.000] and [SMD = -1.13; 95% CI (-2.05, -0.21); = 0.016]}. Patients with AD showed a tendency toward higher CSF ApoA-I levels compared with HCs, although this difference was non-significant [SMD = 0.20; 95% CI (-0.16, 0.56); = 0.273]. In addition, when we analyzed the ApoA-I levels of serum and plasma together, the circulating ApoA-I levels in AD patients was significantly lower [SMD = -1.15; 95% CI (-1.63, -0.66); = 0.000]. These results indicate that ApoA-I deficiency may be a risk factor of AD, and ApoA-I has the potential to serve as a biomarker for AD and provide experimental evidence for diagnosis of AD. PROSPERO, identifier: 325961.
PubMed: 35663584
DOI: 10.3389/fnagi.2022.899175 -
International Journal of Molecular... May 2022Bipolar disorder (BD) is a clinically heterogeneous condition, presenting a complex underlying etiopathogenesis that is not sufficiently characterized. Without molecular... (Meta-Analysis)
Meta-Analysis Review
Bipolar disorder (BD) is a clinically heterogeneous condition, presenting a complex underlying etiopathogenesis that is not sufficiently characterized. Without molecular biomarkers being used in the clinical environment, several large screen proteomics studies have been conducted to provide valuable molecular information. Mass spectrometry (MS)-based techniques can be a powerful tool for the identification of disease biomarkers, improving prediction and diagnosis ability. Here, we evaluate the efficacy of MS proteomics applied to human peripheral fluids to assess BD biomarkers and identify relevant networks of biological pathways. Following PRISMA guidelines, we searched for studies using MS proteomics to identify proteomic differences between BD patients and healthy controls (PROSPERO database: CRD42021264955). Fourteen articles fulfilled the inclusion criteria, allowing the identification of 266 differentially expressed proteins. Gene ontology analysis identified complement and coagulation cascades, lipid and cholesterol metabolism, and focal adhesion as the main enriched biological pathways. A meta-analysis was performed for apolipoproteins (A-I, C-III, and E); however, no significant differences were found. Although the proven ability of MS proteomics to characterize BD, there are several confounding factors contributing to the heterogeneity of the findings. In the future, we encourage the scientific community to use broader samples and validation cohorts, integrating omics with bioinformatics tools towards providing a comprehensive understanding of proteome alterations, seeking biomarkers of BD, and contributing to individualized prognosis and stratification strategies, besides aiding in the differential diagnosis.
Topics: Biomarkers; Bipolar Disorder; Humans; Mass Spectrometry; Proteome; Proteomics
PubMed: 35628270
DOI: 10.3390/ijms23105460 -
Cardiology Research and Practice 2022We aimed to investigate the effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on blood lipid levels in patients with high and very-high... (Review)
Review
OBJECTIVES
We aimed to investigate the effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on blood lipid levels in patients with high and very-high cardiovascular risk.
DESIGN
14 trials ( = 52,586 patients) comparing treatment with or without PCSK9 inhibitors were retrieved from PubMed and Embase updated to 1st Jun 2021. The data quality of included studies was assessed by two independent researchers using the Cochrane systematic review method. All-cause mortality, cardiovascular mortality, and changes in serum low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), apolipoprotein B (ApoB), lipoprotein (a) (LP (a)), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein A1 (ApoA1) from baseline were analyzed using Rev Man 5.1.0 software.
RESULTS
Compared with treatments without PCSK9 inhibitor, addition of PCSK9 inhibitors (evolocumab and alirocumab) had obvious decreasing effects on the levels of LDL-C [MD = -46.86, 95% CI (-54.99 to -38.72), < 0.00001], TC [MD = -31.92, 95% CI (-39.47 to -24.38), < 0.00001], TG [MD = -8.13, 95% CI (-10.48 to -5.79), < 0.00001], LP(a) [MD = -26.69, 95% CI (-27.93 to -25.44), < 0.00001], non-HDL-C [MD = -42.86, 95% CI (-45.81 to -39.92), < 0.00001], and ApoB [MD = -38.44, 95% CI (-42.23 to -34.65), < 0.00001] in high CVD risk patients. Conversely, changes of HDL-C [MD = 6.27, CI (5.17 to 7.36), < 0.00001] and ApoA1 [MD = 4.33, 95% CI (3.53 to 5.13), < 0.00001] from baseline were significantly more in high cardiovascular disease risk patients who received PCSK9 inhibitors treatment.
CONCLUSION
Addition of PCSK9 inhibitors to standard therapy resulted in definite improvement in blood lipid levels compared with therapies that did not include them.
PubMed: 35529059
DOI: 10.1155/2022/8729003 -
Acta Ophthalmologica Aug 2022The pathophysiology of diabetic macular oedema (DME) remains poorly understood. Proteomic analysis of the vitreous using mass spectrometry (MS) can potentially identify... (Review)
Review
The pathophysiology of diabetic macular oedema (DME) remains poorly understood. Proteomic analysis of the vitreous using mass spectrometry (MS) can potentially identify proteins of pathophysiological importance. In this systematic review, we summarize the available evidence on protein changes in DME detected by MS. We systematically searched 13 literature databases on 19 September 2021. Eligible studies were defined as those using samples from human eyes with DME analysed with MS. Two authors assessed the studies for eligibility, extracted data and evaluated risk of bias independently. Six eligible studies were identified. All were designed in a cross-sectional fashion comparing results to either a non-diabetic control group or a control group without DME. A total of 62 eyes from 60 patients contributed as study group and 48 eyes from 48 patients served as control group. Proteomic analyses revealed significant differences in the vitreous protein levels in patients with DME when compared with controls. Three studies or more identified increased contents of apolipoprotein A-I, apolipoprotein A-II, apolipoprotein A-IV, apolipoprotein C-III, gelsolin, pigment epithelium-derived factor, serum albumin, transthyretin, vitamin D-binding protein in DME. Two studies found increased levels of complement factors B and C3. Protein changes reproduced across the studies suggested that DME was associated with retinal lipid accumulation, angiogenesis, retinal protective mechanisms, inflammation and complement activation. Proteome studies support the multifactorial pathogenesis of DME as proteins with highly different biological functions are regulated in DME. An important number of proteins differ, provide pathophysiological insight and suggest the direction for future research.
Topics: Cross-Sectional Studies; Diabetes Mellitus; Diabetic Retinopathy; Humans; Macular Edema; Proteomics; Vitreous Body
PubMed: 35507578
DOI: 10.1111/aos.15168 -
Frontiers in Aging Neuroscience 2022Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no cure, and available treatments are only able to postpone the progression of the disease....
BACKGROUND AND PURPOSE
Alzheimer's disease (AD) is a devastating neurodegenerative disorder with no cure, and available treatments are only able to postpone the progression of the disease. Mild cognitive impairment (MCI) is considered to be a transitional stage preceding AD. Therefore, prediction models for conversion from MCI to AD are desperately required. These will allow early treatment of patients with MCI before they develop AD. This study performed a systematic review and meta-analysis to summarize the reported risk prediction models and identify the most prevalent factors for conversion from MCI to AD.
METHODS
We systematically reviewed the studies from the databases of PubMed, CINAHL Plus, Web of Science, Embase, and Cochrane Library, which were searched through September 2021. Two reviewers independently identified eligible articles and extracted the data. We used the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS) checklist for the risk of bias assessment.
RESULTS
In total, 18 articles describing the prediction models for conversion from MCI to AD were identified. The dementia conversion rate of elderly patients with MCI ranged from 14.49 to 87%. Models in 12 studies were developed using the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). C-index/area under the receiver operating characteristic curve (AUC) of development models were 0.67-0.98, and the validation models were 0.62-0.96. MRI, apolipoprotein E genotype 4 (APOE4), older age, Mini-Mental State Examination (MMSE) score, and Alzheimer's Disease Assessment Scale cognitive (ADAS-cog) score were the most common and strongest predictors included in the models.
CONCLUSION
In this systematic review, many prediction models have been developed and have good predictive performance, but the lack of external validation of models limited the extensive application in the general population. In clinical practice, it is recommended that medical professionals adopt a comprehensive forecasting method rather than a single predictive factor to screen patients with a high risk of MCI. Future research should pay attention to the improvement, calibration, and validation of existing models while considering new variables, new methods, and differences in risk profiles across populations.
PubMed: 35493941
DOI: 10.3389/fnagi.2022.840386 -
Frontiers in Pharmacology 2022The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent LDL-C lowering agents. However, few head-to-head studies evaluated the efficacy on the...
Efficacy and Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors as Adjuvant Treatments for Patients with Hypercholesterolemia Treated with Statin: A Systematic Review and Network Meta-analysis.
The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent LDL-C lowering agents. However, few head-to-head studies evaluated the efficacy on the lowering in other atherogenic apolipoproteins and safety of PCSK9 inhibitors at different dosages as an add-on statins therapy in hypercholesterolemia patients. This study is a systematic review and network meta-analysis of randomized control trials to compare the efficacy of lipid reduction and adverse events of PCSK9 inhibitors in statin-treated hypercholesterolemia patients. PubMed, EMBASE, and Cochrane Library databases were searched till April 20, 2021, for randomized controlled trials. Random-effect network meta-analyses were undertaken to compare the differences in the percent reduction in low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) [Lp(a)] levels and the risk of AEs among different PCSK9 inhibitors. A total of 22 articles with 42,786 patients were included. The lipid reductions in LDL-C, ApoB, and Lp(a) with add-on PCSK9 inhibitors vs. placebo in statin-treated patients across all trials were 50-63%, 43-52%, and 23-31%, respectively. Evolocumab 140 mg Q2W was ranked the best among all treatment strategies for lowering LDL-C, ApoB, and Lp(a) levels, and the treatment difference was 68.05% (95% confidence interval (CI), 62.43% to 73.67) in LDL-C reduction, 54.95% (95% CI, 49.55% to 60.35%) in ApoB reduction, and 34.25% (95% CI, 27.59% to 40.91%) in Lp(a) reduction compared with the placebo. No significant risk difference of adverse events between PCSK9 inhibitors and placebo was found. PCSK9 inhibitors showed a significant effect on the reduction in LDL-C, ApoB, and Lp(a) levels in statin-treated patients. Evolocumab 140 mg Q2W showed significantly larger degrees of LDL-C, ApoB, and Lp(a) reduction.
PubMed: 35444537
DOI: 10.3389/fphar.2022.832614 -
American Heart Journal Plus :... Jan 2022This systematic review and meta-analysis aimed to assess the efficacy and safety profile of treatment with inclisiran, a drug that has been recently approved by the...
STUDY OBJECTIVE
This systematic review and meta-analysis aimed to assess the efficacy and safety profile of treatment with inclisiran, a drug that has been recently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
DESIGN
A systematic literature search was conducted in order to identify randomized controlled trials (RCTs) assessing the effect on lipoproteins and the safety profile of inclisiran.
RESULTS
Data were pooled from 5 RCTs, which included 4226 subjects. Meta-analyses of data suggested that the multiple-dose regimens of inclisiran yielded a significant reduction in serum levels of proprotein convertase subtilisin/kexin type 9 (MD = -78.23%, 95%CI: -86.74, -69.71) and low-density lipoprotein cholesterol (MD = -45.48%, 95%CI: -50.36%, -40.61%) throughout the studies. Furthermore, treatment with inclisiran significantly affected total cholesterol (MD = -13.67%, 95%CI: -20.78%, -6.57%), high-density lipoprotein cholesterol (MD = 8.29%, 95%CI: 4.66%,11.93%), non-HDL cholesterol (MD = -39.45%, 95%CI: -43.6%, -35.31%), apolipoprotein B (MD = -34.58%, 95%CI: -38.78%, -30.78%) and lipoprotein(a) (MD = -20.9%, 95%CI: -25.8%, -15.99%). Multiple-dose regimens of inclisiran were associated with increased risk of injection-site reactions (any reaction: OR = 5.86, 95%CI: 3.44, 9.98; mild reactions: OR = 5.19, 95%CI: 1.68, 16.07; moderate reactions: OR = 13.37, 95%CI: 3.17, 56.46), and bronchitis (OR = 1.58, 95%CI: 1.10, 2.26), while the incidence of the pre-specified exploratory CV endpoint significantly decreased at 18 months (OR = 0.74, 95%CI: 0.58, 0.94).
CONCLUSION AND RELEVANCE
Inclisiran has favourable effects on serum lipid levels and an acceptable safety profile. Further well-designed RCTs are needed to explore its longer-term safety.
PubMed: 38560059
DOI: 10.1016/j.ahjo.2022.100127