Machine Learning Empowering Drug Discovery: Applications, Opportunities and Challenges.

Drug discovery plays a critical role in advancing human health by developing new medications and treatments to combat diseases. How to accelerate the pace and reduce the costs of new drug discovery has long been a key concern for the pharmaceutical industry. Fortunately, by leveraging advanced algorithms, computational power and biological big data, artificial intelligence (AI) technology, especially machine learning (ML), holds the promise of making the hunt for new drugs more efficient. Recently, the Transformer-based models that have achieved revolutionary breakthroughs in natural language processing have sparked a new era of their applications in drug discovery. Herein, we introduce the latest applications of ML in drug discovery, highlight the potential of advanced Transformer-based ML models, and discuss the future prospects and challenges in the field.

Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans.

Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans.

Palladium-catalyzed intramolecular asymmetric hydrocyclopropanylation of alkynes: synthesis of cyclopropane-fused γ-lactams.

A palladium-catalyzed intramolecular asymmetric hydrocyclopropanylation of alkynes via C(sp3)-H activation has been developed for the synthesis of cyclopropane-fused γ-lactams. The presented strategy proceeds in a selective and 100% atom-economical manner. A range of cyclopropane-fused γ-lactams were prepared from readily available substrates in good yields and enantioselectivities with a chiral phosphoramidite ligand.

Incidence of acute cerebrovascular events in patients with rheumatic or calcific mitral stenosis: A systematic review and meta-analysis.

BACKGROUND: Patients with mitral stenosis (MS) may be predisposed to acute cerebrovascular events (ACE) and peripheral thromboembolic events (TEE). Concomitant atrial fibrillation (AF), mitral annular calcification (MAC) and rheumatic heart disease (RHD) are independent risk factors. Our aim was to evaluate the incidence of ACEs in MS patients and the implications of AF, MAC and RHD on thromboembolic risks. METHODS: This systematic review was registered on PROSPERO (CRD42021291316). Six databases were searched from inception to 19th December 2021. The clinical outcomes were composite ACE, ischaemic stroke/transient ischaemic attack (TIA) and peripheral TEE. RESULTS: We included 16 and 9 papers, respectively, in our qualitative and quantitative analyses. The MS cohort with AF had the highest incidence of composite ACE (31.55%; 95% CI 3.60-85.03; I2 = 99%), followed by the MAC (14.85%; 95% CI 7.21-28.11; I2 = 98%), overall MS (8.30%; 95% CI 3.45-18.63; I2 = 96%) and rheumatic MS population (4.92%; 95% CI 3.53-6.83; I2 = 38%). Stroke/TIA were reported in 29.62% of the concomitant AF subgroup (95% CI 2.91-85.51; I2 = 99%) and in 7.11% of the overall MS patients (95% CI 1.91-23.16; I2 = 97%). However, the heterogeneity of the pooled incidence of clinical outcomes in all groups, except the rheumatic MS group, was substantial and significant. The logit-transformed proportion of composite ACE increased by 0.0141 (95% CI 0.0111-0.0171; p < 0.01) per year of follow-up. CONCLUSION: In the MS population, MAC and concomitant AF are risk factors for the development of ACE. The scarcity of data in our systematic review reflects the need for further studies to explore thromboembolic risks in all MS subtypes.

Ischaemic events in hypertrophic cardiomyopathy patients with and without atrial fibrillation: a systematic review and meta-analysis.

Hypertrophic cardiomyopathy predisposes to acute cerebrovascular events including ischaemic stroke, transient ischaemic attack and systemic thromboembolism. Atrial fibrillation confers even higher risk. We aim to report the incidence of these complications and to investigate the impact of atrial fibrillation on the ischaemic risk in patients with hypertrophic cardiomyopathy. A literature search was performed on PubMed, Scopus, Embase/Ovid and Cochrane library from inception to 20th March 2021. We compared the incidence of ischaemic strokes, transient ischaemic attack, non-specified thromboembolism events and systemic thromboembolism in hypertrophic cardiomyopathy patients with or without atrial fibrillation. Non-specified thromboembolism events in our paper referred to thromboembolic events whereby types were not specified in the studies. Meta-analysis was performed using StataSE 16 software, and heterogeneity was assessed using I2 test. A total of 713 studies were identified. Thirty-five articles with 42,570 patients were included. The pooled incidence of stroke/ transient ischaemic attack was 7.45% (95% confidence interval [CI] 5.80-9.52, p < 0.001) across 24 studies with a total of 37,643 hypertrophic cardiomyopathy patients. Atrial fibrillation significantly increased the risk of total stroke/ transient ischaemic attack (Risk Ratio 3.26, 95% CI 1.75-6.08, p < 0.001, I2 = 76.0). The incidence of stroke/ transient ischaemic attack was 9.30% (95% CI 6.64-12.87, p = 0.316) in the apical hypertrophic cardiomyopathy subgroup. Concomitant atrial fibrillation in hypertrophic cardiomyopathy increases the risk of thromboembolic events including ischaemic stroke and transient ischaemic attack. The apical subgroup shows a similar risk of acute cerebrovascular events as the overall hypertrophic cardiomyopathy population.

Study on the application of model transfer technology in the extraction process of Xiao'er Xiaoji Zhike oral liquid / 药学学报

The modernization and development of traditional Chinese medicine has led to higher standards for the quality of traditional Chinese medicine products. The extraction process is a crucial component of traditional Chinese medicine production, and it directly impacts the final quality of the product. However, the currently relied upon methods for quality assurance of the extraction process, such as simple wet chemical analysis, have several limitations, including time consumption and labor intensity, and do not offer precise control of the extraction process. As a result, there is significant value in incorporating near-infrared spectroscopy (NIRS) in the production process of traditional Chinese medicine to improve the quality control of the final products. In this study, we focused on the extraction process of Xiao'er Xiaoji Zhike oral liquid (XXZOL), using near-infrared spectra collected by both a Fourier transform near-infrared spectrometer and a portable near-infrared spectrometer. We used the concentration of synephrine, a quality control index component specified by the pharmacopoeia, to achieve rapid and accurate detection in the extraction process. Moreover, we developed a model transfer method to facilitate the transfer of models between the two types of near-infrared spectrometers (analytical grade and portable), thus resolving the low resolution, poor performance, and insufficient prediction accuracy issues of portable instruments. Our findings enable the rapid screening and quality analysis of XXZOL onsite, which is significant for quality monitoring during the traditional Chinese medicine production process.

Total flavonoids of Abrus cantoniensis inhibit CD14/TLR4/NF-κB/MAPK pathway expression and improve gut microbiota disorders to reduce lipopolysaccharide-induced mastitis in mice.

Established a model of lipopolysaccharide (LPS)-induced mastitis in mice, pathological sections and myeloperoxidase were used to detect the degree of tissue damage, enzyme-linked immunosorbent assay (ELISA) was performed to detect the expression of pro-inflammatory cytokines, meanwhile fluorescence quantitative PCR experiments were performed to detect the mRNA expression of CD14/TLR4/NF-κB/MAPK signalling pathway, and the faeces of mice were collected for 16S measurement of flora. The results showed that Abrus cantoniensis total flavonoids (ATF) could significantly reduce the damage of LPS on mammary tissue in mice and inhibit the secretion of inflammatory factors such as TNF-α, IL-1ß and IL-6. At the mRNA level, ATF inhibited the expression of CD14/TLR4/NF-κB/MAPK pathway and enhanced the expression of tight junction proteins in the blood-milk barrier. In the results of the intestinal flora assay, ATF were found to be able to regulate the relative abundance of the dominant flora from the phylum level to the genus level, restoring LPS-induced gut microbial dysbiosis. In summary, ATF attenuated the inflammatory response of LPS on mouse mammary gland by inhibiting the expression of CD14/TLR4/NF-κB/MAPK pathway, enhancing the expression of tight junction proteins and restoring LPS-induced gut microbial dysbiosis. This suggests that ATF could be a potential herbal remedy for mastitis.

Prescribing costs of hypoglycaemic agents and associations with metabolic control in Wales; a national analysis of primary care data.

AIMS: There has been a dramatic increase in hypoglycaemic agent expenditure. We assessed the variability in prescribing costs at the practice level and the relationship between expenditure and the proportion of patients achieving target glycaemic control. METHODS: We utilized national prescribing data from 406 general practices in Wales. This was compared against glycaemic control (percentage of patients achieving a HbA1c level < 59 mmol/mol in the preceding 12 months). Analyses were adjusted for the number of patients with diabetes in each general practice and the Welsh Index of Multiple Deprivation. RESULTS: There was considerable heterogeneity in hypoglycaemic agent spend per patient with diabetes, Median = £289 (IQR 247-343) range £31.1-£1713. Higher total expenditure was not associated with improved glycaemic control B(std)  = -0.01 (95%CI -0.01, 0.002) p = 0.13. High-spend practices spent more on SGLT2 inhibitors (16 vs. 9% p < 0.001) and GLP-1 agonists (13 vs. 11% p < 0.001) and less on insulin (34 vs. 42% p < 0.001), biguanides (9 vs. 11% p = 0.001) and sulphonylureas (2 vs. 3% p < 0.001) than low spend practices. There were no differences in the pattern of drug prescribing between high spend practices with better glycaemic control (mean 68% of patients HbA1c <59 mmol/mol) and those with less good metabolic control (mean 58% of patients HbA1c <59 mmol/mol). CONCLUSIONS: Spend on hypoglycaemic agents is highly variable between practices and increased expenditure per patient is not associated with better glycaemic control. Whilst newer, more expensive agents have additional benefits, in individuals where these advantages are more marginal widespread use of these agents has important cost implications.

Palladium-Catalyzed Carbonylative Sonogashira/Annulation Reaction: Synthesis of Indolo[1,2-b]isoquinolines.

A palladium-catalyzed carbonylative Sonogashira/annulation reaction for the synthesis of indolo[1,2-b]isoquinolines has been developed. Tetracyclic 6/5/6/6 indoline skeletons were synthesized in moderate to good yields from easily available 2-bromo-N-(2-iodophenyl)benzamides and terminal alkynes. Notably, this efficient methodology established three C-C bonds and a C-N bond through a one-step transformation and provided a new method for the synthesis of indolo[1,2-b]isoquinoline derivatives.

Two novel polyketones from the leaves and twigs of Clerodendrum trichotomum.

Two novel polyketones, along with four known compounds, were isolated from the leaves and twigs of Clerodendrum trichotomum. Their structures were determined to be clerodendruketone A (1), clerodendruketone B (2), ecdysanols E (3), ecdysanols D (4), 5,5'-dimethoxy-7-oxolariciresinol (5), and (-)-(7'S,8S,8'R)-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxy-lignan-9'-ol-7-one (6) through the methods of NMR, HRESIMS and ECD data analyses. The antioxidant effects against free radical were tested by DPPH assay. The antibacterial activity against Escherichia coli and Staphylococcus aureus were tested by turbidimetry assay. The results demonstrated that compounds 1 and 2 had significative antibacterial activity, and compound 3 had moderate antioxidant activity.

Visible-Light-Induced Carbonylation of Indoles with Phenols under Metal-Free Conditions: Synthesis of Indole-3-carboxylates.

A visible-light-induced carbonylation of indoles with phenols for the synthesis of indole-3-carboxylates has been developed. The reaction proceeded via a radical carbonylation process in which elementary I2 was used as an effective photosensitive initiator and, thus, avoided the use of transition metal catalysts. A series of different aryl indole-3-carboxylates were prepared in moderate to good yields. The broad applicability of this methodology was further highlighted by the late-stage functionalization of several phenol-containing natural products and pharmaceuticals.

Palladium Catalyzed Cascade Azidation/Carbonylation of Aryl Halides with Sodium Azide for the Synthesis of Amides.

Amide synthesis is one of the most important transformations in organic chemistry due to their ubiquitous presence in our daily life. In this communication, a palladium catalyzed cascade azidation/carbonylation of aryl halides for the synthesis of amides was developed. Both iodo- and bromobenzene derivatives were transformed to the corresponding amides using PdCl2 /xantphos as the catalyst system and sodium azide as the nitrogen-source. The reaction proceeds via a cascade azidation/carbonylation process. A range of alkyl and halogen substituted amides were prepared in moderate to good yields.

Carvacryl acetate, a semisynthetic monoterpenic ester obtained from essential oils, provides neuroprotection against cerebral ischemia reperfusion-induced oxidative stress injury via the Nrf2 signalling pathway.

Carvacryl acetate (CA) is a semisynthetic monoterpenic ester obtained from essential oils, and it exerts an antioxidation effect. The purpose of our study was to investigate whether CA could provide neuroprotection against oxidative stress caused by cerebral ischemia-reperfusion injury (CIRI) and elucidate the underlying mechanism. Middle cerebral artery occlusion (MCAO)-induced damage was established in Sprague Dawley (SD) rats and PC12 cells were exposed to hydrogen peroxide (H2O2) to imitate oxidative stress damage. TTC, HE and Nissl staining were used to observe the pathological morphology of lesions. The contents of ROS and MDA, and the activity of SOD were measured to reflect the level of oxidative stress. In addition, the TUNEL method was used to assess injuries in vitro, and the expression of Nrf2 was determined by immunohistochemical staining and western blot analysis. Importantly, we constructed and validated Nrf2 knockdown PC12 cells to confirm the key role of Nrf2 in the neuroprotective effect of CA against oxidative stress injuries. CA alleviated CIRI in rats with MCAO, as shown by brain tissue pathophysiology. The contents of ROS and MDA were reduced, and the SOD activity was augmented by the simultaneous promotion of Nrf2 expression. In addition, the H2O2-induced injury in Nrf2-knockdown PC12 cells was more serious than it was in control cells, and CA-mediated neuroprotection was exclusively inhibited by the knock down of Nrf2 in PC12 cells. In conclusion, it is shown here that CA has the effect of relieving cerebral ischemia reperfusion-induced oxidative stress injury via the Nrf2 signalling pathway.

Rapidly detecting antibiotics with magnetic nanoparticle coated CdTe quantum dots.

A reusable magnetic-quantum dot material (MNP-SiO2-QD) with good magnetic properties and high fluorescence retention was successfully fabricated from linked magnetic nanoparticles and quantum dots. The resulting material can qualitatively and quantitatively detect four kinds of antibiotics and maintain high recovery rates.

Plasma exchange and rituximab treatments in primary membranous nephropathy combined with crescentic glomerulonephritis: A case report.

RATIONALE: Crescent formation is rare in primary membranous nephropathy (MN). Anti-phospholipase A2 receptor (PLA2R) antibodies are detectable in these patients. The mechanism and treatments are unknown. PATIENT CONCERNS: A 72-year-old female patient who presented with nephrotic syndrome, hematuria, and rapidly progressive kidney dysfunction. DIAGNOSES: Kidney biopsy was performed and the diagnosis was MN in combination with crescentic glomerulonephritis. Circulating anti-PLA2R IgG3 and IgG4 were detected of high level. INTERVENTIONS: The patient received plasma exchange and rituximab besides corticosteroids. OUTCOMES: The patient achieved complete remission of proteinuria and recovery of kidney function after the clearance of anti-PLA2R antibodies. LESSON: This case suggests a pathogenic role of anti-PLA2R antibodies in the mechanism of crescent formation in MN, which may need intensive therapy to eliminate the antibodies quickly.

Identification and characterization of novel isothiazolones with potent bactericidal activity against multi-drug resistant Acinetobacter baumannii clinical isolates.

Acinetobacter baumannii has emerged as a globally important nosocomial pathogen characterized by an increased multi-drug resistance (MDR), leaving limited options for treating its infection. To identify novel antibacterial compounds with activity against clinical isolates of A. baumannii, we performed high-throughput screening against a chemical library of 42,944 compounds using nonpathogenic Escherichia coli MG1655 and identified 55 hit compounds. The antibacterial activities of 30 pure compounds were determined against MDR clinical isolates of A. baumannii obtained from Los Angeles County hospitals. Two isothiazolones identified, 5-chloro-2-(4-chloro-3-methylphenyl)-4-methyl-3(2H)-isothiazolone (Compound 6) and 5-chloro-2-(4-chlorophenyl)-4-methyl-3(2H)-isothiazolone (Compound 7), possess novel structure and exhibited consistent, potent and cidal activity against all 46 MDR A. baumannii clinical isolates and reference strains. Additionally, structure-activity relationship analysis involving several additional isothiazolones supports the link between a chloro-group on the heterocyclic ring or a fused benzene ring and the cidal activity. Attempts to obtain isothiazolone resistant mutants failed, consistent with the rapid cidal action and indicative of a complex mechanism of action. While cytotoxicity was observed with Compound 7, it had a therapeutic index value of 28 suggesting future therapeutic potential. Our results indicate that high-throughput screening of compound libraries followed by in vitro biological evaluations is a viable approach for the discovery of novel antibacterial agents to contribute in the fight against MDR bacterial pathogens.

T cell responses to peptides of Goodpasture autoantigen in patients with anti-glomerular basement membrane disease.

AIM: Cell-mediated autoimmunity, especially autoreactive T cells, is crucial in the initiation of anti-glomerular membrane (GBM) disease. Epitopes for T cells on Goodpasture autoantigen are not fully defined. This study investigated T cell epitopes in anti-GBM patients, aiming to identify the epitopes and their clinical significance. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 13 patients with anti-GBM disease. Twenty-four overlapping linear peptides were synthesized covering the whole sequence of human α3(IV)NC1. PBMC response to each peptide was detected by proliferation assay. Their associations with clinical features were further analyzed. RESULTS: Peripheral blood mononuclear cells proliferative responses to linear peptides on α3(IV)NC1 could be detected in all patients. Five major epitopes were identified as stimulatory in over half of the patients: α3(IV)NC1127-148 (P14) (69.2%), α3(IV)NC1159-178 (77.8%), α3(IV)NC1179-198 (55.6%), α3(IV)NC1189-208 (P19) (75.0%) and α3(IV)NC1141-154 (57.1%). P14 and P19 were highly recognized in patients comparing with healthy controls (69.2% vs. 0.0%, P = 0.011; 75.0% vs. 0.0%, P = 0.021, respectively). CONCLUSION: T cell proliferation to linear epitopes was detected in human anti-GBM disease. α3127-148 was a mutual T and B cell epitope, implying its initial role in epitope spreading process.

Value of four-dimensional echocardiography combined with speckle tracking technique on the assessment of right heart function and prognosis in patients with pulmonary arterial hypertension / 中华心血管病杂志

Objective@#To investigate the value of four-dimensional echocardiography combined with speckle tracking technique on the assessment of right heart function and prognosis in patients with pulmonary arterial hypertension (PAH).@*Methods@#In this prospective study, 51 patients with PAH diagnosed by right heart catheterization in east hospital and south hospital of Renji hospital affiliated to school of medicine of Shanghai Jiaotong University from September 2015 to July 2017 were enrolled as PAH group from July to November 2017. Meanwhile, 26 healthy volunteers with age and sex matched with pulmonary hypertension patients were recruited as control group. The patients were aged (45.8±15.5) years old in PAH group, and there were 6 males and 45 females. The healthy volunteers were aged (45.4±14.6) years old in control group, and there were 4 males and 22 females. Two-dimensional and four-dimensional echocardiographic images were obtained to measure the structure and function of the right heart. The myocardial strain of each ventricle and atrium was measured by sparkle tracking. The patients in PAH group were followed up from July 2017 to August 2018 to observe the endpoint events including all-cause death, re-hospitalization, and clinical deterioration.@*Results@#There were significant differences in two-dimensional echocardiographic parameters(including tricuspid annular plane systolic excursion (TAPSE), right ventricular area change fraction (FAC), and right ventricular systolic pressure (RVSP)), speckle tracking parameters (including global longitudinal systolic peak strain of left ventricle (LVGLS), global longitudinal systolic peak strain of right ventricle (RVGLS),left atrial reservoir function(LASr), left atrial conduit function (LASc), left atrial pump function (LASp), right atrial reservoir function (RASr), right atrial conduit function (RASc), and right atrial pump function (RASp)), and four-dimensional echocardiographic parameters(including right ventricular end diastolic volume (RVEDV) , right ventricular end systolic volume(RVESV), right ventricular stroke volume(RVSV), right ventricular freewall longitudinal strain(RVLSf), interventricular septum longitudinal strain(IVSLS), right ventricular ejection fraction(RVEF)) between control group and PAH group (all P<0.01 or 0.05).Spearman correlation analysis showed that RVEF was correlated with 6-minute walking distance (r=0.540, P<0.001), B-type natriuretic peptide (r=-0.545,P<0.001), New York Heart Association (NYHA) cardiac function classification(r=-0.583, P<0.001), TAPSE(r=0.595, P<0.001), LVGLS (r=-0.461, P=0.001) ,LASc (r=0.453, P=0.002) ,RASc (r=0.532, P<0.001) ,RVESV (r=-0.418, P=0.004) , RVSV (r=0.351, P=0.017) , and IVSLS (r=-0.450, P=0.002) . Pearson correlation analysis also showed that RVEF was correlated with FAC(r=0.579, P<0.001),RVSP (r=-0.442, P=0.002) ,RVGLS (r=-0.521, P<0.001) , LASr (r=0.483, P=0.001) , RASr (r=0.617, P<0.001) , RASp (r=0.513, P<0.001) , and RVLSf (r=-0.592, P<0.001) .After a follow-up of (10.4±2.7) months, there were 4 all-cause deaths, 5 re-hospitalizations and 5 clinical deterioration. Multivariate Cox regression analysis showed that increased RVEF was independent protective factor for end-point events in PAH patients (HR=0.702, P=0.043), and increased RVSP was independent risk factor for end-point events in PAH patients (HR=1.083, P=0.017). The receiver operating characteristic (ROC) curve showed that RVEF and RVSP could be used to predict the end-point events in PAH patients. The area under the curve (AUC) was 0.835(P=0.001) and 0.820(P=0.001), respectively.@*Conclusions@#RVEF measured by four-dimensional echocardiography is correlated with right ventricular function parameters measured by two-dimensional echocardiography and can be used to estimate the prognosis of PAH patients. The right atrial and left atrial function assessed by speckle tracking can also reflect the right ventricular function to a certain extent.

Coiling Is Not Superior to Clipping in Patients with High-Grade Aneurysmal Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis.

BACKGROUND: Outcomes of coiling embolization versus clipping for patients with high-grade aneurysmal subarachnoid hemorrhage (aSAH) have not been previously compared. We reviewed current evidence regarding the safety and efficacy of clipping versus coiling for high-grade aSAH. METHODS: We conducted a meta-analysis of studies that compared clipping with coiling in patients with high-grade aSAH published from January 1999 to February 2016 in Medline, Embase, and Cochrane databases based on PRISMA inclusion and exclusion criteria. Binary outcome comparisons between clipping and coiling were described using odds ratios (ORs). RESULTS: Three randomized controlled trials (RCTs) and 16 observational studies were included. There was no statistical difference in good outcome rates between the clipping and coiling groups (OR, 1.44; 95% confidence interval [CI], 0.97-2.13). Subgroup analysis showed no significant difference between the 2 treatments in non-RCTs (OR, 1.49; 95% CI, 0.95-2.36) and RCTs (OR, 1.15; 95% CI, 0.59-2.25). Coiling was associated with higher mortality (OR, 0.55; 95% CI, 0.41-0.75). Lower mortality was associated with clipping in non-RCTs (OR, 0.54; 95% CI, 0.40-0.74), but there was no difference in the RCTs (OR, 0.79; 95% CI, 0.19-3.39). Coiling was not associated with lower rates of complications including rebleeding (OR, 0.62; 95% CI, 0.30-1.29), ischemic infarct (OR, 0.89; 95% CI, 0.53-1.49), symptomatic vasospasm (OR, 0.76; 95% CI, 0.45-1.29), or shunt-dependent hydrocephalus (OR, 1.33; 95% CI, 0.52-3.40). CONCLUSION: The outcome with coiling is not superior to clipping in patients with high-grade aSAH; moreover, coiling has a greater risk of mortality.