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Background: Cardiac arrest remains a critical condition with high mortality and catastrophic neurological impact. Extracorporeal cardiopulmonary resuscitation (ECPR) has been introduced as an adjunct in cardiopulmonary resuscitation modalities. However, survival with good neurological outcomes remains a major concern. This study aims to explore our early experience with ECPR and identify the factors associated with survival in patients presenting with refractory cardiac arrest., Methods: This is a retrospective cohort study analyzing 6-year data from a tertiary center, the country reference for ECPR. This study was conducted at a national center of ECPR. Participants of this study were adult patients who experienced witnessed refractory cardiopulmonary arrest and were supported by ECPR. ECPR was performed for eligible patients as per the local service protocols., Results: Data from 87 patients were analyzed; of this cohort, 62/87 patients presented with in-hospital cardiac arrest (IHCA) and 25/87 presented with out-of-hospital cardiac arrest (OHCA). Overall survival to decannulation and hospital discharge rates were 26.4% and 25.3%, respectively. Among survivors (n = 22), 19 presented with IHCA (30.6%), while only 3 survivors presented with OHCA (12%). A total of 15/87 (17%) patients were alive at 6-month follow-up. All survivors had good neurological function assessed as Cerebral Performance Category 1 or 2. Multivariate logistic regression to predict survival to hospital discharge showed that IHCA was the only independent predictor (odds ratio: 5.8, P = 0.042); however, this positive association disappeared after adjusting for the first left ventricular ejection fraction after resuscitation., Conclusions: In this study, the use of ECPR for IHCA was associated with a higher survival to discharge compared to OHCA. This study demonstrated a comparable survival rate to other established centers, particularly for IHCA. Neurological outcomes were comparable in both IHCA and OHCA survivors. However, large multicenter studies are warranted for better understanding and improving the outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Motivation: Transcriptomic long-read (LR) sequencing is an increasingly cost-effective technology for probing various RNA features. Numerous tools have been developed to tackle various transcriptomic sequencing tasks (e.g. isoform and gene fusion detection). However, the lack of abundant gold-standard datasets hinders the benchmarking of such tools. Therefore, the simulation of LR sequencing is an important and practical alternative. While the existing LR simulators aim to imitate the sequencing machine noise and to target specific library protocols, they lack some important library preparation steps (e.g. PCR) and are difficult to modify to new and changing library preparation techniques (e.g. single-cell LRs)., Results: We present TKSM, a modular and scalable LR simulator, designed so that each RNA modification step is targeted explicitly by a specific module. This allows the user to assemble a simulation pipeline as a combination of TKSM modules to emulate a specific sequencing design. Additionally, the input/output of all the core modules of TKSM follows the same simple format (Molecule Description Format) allowing the user to easily extend TKSM with new modules targeting new library preparation steps., Availability and Implementation: TKSM is available as an open source software at https://github.com/vpc-ccg/tksm., (© The Author(s) 2024. Published by Oxford University Press.)

Acute coronary syndrome (ACS) is a leading cause of mortality worldwide. Despite optimal antiplatelet therapy recommendation after ischemic events, recurrent thrombotic complications rate remains high. The recurrent events maybe in part due to increased thrombin levels during ACS which may underscore the need for an additional anticoagulation therapy. Given the advantages of non-vitamin K antagonist oral anticoagulants (NOACs) over warfarin, they have the potential to prevent thrombus formation, in the presence or absence of atrial fibrillation, but at the cost of increased risk of bleeding. NOACs have also shown a promising efficacy in managing left ventricular thrombus and a potential benefit in avoiding stent thrombosis after percutaneous coronary revascularization. Taken as a whole, NOACs are increasingly used for off-licence indications, and continue to evolve as essential therapy in preventing and treating thrombotic events. Herein, this review discusses NOACs off-label indications in the setting of ischemic coronary disease., Competing Interests: All authors are from Hamad Medical Corporation. The authors declare no conflict of interest., (Copyright: © 2023 The Author(s). Published by IMR Press.)

Background: Acute coronary syndrome (ACS) is a leading cause of mortality and morbidity in Qatar and globally., Aim: The primary objective of the study was to evaluate the effectiveness of a structured clinical pharmacist-delivered intervention on all-cause hospitalizations and cardiac-related readmissions in patients with ACS., Method: A prospective quasi-experimental study was conducted at Heart Hospital in Qatar. Discharged ACS patients were allocated to one of three study arms: (1) an intervention group (received a structured clinical pharmacist-delivered medication reconciliation and counselling at discharge, and two follow-up sessions at 4 weeks and 8 weeks post-discharge), (2) a usual care group (received the general usual care at discharge by clinical pharmacists) or, (3) a control group (discharged during weekends or after clinical pharmacists' working hours). Follow-up sessions for the intervention group were designed to re-educate and counsel patients about their medications, remind them about the importance of medication adherence, and answer any questions they may have. At the hospital, patients were allocated into one of the three groups based on intrinsic and natural allocation procedures. Recruitment of patients took place between March 2016 and December 2017. Data were analyzed based on intention-to-treat principles., Results: Three hundred seventy-three patients were enrolled in the study (intervention = 111, usual care = 120, control = 142). Unadjusted results showed that the odds of 6-month all-cause hospitalizations were significantly higher among the usual care (OR 2.034; 95% CI: 1.103-3.748, p = 0.023) and the control arms (OR 2.704; 95% CI: 1.456-5.022, p = 0.002) when compared to the intervention arm. Similarly, patients in the usual care arm (OR 2.304; 95% CI: 1.122-4.730, p = 0.023) and the control arm (OR 3.678; 95% CI: 1.802-7.506, p ≤ 0.001) had greater likelihood of cardiac-related readmissions at 6 months. After adjustment, these reductions were only significant for cardiac-related readmissions between control and intervention groups (OR 2.428; 95% CI: 1.116-5.282, p = 0.025)., Conclusion: This study demonstrated the impact of a structured intervention by clinical pharmacists on cardiac-related readmissions at 6 months post-discharge in patients post-ACS. The impact of the intervention on all-cause hospitalization was not significant after adjustment for potential confounders. Large cost-effective studies are required to determine the sustained impact of structured clinical pharmacist-provided interventions in ACS setting., Trial Registration: Clinical Trials: NCT02648243 Registration date: January 7, 2016., (© 2023. The Author(s).)

Alternative splicing (AS) is an important mechanism in the development of many cancers, as novel or aberrant AS patterns play an important role as an independent onco-driver. In addition, cancer-specific AS is potentially an effective target of personalized cancer therapeutics. However, detecting AS events remains a challenging task, especially if these AS events are novel. This is exacerbated by the fact that existing transcriptome annotation databases are far from being comprehensive, especially with regard to cancer-specific AS. Additionally, traditional sequencing technologies are severely limited by the short length of the generated reads, which rarely spans more than a single splice junction site. Given these challenges, transcriptomic long-read (LR) sequencing presents a promising potential for the detection and discovery of AS. We present Freddie, a computational annotation-independent isoform discovery and detection tool. Freddie takes as input transcriptomic LR sequencing of a sample alongside its genomic split alignment and computes a set of isoforms for the given sample. It then partitions the input reads into sets that can be processed independently and in parallel. For each partition, Freddie segments the genomic alignment of the reads into canonical exon segments. The goal of this segmentation is to be able to represent any potential isoform as a subset of these canonical exons. This segmentation is formulated as an optimization problem and is solved with a dynamic programming algorithm. Then, Freddie reconstructs the isoforms by jointly clustering and error-correcting the reads using the canonical segmentation as a succinct representation. The clustering and error-correcting step is formulated as an optimization problem-the Minimum Error Clustering into Isoforms (MErCi) problem-and is solved using integer linear programming (ILP). We compare the performance of Freddie on simulated datasets with other isoform detection tools with varying dependence on annotation databases. We show that Freddie outperforms the other tools in its accuracy, including those given the complete ground truth annotation. We also run Freddie on a transcriptomic LR dataset generated in-house from a prostate cancer cell line with a matched short-read RNA-seq dataset. Freddie results in isoforms with a higher short-read cross-validation rate than the other tested tools. Freddie is open source and available at https://github.com/vpc-ccg/freddie/., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We conducted a systematic review and meta-analysis to assess all-cause mortality and heart failure (HF) hospitalization with sacubitril/valsartan (S/V) compared to standard HF therapy in patients with HF with reduced ejection fraction (HFrEF) using real-world data. We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed and Google Scholar for the observational studies published in English exploring the clinical outcomes of S/V use in HFrEF till March 14, 2022. Two independent reviewers assessed the quality and risk of bias of the included studies. A random-effect model was used to combine data. The outcomes assessed were all-cause mortality and HF hospitalization associated with S/V use in comparison to standard HF therapy. A total of 9 observational studies comparing S/V to Angiotensin-converting enzyme inhibitors (ACE-I)/Angiotensin II receptor blockers (ARB) in HFrEF were included in the systematic review, with more than 32000 patients included in the final analysis. Overall, S/V use was associated with a significant reduction in all-cause mortality (Risk Ratio [RR] = 0.70, 95% CI 0.53-0.93, I 2  = 83%) and HF hospitalization (RR = 0.62; 95% CI, 0.48-0.80, I 2 = 94%). Similar to the landmark controlled evidence, real-world data of S/V use in HFrEF demonstrated a significant reduction in all-cause mortality and HF hospitalization., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

A high-intensity statin is recommended for the secondary prevention of cardiovascular diseases (CVD). However, real-world evidence of the effectiveness of rosuvastatin following acute coronary syndrome (ACS) is scarce. This retrospective cohort study included patients diagnosed with ACS to compare between the 2 high-intensity statin therapies (rosuvastatin vs atorvastatin) in terms of a primary composite outcome of CVD-associated death, non-fatal ACS, and non-fatal stroke at 1 month and 12 months post discharge. The primary effectiveness outcome did not differ between the 2 groups at 1 month (1.3% vs 1%; aHR = 1.64, 95% CI 0.55-4.94, P= 0.379) and at 12 months (4.8% vs 3.5%; aHR = 1.48, 95% CI 0.82-2.67, P= 0.199). Similarly, the 2 groups had comparable safety outcomes. In conclusion, the use of high-intensity rosuvastatin compared to high-intensity atorvastatin therapy in patients with ACS had resulted in comparable cardiovascular effectiveness and safety outcomes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Single-cell RNA sequencing allows for characterizing the gene expression landscape at the cell type level. However, because of its use of short-reads, it is severely limited at detecting full-length features of transcripts such as alternative splicing. New library preparation techniques attempt to extend single-cell sequencing by utilizing both long-reads and short-reads. These techniques split the library material, after it is tagged with cellular barcodes, into two pools: one for short-read sequencing and one for long-read sequencing. However, the challenge of utilizing these techniques is that they require matching the cellular barcodes sequenced by the erroneous long-reads to the cellular barcodes detected by the short-reads. To overcome this challenge, we introduce scTagger, a computational method to match cellular barcodes data from long-reads and short-reads. We tested scTagger against another state-of-the-art tool on both real and simulated datasets, and we demonstrate that scTagger has both significantly better accuracy and time efficiency., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Emerging worldwide data have been suggesting that coronavirus disease 2019 (COVID-19) pandemic consequences are not limited to the respiratory and cardiovascular systems but encompass adverse gastrointestinal manifestations including acute liver injury as well. Severe cases of liver injury associated with higher fatality rates were observed in critically ill patients with COVID-19. Intensive care units (ICU) have been the center of disposition of severe cases of COVID-19. This review discusses the pathogenesis of acute liver injury in ICU patients with COVID-19, and analyzes its prevalence, consequences, possible drug-induced liver injury, and the impact of the pandemic on liver diseases and transplantation programs., Competing Interests: Conflict-of-interest statement: The authors declare that they do not have conflict of interest related to this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: Treatment of dyslipidemia lowers cardiovascular (CV) risk. Although statin use is a cornerstone therapy, many patients are not achieving their risk-specific low-density lipoprotein cholesterol (LDL-C) goals. The proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies have been extensively studied as lipid-lowering therapy (LLT). Herein, we present an updated evidence-based review of the efficacy and safety of PCSK9 monoclonal antibodies in the treatment of familial and non-familial hypercholesterolemia., Methods: PubMed database was searched to review Phase III studies on PCSK9 monoclonal antibodies. Then, the US National Institutes of Health Registry and the WHO International Clinical Trial Registry Platform were searched to identify and present the ongoing research., Results: PCSK9 monoclonal antibodies were investigated for the treatment of dyslipidemia, as a single therapeutic agent or as an add-on therapy to the traditional LLT. They proved effective and safe in the treatment of familial and non-familial hypercholesterolemia, and in the prevention of adverse CV events., Conclusions: The use of PCSK9 monoclonal antibodies in the treatment of dyslipidemia is currently recommended to achieve risk-specific LDL-C goal to reduce adverse CV events. Future results of the ongoing research might expand their clinical generalizability to broader patient populations., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

PCSK9 monoclonal antibodies are novel lipid-lowering therapy that have been extensively studied in patients with hypercholesterolemia either as monotherapy or as an add-on to other LLTs. PCSK9 monoclonal antibodies have significantly reduced the low-density lipoprotein cholesterol (LDL-C) plasma level resulting in a better LDL-C goal attainment. The commercially available PCSK9 monoclonal antibodies, alirocumab and evolocumab, have demonstrated reductions in major adverse cardiovascular events such as myocardial infarction, stroke, unstable angina, and the need for coronary revascularization but not mortality. PCSK9 monoclonal antibodies have demonstrated a favorable safety profile. The most reported side effects are mild injection site with no causal relationship proven between the inhibition of PCSK9 and neurocognitive or glycemic adverse events. In this overview, the efficacy and safety of PCSK9 monoclonal antibodies in the treatment of primary and familial hypercholesterolemia will be discussed., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Heart Views.)

Motivation: Next-Generation Sequencing has led to the availability of massive genomic datasets whose processing raises many challenges, including the handling of sequencing errors. This is especially pertinent in cancer genomics, e.g. for detecting low allele frequency variations from circulating tumor DNA. Barcode tagging of DNA molecules with unique molecular identifiers (UMI) attempts to mitigate sequencing errors; UMI tagged molecules are polymerase chain reaction (PCR) amplified, and the PCR copies of UMI tagged molecules are sequenced independently. However, the PCR and sequencing steps can generate errors in the sequenced reads that can be located in the barcode and/or the DNA sequence. Analyzing UMI tagged sequencing data requires an initial clustering step, with the aim of grouping reads sequenced from PCR duplicates of the same UMI tagged molecule into a single cluster, and the size of the current datasets requires this clustering process to be resource-efficient., Results: We introduce Calib, a computational tool that clusters paired-end reads from UMI tagged sequencing experiments generated by substitution-error-dominant sequencing platforms such as Illumina. Calib clusters are defined as connected components of a graph whose edges are defined in terms of both barcode similarity and read sequence similarity. The graph is constructed efficiently using locality sensitive hashing and MinHashing techniques. Calib's default clustering parameters are optimized empirically, for different UMI and read lengths, using a simulation module that is packaged with Calib. Compared to other tools, Calib has the best accuracy on simulated data, while maintaining reasonable runtime and memory footprint. On a real dataset, Calib runs with far less resources than alignment-based methods, and its clusters reduce the number of tentative false positive in downstream variation calling., Availability and Implementation: Calib is implemented in C++ and its simulation module is implemented in Python. Calib is available at https://github.com/vpc-ccg/calib., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Motivation: Cancer is a complex disease that involves rapidly evolving cells, often forming multiple distinct clones. In order to effectively understand progression of a patient-specific tumor, one needs to comprehensively sample tumor DNA at multiple time points, ideally obtained through inexpensive and minimally invasive techniques. Current sequencing technologies make the 'liquid biopsy' possible, which involves sampling a patient's blood or urine and sequencing the circulating cell free DNA (cfDNA). A certain percentage of this DNA originates from the tumor, known as circulating tumor DNA (ctDNA). The ratio of ctDNA may be extremely low in the sample, and the ctDNA may originate from multiple tumors or clones. These factors present unique challenges for applying existing tools and workflows to the analysis of ctDNA, especially in the detection of structural variations which rely on sufficient read coverage to be detectable., Results: Here we introduce SViCT , a structural variation (SV) detection tool designed to handle the challenges associated with cfDNA analysis. SViCT can detect breakpoints and sequences of various structural variations including deletions, insertions, inversions, duplications and translocations. SViCT extracts discordant read pairs, one-end anchors and soft-clipped/split reads, assembles them into contigs, and re-maps contig intervals to a reference genome using an efficient k-mer indexing approach. The intervals are then joined using a combination of graph and greedy algorithms to identify specific structural variant signatures. We assessed the performance of SViCT and compared it to state-of-the-art tools using simulated cfDNA datasets with properties matching those of real cfDNA samples. The positive predictive value and sensitivity of our tool was superior to all the tested tools and reasonable performance was maintained down to the lowest dilution of 0.01% tumor DNA in simulated datasets. Additionally, SViCT was able to detect all known SVs in two real cfDNA reference datasets (at 0.6-5% ctDNA) and predict a novel structural variant in a prostate cancer cohort., Availability: SViCT is available at https://github.com/vpc-ccg/svict. Contact:faraz.hach@ubc.ca., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors produce some beneficial and deleterious effects in diabetic patients not mediated by their glycemic lowering effects, and there is a need for better understanding of the molecular basis of these effects. They possess antioxidant and anti-inflammatory effects with some direct vasodilatory action (animal and human trial data) that may indirectly influence heart failure (HF). Unlike GLP-1R agonists, signaling for HF adverse effects was observed with two DPP-4 inhibitors, saxagliptin and alogliptin. Accordingly, these drugs should be used with caution in heart failure patients.

Valproic acid (VPA) is the most widely prescribed epilepsy treatment worldwide, but its mechanism of action remains unclear. Our previous work identified a previously unknown effect of VPA in reducing phosphoinositide production in the simple model Dictyostelium followed by the transfer of data to a mammalian synaptic release model. In our current study, we show that the reduction in phosphoinositide [PtdInsP (also known as PIP) and PtdInsP(2) (also known as PIP(2))] production caused by VPA is acute and dose dependent, and that this effect occurs independently of phosphatidylinositol 3-kinase (PI3K) activity, inositol recycling and inositol synthesis. In characterising the structural requirements for this effect, we also identify a family of medium-chain fatty acids that show increased efficacy compared with VPA. Within the group of active compounds is a little-studied group previously associated with seizure control, and analysis of two of these compounds (nonanoic acid and 4-methyloctanoic acid) shows around a threefold enhanced potency compared with VPA for protection in an in vitro acute rat seizure model. Together, our data show that VPA and a newly identified group of medium-chain fatty acids reduce phosphoinositide levels independently of inositol regulation, and suggest the reinvestigation of these compounds as treatments for epilepsy.

RpkA (Receptor phosphatidylinositol kinase A) is an unusual seven-helix transmembrane protein of Dictyostelium discoideum with a G protein coupled receptor (GPCR) signature and a C-terminal lipid kinase domain (GPCR-PIPK) predicted as a phosphatidylinositol-4-phosphate 5-kinase. RpkA-homologs are present in all so far sequenced Dictyostelidae as well as in several other lower eukaryotes like the oomycete Phytophthora, and in the Legionella host Acanthamoeba castellani. Here we show by immunofluorescence that RpkA localizes to endosomal membranes and is specifically recruited to phagosomes. RpkA interacts with the phagosomal protein complex V-ATPase as proteins of this complex co-precipitate with RpkA-GFP as well as with the GST-tagged PIPK domain of RpkA. Loss of RpkA leads to a defect in phagocytosis as measured by yeast particle uptake. The uptake of the pathogenic bacterium Legionella pneumophila was however unaltered whereas its intra-cellular replication was significantly enhanced in rpkA(-). The difference between wild type and rpkA(-) was even more prominent when L. hackeliae was used. When we investigated the reason for the enhanced susceptibility for L. pneumophila of rpkA(-) we could not detect a difference in endosomal pH but rpkA(-) showed depletion of phosphoinositides (PIP and PIP(2)) when we compared metabolically labeled phosphoinositides from wild type and rpkA(-). Furthermore rpkA(-) exhibited reduced nitrogen starvation tolerance, an indicator for a reduced autophagy rate. Our results indicate that RpkA is a component of the defense system of D. discoideum as well as other lower eukaryotes.

Bipolar mood disorder (manic depression) is a major psychiatric disorder whose molecular origins are unknown. Mood stabilisers offer patients both acute and prophylactic treatment, and experimentally, they provide a means to probe the underlying biology of the disorder. Lithium and other mood stabilisers deplete intracellular inositol and it has been proposed that bipolar mood disorder arises from aberrant inositol (1,4,5)-trisphosphate [IP(3), also known as Ins(1,4,5)P(3)] signalling. However, there is no definitive evidence to support this or any other proposed target; a problem exacerbated by a lack of good cellular models. Phosphatidylinositol (3,4,5)-trisphosphate [PIP(3), also known as PtdIns(3,4,5)P(3)] is a prominent intracellular signal molecule within the central nervous system (CNS) that regulates neuronal survival, connectivity and synaptic function. By using the genetically tractable organism Dictyostelium, we show that lithium suppresses PIP(3)-mediated signalling. These effects extend to the human neutrophil cell line HL60. Mechanistically, we show that lithium attenuates phosphoinositide synthesis and that its effects can be reversed by overexpression of inositol monophosphatase (IMPase), consistent with the inositol-depletion hypothesis. These results demonstrate a lithium target that is compatible with our current knowledge of the genetic predisposition for bipolar disorder. They also suggest that lithium therapy might be beneficial for other diseases caused by elevated PIP(3) signalling.