Impact of repurposed drugs on the symptomatic COVID-19 patients.

J Infect Public Health. 2021 Jan;14(1):24-38

Authors: Hussain I, Hussain A, Alajmi MF, Rehman MT, Amir S

Abstract
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus capable of causing coronavirus disease 2019 (COVID-19), was declared as a global public health emergency on January 30, 2020, by the World Health Organization. In this devastating situation, precautionary measures, early diagnosis, and repurposed drugs appear to be timely and decisive factors by which to handle this problem until the discovery of an effective, dedicated vaccine or medicine is made. Currently, some researchers and clinicians have claimed evidence exists in favor of the use of some antimalarial drugs (chloroquine, hydroxychloroquine) antiviral drugs (remdesivir, favipiravir, lopinavir, ritonavir, umifenovir) vitamins, traditional Chinese medicines, and herbal medicines against SARS-CoV-2 infection. Based on the available literature, this review article sought to highlight the current understanding of the origin, transmission, diagnosis, precautionary measures, infection and drug action mechanisms, therapeutic role, and toxicities of targeted drugs for the prevention and cure of COVID-19. This review may be useful for developing further strategies as a blueprint and understanding the mentioned drugs' mechanisms to elucidate the possible target of action by which to successfully freeze the replication of the SARS-CoV-2 virus.

PMID: 33341481 [PubMed - indexed for MEDLINE]

Griffithsin with A Broad-Spectrum Antiviral Activity by Binding Glycans in Viral Glycoprotein Exhibits Strong Synergistic Effect in Combination with A Pan-Coronavirus Fusion Inhibitor Targeting SARS-CoV-2 Spike S2 Subunit.

Virol Sin. 2020 12;35(6):857-860

Authors: Cai Y, Xu W, Gu C, Cai X, Qu D, Lu L, Xie Y, Jiang S

PMID: 33052520 [PubMed - indexed for MEDLINE]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/02/06

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SARS-CoV-2 entry inhibitors by dual targeting TMPRSS2 and ACE2: An in silico drug repurposing study.

Eur J Pharmacol. 2021 Feb 01;:173922

Authors: Baby K, Maity S, Mehta CH, Suresh A, Nayak UY, Nayak Y

Abstract
The coronavirus disease (COVID-19) is spreading between human populations mainly through nasal droplets. Currently, the vaccines have great hope, but it takes years for testing its efficacy in human. As there is no specific drug treatment available for COVID-19 pandemic, we explored in silico repurposing of drugs with dual inhibition properties by targeting transmembrane serine protease 2 (TMPRSS2) and human angiotensin-converting enzyme 2 (ACE2) from FDA-approved drugs. The TMPRSS2 and ACE2 dual inhibitors in COVID-19 would be a novel antiviral class of drugs called "entry inhibitors." For this purpose, approximately 2800 US-FDA approved drugs were docked using a virtual docking tool with the targets TMPRSS2 and ACE2. The best-fit drugs were selected as per docking scores and visual outcomes. Later on, drugs were selected on the basis of molecular dynamics simulations. The drugs alvimopan, arbekacin, dequalinum, fleroxacin, lopinavir, and valrubicin were shortlisted by visual analysis and molecular dynamics simulations. Among these, lopinavir and valrubicin were found to be superior in terms of dual inhibition. Thus, lopinavir and valrubicin have the potential of dual-target inhibition whereby preventing SARS-CoV-2 entry to the host. For repurposing of these drugs, further screening in vitro and in vivo would help in exploring clinically.

PMID: 33539819 [PubMed - as supplied by publisher]

Current and promising pharmacotherapeutic options for candidiasis.

Expert Opin Pharmacother. 2021 Feb 04;:1-21

Authors: Scorzoni L, Fuchs BB, Junqueira JC, Mylonakis E

Abstract
Introduction: Candida spp. are commensal yeasts capable of causing infections such as superficial, oral, vaginal, or systemic infections. Despite medical advances, the antifungal pharmacopeia remains limited and the development of alternative strategies is needed. Areas covered: We discuss available treatments for Candida spp. infections, highlighting advantages and limitations related to pharmacokinetics, cytotoxicity, and antimicrobial resistance. Moreover, we present new perspectives to improve the activity of the available antifungals, discussing their immunomodulatory potential and advances on drug delivery carriers. New therapeutic approaches are presented including recent synthesized antifungal compounds (Enchochleated-Amphotericin B, tetrazoles, rezafungin, enfumafungin, manogepix and arylamidine); drug repurposing using a diversity of antibacterial, antiviral and non-antimicrobial drugs; combination therapies with different compounds or photodynamic therapy; and innovations based on nano-particulate delivery systems. Expert opinion: With the lack of novel drugs, the available assets must be leveraged to their best advantage through modifications that enhance delivery, efficacy, and solubility. However, these efforts are met with continuous challenges presented by microbes in their infinite plight to resist and survive therapeutic drugs. The pharmacotherapeutic options in development need to focus on new antimicrobial targets. The success of each antimicrobial agent brings strategic insights to the next phased approach in treatingCandida spp. infections.

PMID: 33538201 [PubMed - as supplied by publisher]

Identification of a Five-Gene Prognostic Model and Its Potential Drug Repurposing in Colorectal Cancer Based on TCGA, GTEx and GEO Databases.

Front Genet. 2020;11:622659

Authors: Yang F, Cai S, Ling L, Zhang H, Tao L, Wang Q

Abstract
Colorectal cancer (CRC) is a major cause of cancer deaths worldwide. Unfortunately, many CRC patients are still being diagnosed at an advanced stage of the cancer, and the 5-year survival rate is only ~30%. Effective prognostic markers of CRC are therefore urgently needed. To address this issue, we performed a detailed bioinformatics analysis based on the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases to identify prognostic biomarkers for CRC, which in turn help in exploring potential drug-repurposing. We identified five hub genes (PGM2, PODXL, RHNO1, SCD, and SEPHS1), which had good performance in survival prediction and might be involved in CRC through three key pathways ("Cell cycle," "Purine metabolism," and "Spliceosome" KEGG pathways) identified by a KEGG pathway enrichment analysis. What is more, we performed a co-expression analysis between five hub genes and transcription factors to explore the upstream regulatory region. Furthermore, we screened the potential drug-repurposing for the five hub genes in CRC according to the Binding DB and ZINC15 databases. Taking together, we constructed a five-gene signature to predict overall survival of CRC and found the potential drug-repurposing, which may improve the outcome of CRC in the future.

PMID: 33537062 [PubMed]

Repositioning Drugs on Human Influenza A Viruses Based on a Novel Nuclear Norm Minimization Method.

Front Physiol. 2020;11:597494

Authors: Liang H, Zhang L, Wang L, Gao M, Meng X, Li M, Liu J, Li W, Meng F

Abstract
Influenza A viruses, especially H3N2 and H1N1 subtypes, are viruses that often spread among humans and cause influenza pandemic. There have been several big influenza pandemics that have caused millions of human deaths in history, and the threat of influenza viruses to public health is still serious nowadays due to the frequent antigenic drift and antigenic shift events. However, only few effective anti-flu drugs have been developed to date. The high development cost, long research and development time, and drug side effects are the major bottlenecks, which could be relieved by drug repositioning. In this study, we proposed a novel antiviral Drug Repositioning method based on minimizing Matrix Nuclear Norm (DRMNN). Specifically, a virus-drug correlation database consisting of 34 viruses and 205 antiviral drugs was first curated from public databases and published literature. Together with drug similarity on chemical structure and virus sequence similarity, we formulated the drug repositioning problem as a low-rank matrix completion problem, which was solved by minimizing the nuclear norm of a matrix with a few regularization terms. DRMNN was compared with three recent association prediction algorithms. The AUC of DRMNN in the global fivefold cross-validation (fivefold CV) is 0.8661, and the AUC in the local leave-one-out cross-validation (LOOCV) is 0.6929. Experiments have shown that DRMNN is better than other algorithms in predicting which drugs are effective against influenza A virus. With H3N2 as an example, 10 drugs most likely to be effective against H3N2 viruses were listed, among which six drugs were reported, in other literature, to have some effect on the viruses. The protein docking experiments between the chemical structure of the prioritized drugs and viral hemagglutinin protein also provided evidence for the potential of the predicted drugs for the treatment of influenza.

PMID: 33536933 [PubMed]

GPCR and ion channel genes used by influenza virus for replication.

J Virol. 2021 Feb 03;:

Authors: Orr-Burks N, Murray J, Todd KV, Bakre A, Tripp RA

Abstract
Influenza virus causes epidemics and sporadic pandemics resulting in morbidity, mortality and economic losses. Influenza viruses require host genes to replicate. RNA interference (RNAi) screens can identify host genes coopted by influenza for replication. Targeting these pro-influenza genes can provide therapeutic strategies to reduce virus replication. Using human lung (A549) cells, 19 pro-influenza GPCR and 13 pro-influenza ion channel genes were identified using small inferring RNAs (siRNA). These pro-influenza genes were authenticated by testing A/WSN/33, A/CA/04/09, and B/Yamagata/16/1988-infected A549 cells resulting in 16 pro-influenza GPCR and 5 pro-influenza ion channel genes being validated. These findings showed that several GPCR and ion channel genes are needed for production of infectious influenza virus. These data provide potential targets for the development of host-directed therapeutic strategies to impede the influenza productive cycle to limit infection.IMPORTANCE: Influenza epidemics result in morbidity and mortality each year. Vaccines are the most effective preventive measure but require annual reformulation as mismatch of vaccine strains can result in vaccine failure. Antiviral measures are desirable particularly when vaccines fail. In this study, we used RNAi screening to identify several GPCR and ion channel genes needed for influenza virus replication. Understanding the host genes usurped by influenza during viral replication can help identify host genes that can be targeted for drug repurposing or for the development of antiviral drugs. Targeting host genes is also refractory to drug resistance generated by viral mutations, as well as provides a platform for the development of broad spectrum anti-viral drugs.

PMID: 33536179 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/02/04

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/02/03

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15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/02/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

3 Biotech. 2021 Feb;11(2):93. doi: 10.1007/s13205-020-02610-w. Epub 2021 Jan 24.

ABSTRACT

COVID-19 has emerged as a rapidly escalating serious global health issue, affecting every section of population in a detrimental way. Present situation invigorated researchers to look for potent targets, development as well as repurposing of conventional therapeutic drugs. NSP12, a RNA polymerase, is key player in viral RNA replication and, hence, viral multiplication. In our study, we have screened a battery of FDA-approved drugs against SARS-CoV-2 RNA polymerase using in silico molecular docking approach. Identification of potent inhibitors against SARS-CoV-2 NSP12 (RNA polymerase) were screeened from FDA approved drugs by virtual screening for therapeutic applications in treatment of COVID-19. In this study, virtual screening of 1749 antiviral drugs was executed using AutoDock Vina in PyRx software. Binding affinities between NSP12 and drug molecules were determined using Ligplot+ and PyMOL was used for visualization of docking between interacting residues. Screening of 1749 compounds resulted in 14 compounds that rendered high binding affinity for NSP12 target molecule. Out of 14 compounds, 5 compounds which include 3a (Paritaprevir), 3d (Glecaprevir), 3h (Velpatasvir), 3j (Remdesivir) and 3l (Ribavirin) had a binding affinity of - 10.2 kcal/mol, -9.6 kcal/mol, - 8.5 kcal/mol, - 8.0 kcal/mol and - 6.8 kcal/mol, respectively. Moreover, a number of hydrophobic interactions and hydrogen bonding between these 5 compounds and NSP12 active site were observed. Further, 3l (Ribavirin) was docked with 6M71 and molecular dynamic simulation of the complex was also performed to check the stability of the conformation. In silico analysis postulated the potential of conventional antiviral drugs in treatment of COVID-19. However, these finding may be further supported by experimental data for its possible clinical application in present scenario.

PMID:33520579 | PMC:PMC7826501 | DOI:10.1007/s13205-020-02610-w

Med Drug Discov. 2021 Mar;9:100077. doi: 10.1016/j.medidd.2020.100077. Epub 2020 Dec 24.

ABSTRACT

AIMS: Over the past few years, AI has been considered as potential important area for improving drug development and in the current urgent need to fight the global COVID-19 pandemic new technologies are even more in focus with the hope to speed up this process. The purpose of our study was to identify the best repurposing candidates among FDA-approved drugs, based on their predicted antiviral activity against SARS-CoV-2.

MATERIALS AND METHODS: This article describes a drug discovery screening based on a supervised machine learning model, trained on in vitro data encoded in chemical fingerprints, representing particular molecular substructures. Predictive performance of our model has been evaluated using so-called scaffold splits offering a state-of-the-art setup for assessing model's ability to generalize to new chemical spaces, critical for drug repurposing applications.

KEY FINDINGS: Our study identified zafirlukast as the best repurposing candidate for COVID-19.

SIGNIFICANCE: Zafirlukast could be potent against COVID-19 both due to its predicted antiviral properties and its ability to attenuate the so called cytokine storm. Thus, these two critical mechanisms of action may be combined in one drug as a novel and promising pharmacotherapy in the current pandemic.

PMID:33521623 | PMC:PMC7836294 | DOI:10.1016/j.medidd.2020.100077

Biapenem reduces sepsis mortality via barrier protective pathways against HMGB1-mediated septic responses.

Pharmacol Rep. 2021 Jan 30;:

Authors: Kim J, Choo S, Sim H, Baek MC, Bae JS

Abstract
BACKGROUND: As a late mediator of sepsis, the role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies for sepsis. For repositioning of previously FDA-approved drugs to develop new therapies for human diseases, screening of chemical compound libraries, biological active, is an efficient method. Our study illustrates an example of drug repositioning of Biapenem (BIPM), a carbapenem antibiotic, for the modulation of HMGB1-induced septic responses.
METHODS: We tested our hypothesis that BIPM inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model, antiseptic activity of BIPM was investigated from suppression of vascular permeability, pro-inflammatory proteins, and markers for tissue injury.
RESULTS: BIPM significantly suppressed release of HMGB1 both in LPS-activated HUVECs (upto 60%) and the CLP-induced sepsis mouse model (upto 54%). BIPM inhibited hyperpermeability (upto 59%) and reduced HMGB1-mediated vascular disruptions (upto 62%), mortality (upto 50%), and also tissue injury including lung, liver, and kidney in mice.
CONCLUSION: Reduction of HMGB1 release and septic mortality by BIPM (in vitro, from 5 to 15 μM for 6 h; in vivo, from 0.37 to 1.1 mg/kg, 24 h) indicate a possibility of successful repositioning of BIPM for the treatment of sepsis.

PMID: 33515401 [PubMed - as supplied by publisher]

Prenylated Trans-Cinnamic Esters and Ethers against Clinical Fusarium spp.: Repositioning of Natural Compounds in Antimicrobial Discovery.

Molecules. 2021 Jan 27;26(3):

Authors: Oufensou S, Casalini S, Balmas V, Carta P, Chtioui W, Dettori MA, Fabbri D, Migheli Q, Delogu G

Abstract
Onychomycosis is a common nail infection mainly caused by species belonging to the F. oxysporum, F. solani, and F. fujikuroi species complexes. The aim of this study was to evaluate the in vitro susceptibility of six representative strains of clinically relevant Fusarium spp. toward a set of natural-occurring hydroxycinnamic acids and their derivatives with the purpose to develop naturally occurring products in order to cope with emerging resistance phenomena. By introducing a prenylated chain at one of the hydroxy groups of trans-cinnamic acids 1-3, ten prenylated derivatives (coded 4-13) were preliminarily investigated in solid Fusarium minimal medium (FMM). Minimal inhibitory concentration (MIC) and lethal dose 50 (LD50) values were then determined in liquid FMM for the most active selected antifungal p-coumaric acid 3,3'-dimethyl allyl ester 13, in comparison with the conventional fungicides terbinafine (TRB) and amphotericin B (AmB), through the quantification of the fungal growth. Significant growth inhibition was observed for prenylated derivatives 4-13, evidencing ester 13 as the most active. This compound presented MIC and LD50 values (62-250 µM and 7.8-125 µM, respectively) comparable to those determined for TRB and AmB in the majority of the tested pathogenic strains. The position and size of the prenylated chain and the presence of a free phenol OH group appear crucial for the antifungal activity. This work represents the first report on the activity of prenylated cinnamic esters and ethers against clinical Fusarium spp. and opens new avenues in the development of alternative antifungal compounds based on a drug repositioning strategy.

PMID: 33513915 [PubMed - as supplied by publisher]

Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program.

Nat Genet. 2021 Jan 28;:

Authors: Stein MB, Levey DF, Cheng Z, Wendt FR, Harrington K, Pathak GA, Cho K, Quaden R, Radhakrishnan K, Girgenti MJ, Ho YA, Posner D, Aslan M, Duman RS, Zhao H, Department of Veterans Affairs Cooperative Studies Program (no. 575B), VA Million Veteran Program, Polimanti R, Concato J, Gelernter J

Abstract
We conducted genome-wide association analyses of over 250,000 participants of European (EUR) and African (AFR) ancestry from the Million Veteran Program using electronic health record-validated post-traumatic stress disorder (PTSD) diagnosis and quantitative symptom phenotypes. Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood-anxiety-neuroticism) factor. Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment.

PMID: 33510476 [PubMed - as supplied by publisher]

Auto-HMM-LMF: feature selection based method for prediction of drug response via autoencoder and hidden Markov model.

BMC Bioinformatics. 2021 Jan 28;22(1):33

Authors: Emdadi A, Eslahchi C

Abstract
BACKGROUND: Predicting the response of cancer cell lines to specific drugs is an essential problem in personalized medicine. Since drug response is closely associated with genomic information in cancer cells, some large panels of several hundred human cancer cell lines are organized with genomic and pharmacogenomic data. Although several methods have been developed to predict the drug response, there are many challenges in achieving accurate predictions. This study proposes a novel feature selection-based method, named Auto-HMM-LMF, to predict cell line-drug associations accurately. Because of the vast dimensions of the feature space for predicting the drug response, Auto-HMM-LMF focuses on the feature selection issue for exploiting a subset of inputs with a significant contribution.
RESULTS: This research introduces a novel method for feature selection of mutation data based on signature assignments and hidden Markov models. Also, we use the autoencoder models for feature selection of gene expression and copy number variation data. After selecting features, the logistic matrix factorization model is applied to predict drug response values. Besides, by comparing to one of the most powerful feature selection methods, the ensemble feature selection method (EFS), we showed that the performance of the predictive model based on selected features introduced in this paper is much better for drug response prediction. Two datasets, the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE) are used to indicate the efficiency of the proposed method across unseen patient cell-line. Evaluation of the proposed model showed that Auto-HMM-LMF could improve the accuracy of the results of the state-of-the-art algorithms, and it can find useful features for the logistic matrix factorization method.
CONCLUSIONS: We depicted an application of Auto-HMM-LMF in exploring the new candidate drugs for head and neck cancer that showed the proposed method is useful in drug repositioning and personalized medicine. The source code of Auto-HMM-LMF method is available in https://github.com/emdadi/Auto-HMM-LMF .

PMID: 33509079 [PubMed - in process]

Repurposed Tocilizumab in Patients with Severe COVID-19.

J Immunol. 2021 02 01;206(3):599-606

Authors: Tian J, Zhang M, Jin M, Zhang F, Chu Q, Wang X, Chen C, Yue H, Zhang L, Du R, Zhao D, Zeng Z, Zhao Y, Liu K, Wang M, Hu K, Miao X, Zhang H

Abstract
The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable morbidity and mortality. Tocilizumab, an inhibitor of IL-6, has been widely repurposed as a treatment of severely ill patients without robust evidence supporting its use. In this study, we aimed to systematically describe the effectiveness of treatment and prevention of the cytokine storms in COVID-19 patients with tocilizumab. In this multicentered retrospective and observational cohort study, 65 patients with COVID-19 receiving tocilizumab and 130 not receiving tocilizumab were propensity score matched at a ratio of 2:1 based on age, sex, and comorbidities from January 20, 2020 to March 18, 2020 in Wuhan, China. After adjusting for confounding, the detected risk for in-hospital death was lower in the tocilizumab group versus nontocilizumab group (hazard ratio = 0.47; 95% confidence interval = 0.25-0.90; p = 0.023). Moreover, use of tocilizumab was associated with a lower risk of acute respiratory distress syndrome (odds ratio = 0.23; 95% confidence interval = 0.11-0.45; p < 0.0001). Furthermore, patients had heightened inflammation and more dysregulated immune cells before treatment, which might aggravate disease progression. After tocilizumab administration, abnormally elevated IL-6, C-reactive protein, fibrinogen, and activated partial thromboplastin time decreased. Tocilizumab may be of value in prolonging survival in patients with severe COVID-19, which provided a novel strategy for COVID-19-induced cytokine release syndrome. Our findings could inform bedside decisions until data from randomized, controlled clinical trials become available.

PMID: 33298617 [PubMed - indexed for MEDLINE]

The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection.

Peptides. 2021 01;135:170428

Authors: Carvalho PR, Sirois P, Fernandes PD

Abstract
In November 2019 the first cases of a novel acute respiratory syndrome has been reported in Wuhan province, China. Soon after, in January 2020 the World Health Organization declared a pandemic state due to the dissemination of a virus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19). Being an unknown disease, it is essential to assess not only its main characteristic features and overall clinical symptomatology but also its patient infection mode and propagation to design appropriate clinical interventions and treatments. In this review the pathophysiology of SARS-CoV-2 infection and how the virus enters the cells and activates the immune system are described. The role of three systems involved in the SARS- CoV-2 infection (renin-angiotensin, kinin and coagulation systems) is discussed with the objectives to identify and try to explain several of the events observed during the evolution of the disease and to suggest possible targets for therapeutic interventions.

PMID: 33065209 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/01/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.