REVIEW | doi:10.20944/preprints202004.0203.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; masks; pandemic
Online: 12 April 2020 (17:41:10 CEST)
The science around the use of masks by the general public to impede COVID-19 transmission is advancing rapidly. Policymakers need guidance on how masks should be used by the general population to combat the COVID-19 pandemic. Here, we synthesize the relevant literature to inform multiple areas: 1) transmission characteristics of COVID-19, 2) filtering characteristics and efficacy of masks, 3) estimated population impacts of widespread community mask use, and 4) sociological considerations for policies concerning mask-wearing. A primary route of transmission of COVID-19 is likely via small respiratory droplets, and is known to be transmissible from presymptomatic and asymptomatic individuals. Reducing disease spread requires two things: first, limit contacts of infected individuals via physical distancing and contact tracing with appropriate quarantine, and second, reduce the transmission probability per contact by wearing masks in public, among other measures. The preponderance of evidence indicates that mask wearing reduces the transmissibility per contact by reducing transmission of infected droplets in both laboratory and clinical contexts. Public mask wearing is most effective at stopping spread of the virus when compliance is high. The decreased transmissibility could substantially reduce the death toll and economic impact while the cost of the intervention is low. Thus we recommend the adoption of public cloth mask wearing, as an effective form of source control, in conjunction with existing hygiene, distancing, and contact tracing strategies. We recommend that public officials and governments strongly encourage the use of widespread face masks in public, including the use of appropriate regulation.
Fri, 13 March 2020
ARTICLE | doi:10.20944/preprints202003.0226.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-2019; Mpro; 6LU7; medicinal plant compounds; docking
Online: 13 March 2020 (03:19:02 CET)
COVID-19, a new strain of coronavirus (CoV), was identified in Wuhan, China, in 2019. No specific therapies are available and investigations regarding COVID-19 treatment are lacking. Liu et al. (2020) successfully crystallised the COVID-19 main protease (Mpro), which is a potential drug target. The present study aimed to assess bioactive compounds found in medicinal plants as potential COVID-19 Mpro inhibitors, using a molecular docking study. Molecular docking was performed using Autodock 4.2, with the Lamarckian Genetic Algorithm, to analyse the probability of docking. COVID-19 Mpro was docked with several compounds, and docking was analysed by Autodock 4.2, Pymol version 188.8.131.52 Edu, and Biovia Discovery Studio 4.5. Nelfinavir and lopinavir were used as standards for comparison. The binding energies obtained from the docking of 6LU7 with native ligand, nelfinavir, lopinavir, kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, epicatechin-gallate, zingerol, gingerol, and allicin were -8.37, -10.72, -9.41, -8.58, -8.47, -8.17, -7.99, -7.89, -7.83, -7.31, -7.05, -7.24, -6.67, -5.40, -5.38, and -4.03 kcal/mol, respectively. Therefore, nelfinavir and lopinavir may represent potential treatment options, and kaempferol, quercetin, luteolin-7-glucoside, demethoxycurcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate appeared to have the best potential to act as COVID-19 Mpro inhibitors. However, further research is necessary to investigate their potential medicinal use.
Thu, 30 January 2020
Subject: Medicine & Pharmacology, Other Keywords: 2019-nCov; Baicalin; Scutellarin; Hesperetin; Nicotianamine; Glycyrrhizin
Online: 30 January 2020 (03:06:07 CET)
2019-nCoV, a novel coronavirus, caused the pneumonia outbreak in China and continue to expand. The host receptor for 2019-nCoV Angiotensin-converting enzyme 2 (ACE2), which is the same as the host receptor of SARS-CoV. Targeting ACE2 holds the promise for preventing 2019-nCoV infection. Chinese Medicine herbs could be a valuable pool for identifying active compounds for treating infection of 2019-nCoV. In this study, we summarize several active compounds including baicalin, Scutellarin, Hesperetin, Nicotianamine and glycyrrhizin that could have potential anti-2019-nCoV effects, and we conduct molecular docking to predict their capacity for binding ACE2, which may subsequently prevent the 2019-nCoV infection. We propose that these selected compounds worth further investigation for preventing 2019-nCoV.
Thu, 12 March 2020
ARTICLE | doi:10.20944/preprints202003.0214.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: SARS-Cov-2; Citrus sp.; Galangal; Curcuma sp.; Sappan wood
Online: 12 March 2020 (13:59:40 CET)
COVID-19 pandemic is a serious problem in the world today. The SARS-CoV-2 virus that causes COVID-19 has important proteins used for its infection and development, namely the protease and spike glycoprotein. The RBD (Receptor Binding Domain) of spike glycoprotein (RBD-S) can bind to the ACE2 (Angiotensin Converting Enzyme-2) receptor at the protease domain (PD) (PD-ACE2) of the host cell, thereby leading to a viral infection. This study aims to reveal the potential of compounds contained in Curcuma sp., Citrus sp., Alpinia galanga, and Caesalpinia sappan as anti SARS-CoV-2 through its binding to 3 protein receptors. The study was conducted by molecular docking using the MOE 2010 program (licensed from Faculty of Pharmacy UGM, Indonesia). The selected protein targets are RBD-S (PDB ID:6LXT), PD-ACE2 (PDB ID: 6VW1), and SARS-CoV-2 protease (PDB ID:6LU7). The affinities of bonds formed is represented as a docking score. The results show that hesperidin, one of the compounds in Citrus sp., has the lowest docking score for all three protein receptors representing the highest affinity to bind the receptors. Moreover, all of the citrus flavonoids possess good affinity to the respected receptors as well as curcumin, brazilin, and galangin, indicating that those compounds perform inhibitory potential for the viral infection and replication. In general, the results of this study indicate that Citrus sp. exhibit the best potential as an inhibitor to the development of the SARS-CoV-2, followed by galangal, sappan wood, and Curcuma sp. that can be consumed in daily life as prophylaxis of COVID-19.
Tue, 17 March 2020
REVIEW | doi:10.20944/preprints202003.0275.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Antimalarial; Chemoprophylaxis; Chloroquine; Coronavirus; COVID-19; Global Health; Hydroxychloroquine; Public Health; SARS-CoV-2; Virus
Online: 17 March 2020 (09:17:53 CET)
There is a long trail of research studies testing the in vitro and in vivo efficacy of chloroquine and its derivatives in treating and preventing infection by various coronavirus species. More recent findings have highlighted the possibility of treating patients infected with the 2019 novel coronavirus, SARS-CoV-2. This review describes the mechanism of coronavirus infection, the mechanism of action of chloroquine, and summarizes the available literature highlighting the efficacy of chloroquine as an anti-coronavirus agent. These findings should encourage the wider scientific community to conduct thorough research on the possible efficacy of chloroquine and its derivatives in treating and preventing SARS-CoV-2 infection.
Wed, 13 May 2020
REVIEW | doi:10.20944/preprints202004.0203.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; masks; pandemic
Online: 13 May 2020 (13:16:04 CEST)
The science around the use of masks by the general public to impede COVID-19 transmission is advancing rapidly. Policymakers need guidance on how masks should be used by the general population to combat the COVID-19 pandemic. Here,we develop an analytical framework to examine an overlooked aspect of mask usage: masks as source-control targeting egress from the wearer with benefits at the population-level, rather than as PPE used for ingress control for health-care workers with focus on individual outcomes. We consider and synthesize the relevant literature to inform multiple areas: 1) transmission characteristics of COVID-19, 2) filtering characteristics and efficacy of masks, 3) estimated population impacts of widespread community mask use, and 4) sociological considerations for policies concerning mask-wearing. A primary route of transmission of COVID-19 is likely via respiratory droplets, and is known to be transmissible from presymptomatic and asymptomatic individuals. Reducing disease spread requires two things: first, limit contacts of infected individuals via physical distancing and other measures, and second, reduce the transmission probability per contact. The preponderance of evidence indicates that mask wearing reduces the transmissibility per contact by reducing transmission of infected droplets in both laboratory and clinical contexts. Public mask wearing is most effective at reducing spread of the virus when compliance is high. The decreased transmissibility could substantially reduce the death toll and economic impact while the cost of the intervention is low. Given the current shortages of medical masks we recommend the adoption of public cloth mask wearing, as an effective form of source control for now, in conjunction with existing hygiene, distancing, and contact tracing strategies. We recommend that public officials and governments strongly encourage the use of widespread face masks in public, including the use of appropriate regulation.
Sun, 15 March 2020
REVIEW | doi:10.20944/preprints202003.0235.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: ascorbic acid; cahtelicidin; coronavirus; COVID-19; cytokine storm; influenza, pneumonia; prevention; respiratory tract infection; UVB; vitamin C; Vitamn D; solar radiation; treatment; observational; trial
Online: 15 March 2020 (01:47:19 CET)
Low vitamin D status in winter permits viral epidemics. During winter, people who do not take vitamin D supplements are likely to have low serum 25-hydroxyvitamin D [25(OH)D] concentrations. Vitamin D can reduce the risk of viral epidemics and pandemics in several ways. First, higher 25(OH)D concentrations reduce the risk of many chronic diseases, including cancers, cardiovascular disease, chronic respiratory tract infections (RTIs), diabetes mellitus, and hypertension. Patients with chronic diseases have significantly higher risk of death from RTIs than otherwise healthy people. Second, vitamin D reduces risk of RTIs through three mechanisms: maintaining tight junctions, killing enveloped viruses through induction of cathelicidin and defensins, and reducing production of proinflammatory cytokines by the innate immune system, thereby reducing the risk of a cytokine storm leading to pneumonia. Observational and supplementation trials have reported higher 25(OH)D concentrations associated with reduced risk of dengue, hepatitis, herpesvirus, hepatitis B and C viruses, human immunodeficiency virus, influenza, respiratory syncytial virus infections, and pneumonia. Results of a community field trial reported herein indicated that 25(OH)D concentrations above 50 ng/ml (125 nmol/l) vs. <20 ng/ml were associated with a 27% reduction in influenza-like illnesses. From the available evidence, we hypothesize that raising serum 25(OH)D concentrations through vitamin D supplementation could reduce the incidence, severity, and risk of death from influenza, pneumonia, and the current COVID-19 epidemic.
Wed, 8 April 2020
HYPOTHESIS | doi:10.20944/preprints202004.0124.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; Therapy; Chloroquine; Hydroxychloroquine; Zinc
Online: 8 April 2020 (10:54:33 CEST)
Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.
Fri, 3 April 2020
HYPOTHESIS | doi:10.20944/preprints202004.0023.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; bradykinin; ACE2; pulmonary angioedema; ARDS; icatibant
Online: 3 April 2020 (04:13:43 CEST)
Most striking observations in COVID-19 patients are the hints on pulmonary edema (also seen on CT scans as ground glass opacities), dry cough, fluid restrictions to prevent more severe hypoxia, the huge PEEP that is needed while lungs are compliant, and the fact that anti-inflammatory therapies are not powerful enough to counter the severity of the disease. We propose that the severity of the disease and many deaths are due to a local vascular problem due to activation of B1 receptors on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2, a cell membrane bound molecule with enzymatic activity that next to its role in RAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the bradykinin receptor type 1 (B1). In contrast to bradykinin receptor 2 (B2), the B1 receptor on endothelial cells is upregulated by proinflammatory cytokines. Without ACE2 acting as a guardian to inactivate the ligands of B1, the lung environment is prone for local vascular leakage leading to angioedema. Angioedema is likely a feature already early in disease, and might explain the typical CT scans and the feeling of people that they drown. In some patients, this is followed by a clinical worsening of disease around day 9 due to the formation antibodies directed against the spike (S)-antigen of the corona-virus that binds to ACE2 that could contribute to disease by enhancement of local immune cell influx and proinflammatory cytokines leading to damage. In parallel, inflammation induces more B1 expression, and possibly via antibody-dependent enhancement of viral infection leading to continued ACE2 dysfunction in the lung because of persistence of the virus. In this viewpoint we propose that a bradykinin-dependent local lung angioedema via B1 and B2 receptors is an important feature of COVID-19, resulting in a very high number of ICU admissions. We propose that blocking the B1 and B2 receptors might have an ameliorating effect on disease caused by COVID-19. This kinin-dependent pulmonary edema is resistant to corticosteroids or adrenaline and should be targeted as long as the virus is present. In addition, this pathway might indirectly be responsive to anti-inflammatory agents or neutralizing strategies for the anti-S-antibody induced effects, but by itself is likely to be insufficient to reverse all the pulmonary edema. Moreover, we provide a suggestion of how to ventilate in the ICU in the context of this hypothesis.
Fri, 24 April 2020
Subject: Medicine & Pharmacology, Allergology Keywords: antibodies; COVID-19; glycans; immunoglobulin M; SARS-CoV-2; pneumonia; prediction; protection
Online: 24 April 2020 (10:25:27 CEST)
The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic infection, to pneumonia, and to complications eventually fatal. We propose here the first model, explaining how the outcome of first, crucial 10-15 days after infection, hangs on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, MBL). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm) leading to complications often requiring intensive therapy and being, in some patients, fatal. Strenuous exercise and high flow air in the incubation days and early stages of COVID-19, facilitates direct penetration of the virus to the lower airways and the alveoli, without impacting on the airway’s mucosae covered by neutralizing antibodies. This allows the virus to bypass the efficient immune barrier of the upper airways mucosa in young and healthy athletes. In conclusion, whether the virus or the adaptative immune response reach the lungs first, is a crucial factor deciding the fate of the patient. This “quantitative and time-sequence dependent” model has several implications for prevention, diagnosis, and therapy of COVID-19.
Fri, 14 February 2020
ARTICLE | doi:10.20944/preprints202002.0179.v1
Online: 14 February 2020 (02:34:55 CET)
Ongoing outbreak of pneumonia caused by novel coronavirus (2019-nCoV) began in December 2019 in Wuhan, China, and the number of new patients continues to increase. On the contrary to ongoing outbreak in China, however, there are limited secondary outbreaks caused by exported case outside the country. We here conducted simulations to estimate the impact of potential secondary outbreaks at a community outside China. Simulations using stochastic SEIR model was conducted, assuming one patient was imported to a community. Among 45 possible scenarios we prepared, the worst scenario resulted in total number of persons recovered or removed to be 997 (95% CrI 990-1,000) at day 100 and maximum number of symptomatic infectious patients per day of 335 (95% CrI 232-478). Calculated mean basic reproductive number (R0) was 6.5 (Interquartile range, IQR 5.6-7.2). However, with good case scenarios with different parameter led to no secondary case. Altering parameters, especially time to hospital visit could change the impact of secondary outbreak. With this multiple scenarios with different parameters, healthcare professionals might be able to prepare for this viral infection better.
Mon, 17 February 2020
BRIEF REPORT | doi:10.20944/preprints202002.0242.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-19; molecular docking; HIV protease inhibitor; nucleotide analogues
Online: 17 February 2020 (07:28:31 CET)
The outbreak of novel coronavirus (COVID-19) infections occurring in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking strategies to repurpose HIV protease inhibitors and nucleotide analogues for COVID-19. The evaluation was made on docking scores calculated by AutoDock Vina and RosettaCommons. Preliminary results suggested that Indinavir and Remdesivir have the best docking scores and the comparison of the docking sites of these two drugs shows a near perfect dock in the overlap region of the protein pocket. However, the active sites inferred from the proteins of SARS coronavirus are not compatible with the docking site of COVID-19, which may give rise to concern in the efficacy of drugs.
Mon, 13 April 2020
REVIEW | doi:10.20944/preprints202004.0204.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: Covid-19; coronavirus; cardiovascular disease; thrombosis; hypertension; endothelial dysfunction
Online: 13 April 2020 (02:23:33 CEST)
The symptoms most commonly reported by patients affected by coronavirus disease 2019 (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g. high blood pressure, thrombosis, pulmonary embolism) seem to suggest that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ of COVID-19.
Tue, 5 May 2020
ARTICLE | doi:10.20944/preprints202005.0057.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; treatment; drug; survival; antiviral; hydroxychloroquine
Online: 5 May 2020 (03:32:22 CEST)
Background: There is no treatment proven effective against COVID-19. Several drugs with in vitro potential against SARS-CoV-2 virus have been proposed. Hydroxychloroquine has in vitro anti-viral and immunomodulatory activity, but there is no current clinical evidence of its effectiveness changing the outcome of the disease. Methods: We enrolled all 18-85 years old inpatients from Central Defense Hospital “Gómez Ulla”, Madrid, Spain, who were hospitalised for COVID-19 and had a definitive outcome (dead or discharged). We used a statistical survival analysis to detect treatment differences associated with in-hospital death. Results: We analysed first 220 medical records. 166 patients met the inclusion criteria. 48,8 % of patients not treated with HCQ died, 22% of those treated with hydroxychloroquine (p=0,002). According to clinical picture at admission, hydroxychloroquine increased the mean cumulative survival in all groups from 1,4 to 1,8 times. This difference was statistically significant in the mild group. Conclusions: in a cohort of 166 patients from 18 to 85 years hospitalised with COVID-19, hydroxychloroquine treatment with 800mg added loading dose increased survival when patients were admitted in early stages of the disease. There was a non-statistically significant trend towards survival in all groups, which will have to be clarified in subsequent studies.
Tue, 17 March 2020
HYPOTHESIS | doi:10.20944/preprints202003.0279.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: chloroquine; COVID-19; SARS-CoV2; antiviral; viral prophylaxis
Online: 17 March 2020 (15:57:38 CET)
The novel coronavirus 2019 (COVID-19) pandemic is rapidly advancing despite public health measures. Pharmaceutical prophylaxis is an established approach to potentially control infectious diseases and is one solution to the urgent public health challenge posed by COVID-19. Screening and development of new vaccines and antivirals is expensive and time consuming while the repositioning of available drugs should receive priority attention as well as international government and agency support. Here we propose an old drug chloroquine (CQ) to be urgently repositioned as an ideal antiviral prophylactic against COVID-19. CQ has ability to block viral attachment and entry to host cells. Its proven clinical efficacy against a variety of viruses including COVID-19 and its current deployment in COVID-19 therapeutic trials strengthens its potential candidacy as a prophylactic. Furthermore, CQ has a long safety record, is inexpensive and widely available. Here we reviewed CQ's antiviral mechanisms, its laboratory efficacy activity against COVID-19, as well as CQ's pharmacokinetics in its established use against malaria and autoimmune diseases to recommend safe and potentially efficacious dose regimens for protection against COVID-19: a pre-exposure prophylaxis of 250-500mg daily and post-exposure prophylaxis at 8mg/kg/day for 3 days. We recommend further urgent research on CQ for COVID-19 prevention and urge that the above regimens be investigated in parallel with mass deployment by relevant agencies in attempts to contain the pandemic without unnecessary regulatory delays as benefits far outweigh risks or costs.
Sun, 1 March 2020
REVIEW | doi:10.20944/preprints202003.0001.v1
Subject: Medicine & Pharmacology, Other Keywords: emerging coronavirus; 2019-nCoV; SARS-CoV-2; COVID-19; diagnosis; vaccines; therapy; one health
Online: 1 March 2020 (02:48:13 CET)
In the past decades, several new diseases have emerged in new geographical areas, with pathogens including Ebola, Zika, Nipah, and coronaviruses (CoV). Recently, a new type of viral infection has emerged in Wuhan City, China, and initial genomic sequencing data of this virus does not match with previously sequenced CoVs, suggesting a novel CoV strain (2019-nCoV), which has now been termed as severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Although CoV disease 2019 (COVID-19) is suspected to originate from an animal host (zoonotic origin) followed by human-to-human transmission, the possibility of other routes such as food-borne transmission should not be ruled out. Compared to diseases caused by previously known human CoVs, COVID-19 shows a less severe pathogenesis but higher transmission competence, as is evident from the continuously increasing number of confirmed cases. Compared to other emerging viruses such as Ebola virus, avian H7N9, SARS-CoV, or MERS-CoV, SARS-CoV-2 has shown relatively low pathogenicity and moderate transmissibility Codon usage studies suggest that this novel virus may have been transferred from an animal source such as bats. Early diagnosis by real-time PCR and next-generation sequencing has facilitated the identification of the pathogen at an early stage. Since no antiviral drug or vaccine exists to treat or prevent SARS-CoV-2, potential therapeutic strategies that are currently being evaluated predominantly stem from previous experience with treating SARS-CoV, MERS-CoV, and other emerging viral diseases. In this review, we address epidemiological, diagnostic, clinical, and therapeutic aspects, including perspectives of vaccines and preventive measures that have already been globally recommended.
Sat, 29 February 2020
BRIEF REPORT | doi:10.20944/preprints202002.0242.v2
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-19; molecular docking; HIV protease inhibitor; nucleotide analogues
Online: 29 February 2020 (12:43:40 CET)
The outbreak of novel coronavirus (COVID-19) infections in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking to repurpose HIV protease inhibitors and nucleoside analogues for COVID-19, with evaluations based on docking scores calculated by AutoDock Vina and RosettaCommons. Our results suggest that Indinavir and Remdesivir possess the best docking scores, and comparison of the docking sites of the two drugs reveal a near perfect dock in the overlapping region of the protein pockets. After further investigation of the functional regions inferred from the proteins of SARS coronavirus, we discovered that Indinavir does not dock on any active sites of the protease, which may give rise to concern in regards to the efficacy of Indinavir. On the other hand, the docking site of Remdesivir is not compatible with any known functional regions, including template binding motifs, polymerization motifs and nucleoside triphosphate (NTP) binding motifs. However, when we tested the active form (CHEMBL2016761) of Remdesivir, the docking site revealed a perfect dock in the overlapping region of the NTP binding motif. This result suggests that Remdesivir could be a potential therapeutic agent. Clinical trials still must be done in order to confirm the curative effect of these drugs.
Tue, 7 April 2020
REVIEW | doi:10.20944/preprints202004.0103.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Coronavirus; SARS-CoV-2; Medical Laboratory; Resource-limited setting, Good Laboratory Practice (GLP)
Online: 7 April 2020 (12:11:35 CEST)
The 2019 Coronavirus pandemic which was initially referred to as 2019-nCoV, was first identified in Wuhan, China. Early response from the Chinese government included quarantine of infected persons, isolation and total lockdown of Wuhan province to prevent further spread. With the spread of the disease across national borders and declaration of the disease as a global pandemic, there has been a robust response by the international community to contain this deadly virus and prevent its further spread worldwide. Africa is not left out of this rampaging pandemic with documented cases in over 40 countries and still rising. Although extensive studies have been carried out on the novel SARS-CoV-2 on its pathogenesis, mode of infection and virulence but much is still unknown. However, potentially infectious samples are received routinely in the medical laboratory for analysis. This technical note reviews good laboratory practice (GLP) and processes across the different specialities of Medical Laboratory practice that should minimize the risk of infection to laboratory staff especially in resource-limited settings.
Mon, 23 March 2020
REVIEW | doi:10.20944/preprints202003.0346.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; nCoV 19; oxidative stress; PARP; PARG; TRPM2
Online: 23 March 2020 (07:40:50 CET)
The emerging new Coronaviridae member, nCoV 19, outbreak announced a pandemic by WHO with an increased morbidity and mortality rate worldwide. nCoV 19 known as the third highly pathogen coronavirus in the human population after the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), the nCoV 19. The renin-angiotensin (RAS) signaling pathway, oxidative stress and cell death, cytokines storm and endothelial dysfunction are four major pathways involved in the pathogenesis of nCoV 19. Acute respiratory distress syndrome (ARDS) generally develops with a massive oxidative/nitrosative stress following virus entry and RAS activation. The DNA damage subsequent to oxidative burst activates poly-ADP ribose polymerase-1 (PARP-1), viral macrodomain (NSP3) poly (ADP-ribose) glycohydrolase (PARG) and transient receptor potential channel, melastatin 2 (TRPM2) in a sequential manner ultimately leading to apoptosis and necrosis due to NAD and ATP depletion. Regarding the molecular mechanisms involved in nCoV 19 pathogenesis, angiotensin II receptor blockers and/or PARP, PARG and TRPM2 blockers could be engaged as therapeutic candidates for inhibition of RAS and quenching oxidative stress, respectively. In this review, the molecular aspects of nCoV 19 pathogenesis would be studied precisely and possible therapeutic targets would be proposed. It is recommended to evaluate the proposed drugs and supplements via registered clinical trials along with conventional guideline-based multi-drug regimen.
Sun, 23 February 2020
ARTICLE | doi:10.20944/preprints202002.0315.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; adipose tissue; cancer; ACE2
Online: 23 February 2020 (10:30:06 CET)
The spread of 2019 novel coronavirus disease (COVID-19) throughout the world has been a severe challenge for public health. The human angiotensin-converting enzyme 2 (ACE2) has a remarkably high affinity binding to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the search for network database and re-analysis of pubic data, we found the level of ACE2 expression in adipose tissue was higher than that in lung tissue, which indicated the adipose tissue might be vulnerable to SARS-CoV-2 as well; the levels of ACE2 expressed by adipocytes and adipose progenitor cells were similar between non-obese individuals and obese individuals, but obese individuals have more adiposes so as to increase the number of ACE2-expressing cells; the expression of ACE2 in tumor tissues posed by five different types of cancers increased significantly compared with that in adjacent tissues. Thus, we suggest that more attentions might be given to obese individuals and the five types of cancer patients during the outbreak of COVID-19.
Fri, 3 July 2020
ARTICLE | doi:10.20944/preprints202007.0025.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; COVID-19; outpatients; treatment; zinc; hydroxychloroquine; azithromycin
Online: 3 July 2020 (08:52:22 CEST)
Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-60; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.
Wed, 26 February 2020
Subject: Medicine & Pharmacology, Allergology Keywords: Coronavirus; SARS-CoV-2; COVID-19; Thalidomide; pneumonia
Online: 26 February 2020 (12:31:47 CET)
A novel coronavirus strain (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first appeared in December 2019 and can cause acute respiratory distress syndrome and death. However, there are only limited therapy choices and no vaccine for SARS-CoV-2 is currently available. Here we report about a case of a SARS-CoV-2 caused pneumonia successfully treated with thalidomide. Thalidomide is an immunomodulatory and anti-inflammatory agent and was combined with a low-dose glucocorticoid. We suggest, that the effects of thalidomide might be related to regulating immunity, inhibiting the inflammatory cytokine surge, alleviating anxiety to reduce oxygen consumption, relieving vomit and lung exudation.
Mon, 30 March 2020
REVIEW | doi:10.20944/preprints202003.0235.v2
Subject: Medicine & Pharmacology, Nutrition Keywords: acute respiratory distress syndrome (ARDS); ascorbic acid; cathelicidin; coronavirus; COVID-19; cytokine storm; influenza; observational; pneumonia, prevention; respiratory tract infection; solar radiation; treatment; UVB; vitamin C; vitamin D
Online: 30 March 2020 (05:48:43 CEST)
The world is in the grips of the COVID-19 pandemic. Public health measures that can reduce the risk of infection and death in addition to quarantines are desperately needed. This article reviews the roles of vitamin D in reducing risk of respiratory tract infections, knowledge about the epidemiology of influenza and COVID-19, and how vitamin D supplementation might be a useful measure to reduce risk. Through several mechanisms, vitamin D can reduce risk of infections. Those mechanisms include inducing cathelicidins and defensins that can lower viral replication rates and reducing concentrations of pro-inflammatory cytokines that produce the inflammation that injures the lining of the lungs, leading to pneumonia, as well as increase concentrations of anti-inflammatory cytokines. Several observational studies and clinical trials reported that vitamin D supplementation reduced risk of influenza, whereas others did not. Evidence supporting the role of vitamin D in reducing risk of COVID-19 includes that the outbreak occurred in winter, a time when 25-hydroxyvitamin D [25(OH)D] concentrations are lowest; that the number of cases in the Southern Hemisphere near the end of summer are low; that vitamin D deficiency has been found to contribute to acute respiratory distress syndrome, and that case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with lower 25(OH)D concentration. To reduce risk of infection, it is recommended that people at risk of influenza and/or COVID-19 consider taking 10,000 IU/d of vitamin D3 for a few weeks to rapidly raise 25(OH)D concentrations, followed by 5000 IU/d. The goal should be to raise 25(OH)D concentrations above 40–60 ng/ml (100–150 nmol/l). For treatment of people who become infected with COVID-19, higher vitamin D3 doses might be useful. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations.
Fri, 20 March 2020
ARTICLE | doi:10.20944/preprints202003.0302.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-2019; SARS-CoV-2; 2019-nCoV; repositioning; UPR/Autophagy; real-world evidence; pathways
Online: 20 March 2020 (03:55:55 CET)
More than 179,000 individuals have fallen ill of the Coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus, which first emerged in China less than four months ago in December 2019. As of today, there exist no approved treatments against COVID-19. Vaccines are being developed, but they will take time, at least one year, to reach the population. Drug repositioning represents a fast track because already approved medicines have been broadly tested through multiple trials. We developed a repositioning strategy that mostly leads to candidates that are commonly used. The advantages are that they will facilitate proof of concept in humans through a “real-world evidence” approach and should be rapidly available to the population. We focus on the established research results that the unfolded protein response (UPR) and autophagy pathways of the host cells are essential to the life cycle of previously known coronaviruses. We performed the relevant bioinformatics analysis to understand and confirm if SARS-CoV-2 may interact with these druggable pathways. Based on these considerations, we prioritized two additional druggable pathways, which are important to the viral life cycle and tightly connected to UPR/autophagy signaling: the mitochondrial permeability transition pores (MPTP) and NLRP-3 inflammasome pathways. These four important pathways are perturbed in most major common diseases and have therefore been targeted by numerous broadly prescribed drugs. We have identified 97 approved drugs that are known to modulate these four identified pathways, and which represent, therefore, interesting repositioning candidates. Although it is indisputable that these drugs should never be used for immediate self-medication against COVID-19, we notice that some of them could also be prescribed to individuals who have COVID-19 comorbidities (e.g., hypertension). It is debated if these comorbidities are linked to the pathology itself (e.g., hypertension) or the drugs used to treat the pathology (e.g., sartans). Therefore, relevant preclinical tests and massive electronic health records (i.e., real-world evidence) must be used to pre-screen them and check the COVID-19 prognosis of individuals taking these drugs.
Thu, 12 March 2020
ARTICLE | doi:10.20944/preprints202003.0206.v1
Subject: Medicine & Pharmacology, Other Keywords: 2019 novel coronavirus infection; coronavirus; SARS-CoV; interferon; systems biology
Online: 12 March 2020 (09:11:00 CET)
As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Thus, gaining more knowledge on the pathogenicity mechanism of SARS-CoV-2, the causing agent of COVID-19, and its interaction with the immune system is of utmost importance. Although this novel virus is not well known yet, its structural and genetic similarity with SARS-CoV as well as the comparable pattern of age-mortality relations suggest that the previous findings on SARS can be applicable for COVID-19. Therefore, a systems biology study was conducted to investigate the underlying mechanism for the differences in the age-specific mortality of SARS and the most important signaling pathways activated by the virus. The results were then validated through a literature review on COVID-19 and the other closely related viruses, SARS and MERS. Interferons have shown to possess a crucial role in the defense against coronavirus diseases. The virus can impede the interferon induction in humans. Moreover, STAT1, a key protein in the interferon mediated immune response, is antagonized by the virus. This could explain the increased response threshold of immune cells to IFNs during CoV infections. A vivid correlation between the innate immune response threshold and the fatality rates in COVID-19 can be found. Differences in the dynamics of the interferons-related innate immune responses in children, adults and elderly may explain the reported fatality rates. The increased mortality rates in the elderly can be explained by the higher threshold of interferon-mediated immune responses. Earlier induction of interferons in children and their less developed immune system could be the reason behind their zero or near to zero fatality rate. Administration of interferon-inducing agents, such as Poly (ICLC), could reduce the mortality of SARS at the very early stages of the disease. Adding interferon-γ to an interferon-I, as a synergistic combination therapy, might maximize the benefits.At the later stages of the disease, however, the balance of the immune reactions would be disrupted and the responses would shift toward immnopathogenic over-reactions and probably cytokine storm. Moderating the activity of the immune system and supportive care in such conditions might be the optimum approach.
Tue, 14 November 2017
REVIEW | doi:10.20944/preprints201711.0081.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: Marfan; connective tissue disease; irritable bowel syndrome; hernia
Online: 14 November 2017 (04:08:45 CET)
Symptoms attributed to the gastrointestinal manifestations of multi-system disorders play an important role in the long-term management of these conditions. Gastrointestinal complications of a variety of connective tissue disorders have been studied and there is an increased interest in the incidence and prevalence of these symptoms. Descriptions of the occurrence of gastrointestinal complications in Marfan syndrome have appeared infrequently in the medical literature. In this review article we focus on both structural and functional gastrointestinal pathology that may occur in patients with Marfan syndrome.
Mon, 2 March 2020
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Novel coronavirus pneumonia; COVID-19; SARS-CoV-2; Pathology; Critical patient
Online: 2 March 2020 (15:32:55 CET)
Background Novel coronavirus pneumonia ( COVID-19) have emerged as major global health threats since December, 2019. Up to now, the histopathology of critical patient with COVID-19 remains largely undisclosed. Methods We here performed the whole lung biopsy, and described the pathological changes of one COVID-19 critical patient done with transplant by HE staining, immunohistochemistry and special staining including Masson staining, PAS staining and silver methenamin staining. Findings The whole lung tissue displayed diffuse congestive appearance or partly haemorrhagic necrosis on gross examination. The haemorrhagic necrosis was prominently present in outer edge of the right lobe of the right lung. The cut surfaces of the lung displayed severe congestive and haemorrhagic changes. The main pathological lung changes showed bronchiolitis and alveolitis with proliferation, atrophy, desquamation and squamous metaplasia of epithelial cells. Massive pulmonary interstitial fibrosis, and partly hyaline degeneration, variable degrees of hemorrhagic pulmonary infarction. Small vessels hyperplasia, vessel wall thickening, lumen stenosis, occlusion and microthrombosis formation. Focal monocytes, lymphocytes and plasma cells infiltrating into pulmonary interstitium. Atrophy, vacuolar degeneration, proliferation, desquamation and squamous metaplasia in alveolar epithelial cells. Alveolar cavity congestion was prominent, and contained mucus, edema fluid, desquamated epithelial cells, and inflammatory cells. We can also found several multinucleate giant cells and intracytoplasmic viral inclusion bodies. Masson staining indicated massive pulmonary interstitial fibrosis. Immunohistochemistry results showed positive for immunity cells including CD3, CD4, CD8, CD20, CD79a, CD5, CD38 and CD68. Interpretation We show clinical pathology biopsy of critical patient with COVID-19, which might provide a deep insight of the pathogenesis and the severity of this disease.
Sun, 31 May 2020
ARTICLE | doi:10.20944/preprints202005.0486.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; azithromycin; hydroxychloroquine; primary care
Online: 31 May 2020 (17:51:52 CEST)
The challenge regarding COVID-19 is to prevent complications and fatal evolution. Azithromycin (AZM) and hydroxychloroquine (HCQ) have proven their antiviral effect in vitro. We aimed to assess the efficacy and safety of AZM alone or combined to HCQ, prescribed, at an early stage, in patients with Covid-19, in a primary care setting. Eighty-eight patients received either no or a symptomatic treatment (NST) (n=34) or AZM alone (n=34) or AZM+HCQ (n=20). The efficacy end point was the time to clinical recovery and the safety end point was the occurrence of cardiovascular events. The mean (SD) times to achieve clinical recovery were respectively 25.8 days (11.1), 12.9 days (13.4) and 9.2 days (9.3), showing a statistically significant difference between NST and AZM alone (p<0.0001) or AZM+HCQ (p<0.0001). To improve the evidence level, a case-control analysis was performed on a sample of 57 patients (19/group) matched for age, sex and BMI. The statistical difference between NST and AZM was confirmed (p=0.0149) as well as the difference with AZM+HCQ (p=0.0002). No cardiac toxicity was recorded in any patient. No statistical difference was shown between AZM and AZM+HCQ groups, although the dual therapy tended to be more effective in patients over 50 years, based on an analysis using the cox model. In conclusion, AZM and AZM+HCQ favourably impacted the course of the disease. We need trials, ideally prospective/double blind, to show if a statistical difference can be evidenced with a broader group, and clarify the indications of each treatment depending on initial clinical presentation.
Tue, 7 April 2020
REVIEW | doi:10.20944/preprints202004.0077.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; native American Indian; treatment; ACE2 receptor; pathophysiology; virulence
Online: 7 April 2020 (02:40:24 CEST)
Background: On Dec 19, 2019 it was reported by the public health department of China that an outbreak of pneumonia was caused by a novel Coronavirus. The virulence of the new virus COVID-19 was much greater than either the SARs or MERSs viruses and on March 11, 2020 the World Health Department (WHO) declared world -wide pandemic. Understanding the pathophysiology of virulence of the COVID-19 virus is absolutely necessary in understanding the transmission, virulence factors, reduce risk factors, clinical presentation, predict outcomes of the disease and provide guidance to any current or future treatment protocols. Methodology: A PubMed search was performed utilizing the words: Wuhan Virus, COVID-19, SARs coronavirus, ACE2, S protein, virulence, clinical presentation, epidemiology, genome, treatment, structure, MERs, pathogenesis and/or pathology alone and in combination with other terms. Each paper was evaluated by three content experts for quality, reproducibility, credibility and reputation of the journal. Results: The COVID-19 virus is much more virulent than either the SARs or MERs virus and its ability to cause serious disease inversely corresponds to the person’s ability to produce T-cells which declines linearly with age. The ACE2 receptor binding site do not vary among different ethnic groups but do in expression levels. This variance in expression level may explain for different infectivity rates among men and women and predict and explain different susceptibilities to infection by different ethnic groups. Furthermore, by understanding the underlying pathophysiology one can explain and provide guidance to the clinical effectiveness of any treatment. Conclusions: The underlying pathophysiology of COVID-19 explains not only the virulence, and clinical presentation, but, explains at a molecular level the comorbidity risk factors such as hypertension, sex, and age. Ethnic and anatomic expression patterns of ACE-2 and associated pathophysiology suggests that Native Americans and Asians may be particularly susceptible to this disease.
Mon, 9 March 2020
COMMUNICATION | doi:10.20944/preprints202002.0418.v2
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: virtual screening; molecular docking; drug repurposing; drug repositioning; anti-viral drugs; Coronavirus; COVID-19; 2019-nCoV; SARS-CoV-2
Online: 9 March 2020 (02:29:04 CET)
SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using molecular docking based virtual screening of all approved drugs. The results of this study confirm preliminary reports that some of the drugs approved for treatment of other viral infections have the potential for treatment of COVID-19. Selected antiviral drugs, approved for human therapeutic applications, were ranked for potential effectiveness against COVID-19, based on predicted binding energy to the target Mpro of SARS-CoV-2, and novel candidates for drug repurposing were identified in this study. In addition, potential mechanisms for beneficial off target effects of some drugs in clinical trials were identified by using molecular docking.
Mon, 24 April 2017
ARTICLE | doi:10.20944/preprints201704.0145.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: emotion and will; music therapy; five phases; five phases music therapy; psychology
Online: 24 April 2017 (05:37:45 CEST)
Music therapy has served as complementary and alternative medicine for various neurological disorders. Five Phases Music Therapy (FPMT) employs the theory of five phases and five music scales or tones (Gong (do), Shang (ri), Jue (mi), Zhi (so) and Yu (la)) to analyze and treat mind-body illness. In Chinese Medicine (CM) the five music scales are used to connect the human body and the universe, summarize personalities and constitution and analyze the influences of climatic changes on health. FPMT has a self-contained theory and routine of practice application. Large amount of clinical and fundamental reports has been available and clinical benefits have been obtained. However more systemic clinic research esp. Evidence-based and random controlled trials must be performed to validate and optimize it’s routines and biological and neurological mechanism must be further explored. It’s reasonable to believe that the introduction of FPMT to the world outside China may attract more attentions to use this effective music therapy.
Sun, 23 February 2020
Subject: Medicine & Pharmacology, Nutrition Keywords: citrus flavnoids; naringin; immunoregulation; ACE2; 2019-nCoV
Online: 23 February 2020 (09:49:10 CET)
The most recent outbreak of 2019 novel coronavirus, named as COVID-19, caused pneumonia epidemic in Wuhan with 2,121 deaths cases as of February 20th 2020. Identification of effective antiviral agents to combat the novel coronavirus is urgently needed. Citrus fruit peel or wild citrus are rich in flavonoid, and is clinically documented for roles in relief of cough and promotion of digestive health. Therefore, citrus fruits are assumed to possess antivirus activities or enhance the host immunity. A previous study found that hesperetin could act as a high potent inhibitor of SARS-CoV 3CLpro. We determined six flavonoid compounds content of in three citrus species by using LC-MS technique. The content of naringin and naringenin was at higher levels in pummelo. Hesperetin and hesperidin were highly accumulated in mandarin and sweet orange. The subsequent in vitro and in vivo experiments indicated that naringin could inhibit the expression of the proinflammatory cytokines (COX-2, iNOS, IL-1β and IL-6) induced by LPS in Raw macrophage cell line, and may restrain cytokine through inhibiting HMGB1 expression in a mouse model. The results revealed that naringin may have a potential application for preventing cytokine storm. We simulated molecular docking to predict the binding affinity of those flavonoids to bind Angiotensin-converting enzyme 2 (ACE 2), which is a receptor of the coronavirus. Consideration of the potential anti-coronavirus and anti-inflammatory activity of flavonoids, the citrus fruit or its derived phytochemicals are promising in the use of prevention and treatment of 2019-nCoV infection.
Mon, 10 July 2017
ARTICLE | doi:10.20944/preprints201707.0014.v1
Subject: Medicine & Pharmacology, Behavioral Neuroscience Keywords: network; topology; integration; segregation; fMRI
Online: 10 July 2017 (05:48:41 CEST)
Recent methodological advances have enabled researchers to track the network structure of the human brain over time. Together, these studies provide novel insights into effective brain function, highlighting the importance of the systems-level perspective in understanding the manner in which the human brain organizes its activity to facilitate behavior. Here, we review a range of recent fMRI and electrophysiological studies that have mapped the relationship between inter-regional communication and network structure across a diverse range of brain states. In doing so, we identify both behavioral and biological axes that may underlie the tendency for network reconfiguration. We conclude our review by providing suggestions for future research endeavors that may help to refine our understanding of the functioning of the human brain.
Thu, 16 April 2020
REVIEW | doi:10.20944/preprints202004.0283.v1
Subject: Medicine & Pharmacology, Other Keywords: Covid-19; coronavirus; SARS-CoV-2; review; pandemic
Online: 16 April 2020 (15:55:12 CEST)
Coronaviruses are an extensive family of viruses that can cause disease in both animals and humans. The current classification of coronaviruses recognizes 39 species in 27 subgenera that belong to the family Coronaviridae. From those, at least seven coronaviruses are known to cause respiratory infections in humans. Four of these viruses can cause common cold-like symptoms, while others that infect animals can evolve and become infectious to humans. Three recent examples of this viral jumps include SARS CoV, MERS-CoV and SARS CoV-2 virus. They are responsible for causing severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and the most recently discovered coronavirus disease during 2019 (COVID-19).COVID-19, a respiratory disease caused by the SARS-CoV-2 virus, was declared a pandemic by the World Health Organization (WHO) on 11 March 2020. The rapid spread of the disease has taken the scientific and medical community by surprise. Latest figures from 14 April 2020 show more than 2 million people had been infected with the virus, causing more than 120,000 deaths in over 210 countries worldwide. The large amount of information we receive every day concerning this new disease is so abundant and dynamic that medical staff, health authorities, academics and the media are not able to keep up with this new pandemic. In order to offer a clear insight of the extensive literature available, we have conducted a comprehensive literature review of the SARS CoV-2 Virus and the Coronavirus Diseases 2019 (COVID-19).
Fri, 20 March 2020
ARTICLE | doi:10.20944/preprints202003.0311.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2; COVID-19; pathology; post-mortem biopsy
Online: 20 March 2020 (09:24:10 CET)
Data on pathologic changes of the 2019 novel coronavirus disease (COVID-19) are scarce. To gain knowledge about the pathology that may contribute to disease progression and fatality, we performed post-mortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. The patients’ ages ranged from 59 to 81, including 3 males and 1 female. Each patient had at least one underlying disease, including immunocompromised status (chronic lymphocytic leukemia and renal transplantation) or other conditions (cirrhosis, hypertension, and diabetes). Time from disease onset to death ranged from 15 to 52 days. All patients had elevated white blood cell counts, with significant rise toward the end, and all had lymphocytopenia except for the patient with leukemia. Histologically, the main findings are in the lungs, including injury to the alveolar epithelial cells, hyaline membrane formation, and hyperplasia of type II pneumocytes, all components of diffuse alveolar damage. Consolidation by fibroblastic proliferation with extracellular matrix and fibrin forming clusters in airspaces is evident. In one patient, the consolidation consists of abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia. The liver exhibits mild lobular infiltration by small lymphocytes, and centrilobular sinusoidal dilation. Patchy necrosis is also seen. The heart shows only focal mild fibrosis and mild myocardial hypertrophy, changes likely related to the underlying conditions. In conclusion, the post-mortem examinations show advanced diffuse alveolar damage, as well as superimposed bacterial pneumonia in some patients. Changes in the liver and heart are likely secondary or related to the underlying diseases.
Mon, 5 September 2016
ARTICLE | doi:10.20944/preprints201609.0018.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: polyphenols, flavonoids, seaweeds, antioxidant activity, anticancer activity
Online: 5 September 2016 (14:23:52 CEST)
Seaweeds are considered as one of the largest biomass producers in marine environment that is rich in bioactive metabolites and a source of natural ingredients for functional foods. The potential antioxidant activity and the potential inhibition of Caco2 cell proliferation, of crude extracts of: Chlorophyta (Ulva lactuca, and Codium tomentosum), Phaeophyta (Cystoseira crinita, Cystoseira stricta, and Sargassum vulgare), and Rhodophyta (Gelidium latifolium, Hypnea musciformis, and Jania rubens) collected from western Libyan coast were evaluated in vitro. The antioxidant activity was determined by reducing power and DPPH assays while cell proliferation, morphological changes and the cell cycle arrest were assessed by MTT, inverted light microscope and flow cytometry methods respectively. The polyphenols and flavonoids rich extracts showed remarkable reducing power and antiradical properties. After exposure of Caco2 cells to; various concentrations of extracts (50, 100,150 and 200 µg/mL) especially from brown algae for 72 h, significantly reduced cell proliferation. The antiproliferative effect of algae extracts was correlated with their polyphenol and flavonoid contents. Cell cycle analysis further showed that cells were arrested in G phases along with an increment in sub-diploidal cell population (sub-G) after extract application. These results imply that seaweeds which are rich in bioactive compounds may be in anticancer drug research programs. However, further investigations are essential to reveal the molecular mechanisms of the anticancer activities of these algae.
Tue, 4 June 2019
ARTICLE | doi:10.20944/preprints201906.0030.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: autism; autistic spectrum disorder; children; behavior; ultrasonography; prenatal; pregnancy
Online: 4 June 2019 (12:56:37 CEST)
For the past several decades, abdominal prenatal ultrasonography has been the most significant technology in obstetrics with a long-established application. However, the frequency, exposure time, thermal and cavitation exposure indices, and increased acoustic output of the ultrasonic waves may be harmful to the embryo/fetus and might increase susceptibility to Autism Spectrum Disorder (ASD). The increase in the prevalence of ASD is associated with an affluent ethnicity, high socioeconomic status, and high parental education where prenatal ultrasonography is readily available and affordable. Enhanced biophysical adverse effects may link the analogous increase in prenatal ultrasonography and autism, and prenatal ultrasonography may emerge as a risk factor for autism. Radiography usage provides historical evidence for this fact: the predominant past opinion was that exposure to X-rays during pregnancy caused no significant risk to a fetus. However, the association between X-ray exposure and childhood leukemia was only established 40 years after X-ray use began. This review focuses on excessive PUS usage and ASD development. Public Abstract Advancements in medical technology over the past several decades have made prenatal ultrasound more frequently accessible to expecting mothers during their pregnancy, especially for the affluent. A parallel development in health care is the increase in autism diagnoses (Autism Spectrum Disorder, or ASD) in children of affluent families. There is a general lack of studies of the impact of prenatal ultrasound on fetuses, especially around varying attributes such as frequency, duration of exposure, and thermal and cavitation indices. There is also a historical precedent set, where exposing fetuses to X-rays was not found to be harmful until it was linked to the development of childhood leukemia decades later. This paper seeks to establish a need to further study these attributes of prenatal ultrasound overuse and their possible impact on a developing fetus, with a special focus on the occurrence of Autism.
Wed, 18 March 2020
ARTICLE | doi:10.20944/preprints202003.0286.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-2019; SARS-CoV-2; repurposing; network bioinformatics
Online: 18 March 2020 (08:50:10 CET)
The COVID-2019 disease caused by the SARS-CoV-2 virus (aka 2019-nCoV) has raised significant health concerns in China and worldwide. While novel drug discovery and vaccine studies are long, repurposing old drugs against the COVID-2019 epidemic can help identify treatments, with known preclinical, pharmacokinetic, pharmacodynamic, and toxicity profiles, which can rapidly enter Phase 3 or 4 or can be used directly in clinical settings. In this study, we presented a novel network based drug repurposing platform to identify potential drugs for the treatment of COVID-2019. We first analysed the genome sequence of SARS-CoV-2 and identified SARS as the closest disease, based on genome similarity between both causal viruses, followed by MERS and other human coronavirus diseases. Using our AutoSeed pipeline (text mining and database searches), we obtained 34 COVID-2019-related genes. Taking those genes as seeds, we automatically built a molecular network for which our module detection and drug prioritization algorithms identified 24 disease-related human pathways, five modules and finally suggested 78 drugs to repurpose. Following manual filtering based on clinical knowledge, we re-prioritized 30 potential repurposable drugs against COVID-2019 (including pseudoephedrine, andrographolide, chloroquine, abacavir, and thalidomide) . We hope that this data can provide critical insights into SARS-CoV-2 biology and help design rapid clinical trials of treatments against COVID-2019.
Sun, 16 February 2020
ARTICLE | doi:10.20944/preprints202002.0220.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: coronavirus; COVID-19 pneumonia; pathology; SARS-CoV-2
Online: 16 February 2020 (14:41:28 CET)
There is currently a lack of pathologic data on the SARS-CoV-2 pneumonia, or COVID-19, from autopsy or biopsy. Two patients who recently underwent lung lobectomies for adenocarcinoma were retrospectively found to have had COVID-19 at the time of surgery. These two cases thus provide important first opportunities to study the pathology of COVID-19. Pathologic examinations revealed that, apart from the tumors, the lungs of both patients exhibited edema, proteinaceous exudate with globules, focal hyperplasia of pneumocytes with only patchy inflammatory cellular infiltration, and multinucleated giant cells. Hyaline membranes were not prominent. Since both patients did not exhibit symptoms of pneumonia at the time of surgery, these changes likely represent an early phase of the lung pathology of COVID-19 pneumonia.
Thu, 19 March 2020
BRIEF REPORT | doi:10.20944/preprints202003.0295.v1
Subject: Medicine & Pharmacology, Other Keywords: Wuhan 2019-nCoV; ACE2; DNA methylation; epigenetics; profiling; lung tissue; age; gender; COVID-19; coronavirus
Online: 19 March 2020 (02:51:45 CET)
Background: Coronavirus disease 2019 (COVID-19) has emerged as a global threat to human health and disease risk increases with advancing age. The regulation of the ACE2 gene that codes for COVID-19 host receptor ACE2 has been shown to be under epigenetic regulation. Here, we examined whether intensive DNA methylation profiling of the ACE2 gene differed by human host tissue and cell type, gender, and age. Results: Accessing four public datasets, we observed unique human cell-type-specific ACE2 DNA methylation patterns. In human lung tissues, gender differences in DNA methylation at 2 sites related to the ACE2 gene were identified. Further, in freshly isolated airway epithelial cells, DNA methylation near the transcription start site of the ACE2 gene associated with biological age. Conclusion: Epigenetic profiling of host tissue may permit discovery of age and gender-related potential risk factors for COVID-19. How perturbations in ACE2 methylation relate to clinical severity across the ages and gender needs to be determined to guide screening tools and potential epigenetic modification targeting to alleviate COVID-19 morbidity in the elderly.
Mon, 5 September 2016
REVIEW | doi:10.20944/preprints201609.0013.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Camellia sinensis; tea ploysaccharides; chemical composition; antioxidant; antitumors; antihyperglycemia; anti-inflammation
Online: 5 September 2016 (10:19:33 CEST)
Tea (Camellia sinenesis) is a health beneficial beverage and is also a source for extracting bioactive components such as theanine, tea polyphenols (TPP) and tea polysaccharides (TPS). TPS is a group of hetero-polysaccharides bounded with proteins. There were tests showing that TPS had various bioactivities, such as antioxidant, antitumors, antihyperglycemia, anti-inflammation and improving immunity. However, inconsistent results concerning chemical composition and bioactivity of TPS were published in recent years. The advances in chemical composition and bioactivities of TPS were reviewed in the present paper. The inconsistent and controversial results regarding composition and bioactivities of TPS were also discussed.
Fri, 23 December 2016
REVIEW | doi:10.20944/preprints201612.0119.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: antibiotic; bacteroidetes; dietary emulsifier; firmicutes; food additive; gut microbiota; non-nutritive sweetener; proteobacteria
Online: 23 December 2016 (11:21:40 CET)
Gut bacteria play an important role in several metabolic processes and human diseases, such as obesity and its co-morbidities, like fatty liver disease, insulin resistance/diabetes and cardiovascular events. Among several factors, dietary patterns, probiotics, prebiotics, synbiotics, antimicrobials and non-dietary factors, such as stress, age, exercise and climatic conditions, can dramatically impact the human gut microbiota diversity and equilibrium. However, the effect of minor food constituents, including food additives and trace contaminants, on human gut microbiota has received less attention. Consequently, the present review aimed to provide an objective perspective of the current knowledge regarding the impacts of minor food constituents on human gut microbiota and consequently, on human health.
Thu, 27 September 2018
ARTICLE | doi:10.20944/preprints201809.0544.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: Bodybuilding; Drug Free; Competing; Peaking; Carbohydrate Loading; Water Loading; Sodium Loading; Fat Loading: Vitamin C; Fibre Restriction
Online: 27 September 2018 (12:58:34 CEST)
Bodybuilders utilize peaking strategies in a bid to fine-tune their aesthetics for competition day. The most prevalent peaking strategies utilized by natural bodybuilders are unreported in the current literature. Eighty-one (M - 59, F - 22) natural bodybuilders were recruited from competitions during the 2016 and 2017 British Natural Bodybuilder Federation seasons. Competitors completed a 34-item questionnaire designed to investigate peaking and contest day strategies. The questionnaire listed commonly utilized peaking strategies and provided additional space for qualitative information. Analysis of the data indicated that carbohydrate (CHO), water and sodium manipulation were the most commonly utilized peak week strategies. The consumption of high glycemic index CHO was the most common competition day strategy. Only 6.2 % of competitors reported following their regular diet the week prior to competition. The CHO manipulation strategies were similar to classical CHO loading, whereby bodybuilders attempt to maximize muscle glycogen concentrations. Furthermore, bodybuilders attempted to remove superfluous water by exploiting the diuretic/polyuria effect associated with water loading/restriction. The potentially deleterious effects of peaking on bodybuilders' health is considered and the efficacy of these strategies to enhance appearance is discussed. The findings of the present investigation are likely to be of interest to bodybuilders and their coaches.
Sat, 25 April 2020
ARTICLE | doi:10.20944/preprints202004.0457.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-19; vitamin K; vitamin K antagonists; SARS-CoV-2; matrix Gla protein; desmosine; protein C; protein S
Online: 25 April 2020 (03:13:45 CEST)
Introduction: Coronavirus 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2. The majority of patients have at most mild symptoms, however, a significant proportion develops respiratory failure. COVID-19 may also progress beyond the lungs. Coagulopathy and thromboembolism are prevalent in severe COVID-19 and relate to decreased survival. Coagulation is an intricate balance between clot promoting and dissolving processes in which vitamin K plays a well-known role. We hypothesized that vitamin K status is reduced in patients with severe COVID-19. Methods: Vitamin K status was assessed by measuring desphospho-uncarboxylated matrix Gla protein (dp-ucMGP; inversely related to vitamin K status) and the rate of elastin degradation by measuring desmosine. We included 123 patients who were admitted with COVID-19 and 184 controls. Results: Dp-ucMGP levels were significantly elevated in COVID-19 patients (1,673Å}1,584 pmol/L) compared to controls (536±291 pmol/L; p<0.0005). Dp-ucMGP levels were significantly higher in COVID-19 patients with unfavorable outcome compared to those with less severe disease. Furthermore, dp-ucMGP and desmosine levels were significantly associated (r=0.65; p<0.0005). Conclusions: Vitamin K status was reduced in patients with COVID-19 and related to poor prognosis. Also, low vitamin K status seems to be associated with accelerated elastin degradation. An intervention trial is now needed to assess whether vitamin K administration improves outcome in patients with COVID-19.
Mon, 6 April 2020
ARTICLE | doi:10.20944/preprints202004.0058.v1
Subject: Medicine & Pharmacology, Other Keywords: coronavirus disease 2019 (COVID-19); school closure; time series analysis; Japan
Online: 6 April 2020 (13:11:12 CEST)
Background: Coronavirus disease 2019 (COVID-19) pandemic are causing significant damages to many nations. For mitigating its risk, Japan’s Prime Minister called on all elementary, junior high and high schools nationwide to close beginning March 1, 2020. However, its effectiveness in decreasing disease burden has not been investigated. Methods: We used daily data on the report of COVID-19 and coronavirus infection incidence in Japan until March 31, 2020. Time series analysis were conducted using Bayesian method. Local linear trend models with interventional effect were constructed for number of newly reported cases of COVID-19, including asymptomatic infections. We considered that the effects of intervention start to appear 9 days after the school closure; i.e., on March 9. Results: The intervention of school closure did not appear to decrease the incidence of coronavirus infection. If the effectiveness of school closure began on March 9, mean coefficient α for effectiveness of the measure was calculated to be 0.08 (95% credible interval -0.36 to 0.65), and the actual reported cases were more than predicted, yet with rather wide credible interval. Sensitivity analyses using different dates also showed similar results. Conclusions: School closure carried out in Japan did not show the effectiveness to mitigate the transmission of novel coronavirus infection.
Tue, 4 February 2020
ARTICLE | doi:10.20944/preprints202002.0047.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: 2019-nCoV; therapeutic strategies; drug; ACE2
Online: 4 February 2020 (10:59:25 CET)
Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Many important aspects about 2019-nCoV remain largely unknown, among which, the limitation of antiviral therapies represents one of the most critical problems. More recently, it was confirmed that human ACE2 is the receptor for the entry of 2019-nCoV into lower respiratory tract epithelial cells. Give this observation, it is thus expected that the virus could be inhibited if we decrease the expression of ACE2. Here by screening two databases, Connectivity Map (CMap) and our JeaMoon Map (JMap), we identified a number of candidate agents that decrease ACE2 expression. CMap analysis identified 5 compounds, among which, Azathioprine is a possible therapeutic strategy for anti-2019-nCoV. Moreover, JMap analysis revealed a number of comounds, biologics, and traditional Chinese medicine, among which, Andrographis, Urtica, Sambucus, Astragalus, valproic acid, butyrate, and epoxomicin represent the most significant and possible strategies for anti-2019-nCoV therapies. This study provides a number of clues and possible therapeutic strategies for 2019-nCoV prevention and treatment.
Sun, 22 January 2017
REVIEW | doi:10.20944/preprints201701.0094.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: theranostics; nuclear medicine; personalized medicine
Online: 22 January 2017 (04:29:27 CET)
The importance of personalized medicine is growing, since there is an urged need to avoid unnecessary and expensive treatments. In nuclear medicine, the theranostic approach is an established tool for a specific molecular targeting in means of diagnostics and therapy. The visualisation of potential targets can help to predict if a patient would benefit from a particular treatment or not. Thanks to the quick development of radiopharmaceuticals and diagnostic techniques, the use of theranostic agents is constantly rising. In this article important milestones of nuclear therapies and diagnostics in the context of theranostics are highlighted. It begins with the well-known radioiodine therapy in patients with thyroid cancer and then guides through different approaches for the treatment of advanced cancer with targeted therapies. The aim of this review is to provide a summary of background knowledge, current applications and advantages of targeted therapies and imaging in nuclear medicine practice.
Thu, 27 February 2020
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Novel coronavirus pneumonia; COVID-19; SARS-CoV-2; Pathology; Critical patient
Online: 27 February 2020 (12:30:45 CET)
Aim: Novel coronavirus pneumonia ( COVID-19) have emerged as major global health threats since December, 2019. Up to now, the histopathology of critical patient with COVID-19 remains largely undisclosed. Methods: We here performed lung organ dissection, and described the pathological changes of one COVID-19 critical patient by HE staining, immunohistochemistry and special staining including Masson staining, PAS staining and silver methenamin staining. Results: The whole lung tissue displayed diffuse congestive appearance or partly haemorrhagic necrosis on gross examination. The haemorrhagic necrosis was prominently present in outer edge of the right lobe of the right lung. The cut surfaces of the lung displayed severe congestive and haemorrhagic changes. The main pathological lung changes showed bronchiolitis and alveolitis with proliferation, atrophy, desquamation and squamous metaplasia of epithelial cells. Massive pulmonary interstitial fibrosis, and partly hyaline degeneration, variable degrees of hemorrhagic pulmonary infarction. Small vessels hyperplasia, vessel wall thickening, lumen stenosis and occlusion. Focal monocytes, lymphocytes and plasma cells infiltrating into pulmonary interstitium. Alveolar congestion was prominent, and contained edema fluid, desquamated epithelial cells, and inflammatory cells. Atrophy, vacuolar degeneration, proliferation, desquamation and squamous metaplasia in alveolar epithelial cells. We can also found several multinucleate giant cells and intracytoplasmic viral inclusion bodies. Masson staining indicated massive pulmonary interstitial fibrosis. Immunohistochemistry results showed positive for immunity cells including CD3, CD20, CD79a, CD4, CD8, CD5, CD68 and CD38. Conclusion: We show clinical pathology of critical patient with COVID-19, which might provide a deep insight of the pathogenesis and the severity of this disease.
Tue, 30 April 2019
REVIEW | doi:10.20944/preprints201904.0327.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: sunscreen; sunburn; UV Radiation; melanoma; photoaging
Online: 30 April 2019 (11:18:23 CEST)
The sunscreen industry is achieving remarkable worldwide prominence by responding to the growing need for skin protection with fast-paced innovation. Increased consumer awareness of the harmful effects of sunlight has fueled the demand for improved photo protection. The need for broad-spectrum protection from both UVA and UVB rays has inspired scientists worldwide to research new cosmetic formulations and delivery systems. More effective sunscreen actives, emollients and novel cosmetic and functional ingredients have been regularly added to the formulator’s repertoire. Creativity in innovation has been hindered only by regulatory agencies and patent restrictions worldwide. Familiarity with the current restrictive regulations and patent law infringements has become integral to any research effort attempting to provide improved protection to individuals affected by the sun’s damaging effects. The increasing incidence of skin cancers and photo damaging effects caused by ultraviolet radiation has increased the use of sun screening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Unlike the situation in Europe where sunscreen ingredients are considered under cosmetics guidelines, the FDA is required to define sunscreens as drugs since they are advertised to prevent sunburn and, more recently, the risk of skin cancer. In the USA, the FDA has been regulating this industry since August 25, 1978, with the publication of the Advance Notice of Proposed Rulemaking. Sunscreens are considered drugs and cosmetics and therefore must be governed by the FDA-OTC monograph. With the variety of sunscreen agents used in cosmetic and UV protection products, Australia, Canada, and the European Union (EU) have also developed regulatory protocols on safe sunscreen product use. Unlike the USA though, Australia has approved 34 active sunscreen ingredients and the EU has approved 28 of these ingredients. Current FDA regulations allow labeling of sunscreen products to a maximum of 30þ, despite the many products currently available with numbers as high as 100. From a cosmetic formulation point of view, increasing the SPF number in a product is governed by simple chemical principles.
Tue, 6 December 2016
REVIEW | doi:10.20944/preprints201612.0027.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: chatbot technology; ontology-based systems; expert systems; diagnosis; conversational agents; robotics; human-robot interaction; physician-patient relationship; intelligent agents
Online: 6 December 2016 (04:46:32 CET)
Access to medical care is a global issue. Technology-aided approaches have been applied in addressing this. Interventions have however not focused on medical diagnosis as a fully automated procedure and available applications employ mainly text-based inputs rather than conversation in natural language. We explored the utility of ontology-based chatbot technology for the design of intelligent agents for medical diagnosis through a systematic review of the most recent related literature. English articles published in 2011-2016 returned 233 hits which yielded 11 relevant articles after a 3-stage screening. Findings showed that the creation of expert systems had been the focus of many the studies which utilize the physician-system-patient framework with system training based mostly on expert knowledge for designing web- or mobile phone-based applications that serve assistive purposes. Findings further indicated gaps in the design and evaluation of more effective systems deployable as standalone applications, for example, on an embodied robotic system. The need for technology supporting the physical examination part of diagnosis, connection to data sources on patients’ vitals and medical history are also indicated in addition to the need for more qualitative work on natural language-based interaction. The system should be one that is continuously learning. Future works should also be directed towards the building of more robust knowledge base as well as evaluation of theory-based diagnostic methodological options
Tue, 21 April 2020
REVIEW | doi:10.20944/preprints202004.0383.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; coronavirus pandemic; big data; epidemic outbreak; artificial intelligence (AI); deep learning
Online: 21 April 2020 (09:01:45 CEST)
The very first infected novel coronavirus case (COVID-19) was found in Hubei, China in Dec. 2019. The COVID-19 pandemic has spread over 215 countries and areas in the world, and has significantly affected every aspect of our daily lives. At the time of writing this article, the numbers of infected cases and deaths still increase significantly and have no sign of a well-controlled situation, e.g., as of 14 April 2020, a cumulative total of 1,853,265 (118,854) infected (dead) COVID-19 cases were reported in the world. Motivated by recent advances and applications of artificial intelligence (AI) and big data in various areas, this paper aims at emphasizing their importance in responding to the COVID-19 outbreak and preventing the severe effects of the COVID-19 pandemic. We firstly present an overview of AI and big data, then identify their applications in fighting against COVID-19, next highlight challenges and issues associated with state-of-the-art solutions, and finally come up with recommendations for the communications to effectively control the COVID-19 situation. It is expected that this paper provides researchers and communities with new insights into the ways AI and big data improve the COVID-19 situation, and drives further studies in stopping the COVID-19 outbreak.
Fri, 24 April 2020
CONCEPT PAPER | doi:10.20944/preprints202004.0432.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: SARS CoV-2; COVID-19; Nitazoxanide; Azithromycin; Interferons
Online: 24 April 2020 (09:24:23 CEST)
Azithromycin has been shown to have a clinical efficacy against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2); ivermectin has also demonstrated a remarkable experimental efficacy with a potential to be used for Coronavirus disease 2019 (COVID-19). Further, BCG vaccination is being considered for clinical trials aiming to test its potential for lowering COVID-19 morbidity and mortality. This article illustrates some structural and functional relationships that may gather these drugs and the author, basing on a combined pathophysiological and pharmacological approach, recommends the FDA-approved antidiarrhea drug; nitazoxanide, which has been previously suggested but unfortunately ignored, to be tested in combination with azithromycin for their potential activity against SARS CoV-2 soonest. The author recommends testing their combined administration as early during the clinical course of COVID-19 as possible. Further, basing on the same represented concept, the author recommends more trials for interferons to be tested against SARS CoV-2 especially in severe and critical cases.
Thu, 8 March 2018
ARTICLE | doi:10.20944/preprints201803.0062.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Lyme disease; Borrelia burgdorferi; Tickborne disease; Chronic infection; Spirochete culture
Online: 8 March 2018 (07:08:02 CET)
Introduction: Lyme disease is a tickborne illness that generates controversy among medical providers and researchers. One of the key topics of debate is the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, in patients who have been treated with recommended doses of antibiotics yet remain symptomatic. Persistent spirochetal infection despite antibiotic therapy has recently been demonstrated in non-human primates. We present evidence of persistent Borrelia infection despite antibiotic therapy in patients with ongoing Lyme disease symptoms. Materials & Methods: In this pilot study, culture of body fluids and tissues was performed in a randomly selected group of 12 patients with persistent Lyme disease symptoms who had been treated or who were being treated with antibiotics. Cultures were also performed on a group of 10 control subjects without Lyme disease. The cultures were subjected to corroborative microscopic, histopathological and molecular testing for Borrelia organisms in four independent laboratories in a blinded manner. Results: Motile spirochetes identified histopathologically as Borrelia were detected in culture specimens, and these spirochetes were genetically identified as Borrelia burgdorferi by three distinct polymerase chain reaction (PCR) methods. Spirochetes identified as Borrelia burgdorferi were cultured from the blood of seven subjects, from the genital secretions of ten subjects, and from a skin lesion of one subject. Cultures from control subjects without Lyme disease were negative for Borrelia using these methods. Conclusions: Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment, similar to findings in non-human primates. The optimal treatment for persistent Borrelia infection remains to be determined.
Tue, 9 August 2016
REVIEW | doi:10.20944/preprints201608.0090.v1
Subject: Medicine & Pharmacology, Veterinary Medicine Keywords: intestinal organoids; dog; practical applications
Online: 9 August 2016 (11:38:04 CEST)
Recent technical advances in the stem cell field have enabled the in vitro generation of complex structures resembling whole organs termed organoids. Most of these approaches employ culture systems that allow stem cell-derived or tissue progenitor cells to self-organize into three-dimensional (3D)-structures. Since organoids can be grown from various species, organs and from patient-derived induced pluripotent stem cells, they create significant prospects for modelling development and diseases, for toxicology and drug discovery studies, and in the field of regenerative medicine. Here, we report on intestinal stem cells, organoid culture, organoid disease modeling, transplantation, current and future uses of this exciting new insight model to veterinary medicine field.
Sun, 23 February 2020
HYPOTHESIS | doi:10.20944/preprints202002.0254.v2
Subject: Medicine & Pharmacology, Other Keywords: 2019-nCoV; novel coronavirus pneumonia; docking; ACE2; viral main protease
Online: 23 February 2020 (02:09:52 CET)
The 2019 novel coronavirus (2019-nCoV) causes novel coronavirus pneumonia (NCP). Given that approved drug repurposing becomes a common strategy to quickly find antiviral treatments, a collection of FDA-approved drugs can be powerful resources for new anti-NCP indication discoveries. In addition to synthetic compounds, Chinese Patent Drugs (CPD), also play a key role in the treatment of virus related infections diseases in China. Here we compiled major components from 38 CPDs that are commonly used in the respiratory diseases and docked them against two drug targets, ACE2 receptor and viral main protease. According to our docking screening, 10 antiviral components, including hesperidin, saikosaponin A, rutin, corosolic acid, verbascoside, baicalin, glycyrrhizin, mulberroside A, cynaroside, and bilirubin, can directly bind to both host cell target ACE2 receptor and viral target main protease. In combination of the docking results, the natural abundance of the substances, and botanical knowledge, we proposed that artemisinin, rutin, glycyrrhizin, cholic acid, hyodeoxycholic acid, puerarin, oleanic acid, andrographolide, matrine, codeine, morphine, chlorogenic acid, and baicalin (or Yinhuang Injection containing chlorogenic acid and baicalin) might be of value for clinical trials during a 2019-nCov outbreak.
Sat, 6 August 2016
ARTICLE | doi:10.20944/preprints201608.0068.v1
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: community-based health insurance; cooperative; benefit package; social inclusion; healthcare; Nepal
Online: 6 August 2016 (11:54:03 CEST)
Background: Health insurance (HI) run by government is providing health care service to large population. Due to poor accountability, participation and sustainability, cooperative health insurance is becoming more popular and effective in low and middle income and some high-income countries too. In Nepal, there are public and cooperative HI is in practice. The aim of this study is to compare the effectiveness of public (government) and cooperative HI in relation to benefit packages, population coverage, inclusiveness, health care utilization, and promptness for treatment in these two health insurance models in Nepal. Method: This is an institution based concurrent mixed study consists of qualitative and quantitative variables from public and cooperative groups. We included all public HI operated by government hospitals and cooperatives groups those purchased hospital service in contract. Two separate study tools were applied to access the effectiveness of insurance models. The key questions were asked for the representatives of government and private health insurance. The numeric information consisted of in quantitative data and subjective response was included in qualitative approach. Descriptive statistics and Mean Whitney U test was applied in numeric data and qualitative information were analyzed by inductive approach Results: The study revealed that new enrolment was not increased, health care utilization rate was increased and the benefit package was almost same in both groups. The overall inclusiveness was higher for the government HI, but enrolment from the religious minority, proportion of negotiated amount during treatment were significantly higher (p<0.05). During illness, the response time to reach hospital was significantly faster in cooperative health insurance than government health insurance. Qualitative findings showed that level of participation, accountability, transparency and recording system was better in cooperative health insurance than public. Conclusion: Cooperative HI could be more sustainable and accountable to the community for all; low, middle and high-income countries.
Sun, 19 April 2020
ARTICLE | doi:10.20944/preprints202004.0345.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; venous thrombosis; pulmonary embolism; venous thromboembolism; anticoagulants; mortality
Online: 19 April 2020 (13:08:16 CEST)
Coronavirus disease 2019 (COVID-19) can lead to systemic coagulation activation and thrombotic complications. We investigated the incidence of objectively confirmed venous thromboembolism (VTE) in 198 hospitalized patients with COVID-19 in a single-center cohort study. Seventy-four patients (37%) were admitted to the intensive care unit (ICU). At time of data collection, 58 (29%) were still hospitalized and 14% had died. During a median follow-up of 5 days (IQR, 3-9), 33 patients (17%) were diagnosed with VTE of whom 22 (11%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7 and 14 days were 15% (95% CI, 9.3-22) and 34% (95% CI, 23-46), respectively. For symptomatic VTE, these were 11% (95% CI, 5.8-17) and 23% (95% CI, 14-33). VTE appeared to be associated with death (adjusted HR, 2.9; 95% CI, 1.02-8.0). The cumulative incidence of VTE was higher in the ICU (25% at 7 days 95% CI, 15-36, and 48% at 14 days, 95% CI, 33-61) than on the wards (any VTE and symptomatic VTE 6.5 % at 7 days (95% CI, 1.5-17) and 10% at 14 days (95% CI, 2.9-24)).The observed risk for VTE in COVID-19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.
Sun, 25 December 2016
COMMUNICATION | doi:10.20944/preprints201612.0122.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: furfuryl alcohol; β- myrcene; carcinogens; occurrence
Online: 25 December 2016 (08:21:19 CET)
For decades, compounds present in foods and beverages have been implicated in the etiology of human cancers. The International Agency for Research on Cancer (IARC) continues to classify such agents regarding their potential carcinogenicity in humans based on new evidence from animal and human studies. Furfuryl alcohol and β-myrcene belong to these potential human carcinogens due to be evaluated. The major source of furfuryl alcohol in foods is thermal processing and ageing of alcoholic beverages while β-myrcene occurs naturally as a constituent of essential oils of plants such as hops, lemongrass and derived products. This study aimed to summarize the occurrence of furfuryl alcohol and β-myrcene in foods and beverages using data from own nuclear magnetic resonance (NMR) analysis and literature review. The highest content of furfuryl alcohol was found in coffee beans (>100 mg/kg) and in some fish products (about 10 mg/kg) while among beverages, wines contained between 1–10 mg/L with 8 mg/L in pineapple juice. The content of β-myrcene was highest in hops. In conclusion, the data about the occurrence of the two agents is either very old or based on single sample analysis, and currently judged as insufficient for exposure and risk assessment. The results of this study point out the food and beverage groups that may be considered for future monitoring of furfuryl alcohol and β-myrcene.
Thu, 3 November 2016
ARTICLE | doi:10.20944/preprints201611.0027.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: vitamin C; hyperuricemia; gout; glomerular filtration rate
Online: 3 November 2016 (10:49:06 CET)
Abstract: Hyperuricemia is commonly diagnosed in subjects with abnormal purine metabolism. Prolonged hyperuricemia often associated with gout, which is a vital risk factor for joint dysfunction. The current study was designed to determine the efficacy of vitamin C supplements for treatment of high serum uric acid (UA) among hyperuricemic and gouty patients, and finding-out the effect of supplementation on serum creatinine (Cr) level and glomerular filtration rate (GFR). This intervention study was started in April, 2013, till two months. A convenient sample of 30 adults aged between 24-75 years of both genders was assigned into two study groups: hyperuricemic (n=15) and gouty (n=15) groups. Each participant supplemented with 500 mg/day vitamin C chewable tablets for 2 months. Serum UA, Cr, and GFR were measured before and after treatment. At the end of this study, Cr and GFR enhanced insignificantly in both groups. UA increased insignificantly in gouty group after 2 months by about 0.31 mg/dl. On the other hand, hyperuricemic group showed significant (P ≤0.05) decrease in UA (-0.78 mg/dl) after 2 months duration. In conclusion, supplementation with 500 mg/day vitamin C for 2 months significantly attenuated serum UA for hyperuricemic patients and insignificantly affected serum UA in gouty patients. The uselessness of vitamin C supplements on gouty patients could be associated to a number of possible reasons.
Tue, 7 April 2020
COMMUNICATION | doi:10.20944/preprints202004.0093.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; virus, bioaerosol; social distancing; aerodynamic size; infection
Online: 7 April 2020 (11:20:42 CEST)
The fast spread of COVID-19 constitutes a worldwide challenge to the public health, educational, and trade systems, affecting the overall wellbeing of human societies. The high transmission and mortality rates of this virus, and the unavailability of a vaccine and antidote, resulted in the decision of multiple governments to force measurements of social distancing. Thus, it is of general interest to consider the validity of the proposal for keeping a social distancing of at least 6.0 ft (1.8 m) from persons with COVID-19. The eventual exposure to the bioaerosol can result in the deposition o the pathogen in the respiratory track of the host causing disease and an immunological response. In the atmospheric context, the work evaluates the effect of aerodynamic particle size in carrying RNA copies of the novel coronavirus. A COVID-19 carrier person talking, sneezing, or coughing at distance of 1.8 m can still provide a pathogenic bioaerosol load with submicron particles that remain viable in air for up to 3 hours for exposure of healthy persons near and far the source in a stagnant environment. The deposited bioaerosol creates contaminated surfaces, which if touched can act as a path to introduce the pathogen by mouth, nose, or eyes and cause disease.
Mon, 2 January 2017
ARTICLE | doi:10.20944/preprints201701.0003.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: pito; beverage; bacteria; coliform; Lower Prampram; Ghana
Online: 2 January 2017 (10:55:07 CET)
Pito is a traditionally brewed alcoholic beverage in some African countries. It is gaining much prominence and the patronage among the youth. Therefore, samples of the drink were collected every week for six weeks from three different popular brewing sites at Lower Prampram in the Ningo-Prampram District of Accra, Ghana. The samples were processed and examined for bacteria and fungi using the Standard Plate Count (SPC) technique. A total of six different bacteria and a fungus were isolated. The bacteria were Escherichia coli, Klesiella pneumoniae, Shigella spp, Enterobacter aerogenes, Staphylococcus aureus and Pseudomonas aeroginosa, whiles the fungus was Saccharomyces cerevisiae. Total viable counts as well as individual isolates counts in all the pito samples were found to be less than 104 cfu/ml. It is noteworthy that, Saccharomyces cerevisiae, the only fungus isolated is known to be associated with fermentation and the microbes isolated from the pito samples were found to be within the permissible limits. However, these potentially pathogenic microbes, if found in unacceptable limits, from the fermenting samples could merit public health attention. Therefore, periodic screening of pito and their brewers, coupled with education on the maintenance of recommended guidelines concerning food and drink production is encouraged.
Tue, 20 September 2016
ARTICLE | doi:10.20944/preprints201609.0066.v1
Subject: Medicine & Pharmacology, Veterinary Medicine Keywords: antibody titre; vaccination; dog; canine distemper virus; Jos
Online: 20 September 2016 (10:14:26 CEST)
Determination of antibody titre of dogs vaccinated against canine distemper in Jos North and South local Government Areas of Plateau State was carried out by collection of sera of vaccinated dogs and administration of well-structured questionnaires to dog owners. The samples collected were analyzed using the immune-blot ELISA Kit to determining the antibody titre (immunoglobulin G). It indicated that dogs vaccinated against the disease mounted adequate protective immunity. The result revealed that 54 (90.0%) of the sampled dogs have protective immunity, with those given more than one dose having higher level of protective antibody. Statistically, the result showed that the antibody titre did not differ significantly in relation to immunity and sex, breed, age and location but significant difference was seen in relation to number of primary vaccination. The result also revealed that those dogs that received booster doses (secondary vaccination) had more protective antibody. The study was aimed at evaluating the antibody titre of dogs vaccinated against canine distemper in Jos, Plateau State.
Sat, 12 November 2016
REVIEW | doi:10.20944/preprints201611.0067.v1
Subject: Medicine & Pharmacology, Veterinary Medicine Keywords: vancomycin; broad view; veterinary use at a glance; rational use; alternatives
Online: 12 November 2016 (11:09:37 CET)
Vancomycin is one of the ‘last-line’ classes of antibiotics used in the treatment of life-threatening infections caused by Gram-positive bacteria. Even though vancomycin was discovered in 1950s it was widely used after 1980s for the treatment of infections caused by methicillin-resistant Staphylococci as prevalence of such strains were increased. However, currently it is evident that vancomycin resistant Staphylococcusaureusandvancomycin-resistant Enterococci have been developed as a result of various reasons including use of avaparcin, which is an analog of vancomycin, as feed additive in livestock. In present day context, more attention should be paid on prevention of emergence of resistance for the antibiotics in order to keep antibiotics effective. In order to prevent emergence of resistance, proper guidance for the responsible use of antimicrobials is indispensable. Therefore, almost all stakeholders who use antibiotics should have in depth understanding on the antibiotic they use. As such, it is imperative to be aware of the important aspects of vancomycin. In the present review, efforts have been made to discussthe pharmacokinetics and pharmacodynamics, indications, emergence of resistance, control of resistance, adverse effects and alternative therapy for vancomycin.
Sat, 13 August 2016
ARTICLE | doi:10.20944/preprints201608.0133.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: calorie restriction; PUFA; meal replacement; metabolic syndrome; middle age
Online: 13 August 2016 (03:39:38 CEST)
The increasing prevalence of obesity and sedentary lifestyles has led to an increased incidence of metabolic syndrome (MetS) worldwide. In Taiwan, middle-aged women are at a greater risk of MetS, type 2 diabetes, and cardiovascular disease than men are because they have more subcutaneous fat and larger waist circumferences compared to men with equal visceral fat levels. This study investigated the effects of calorie restriction supplemented with fish oil (CRF) in middle-aged women with MetS. For 12 weeks, 75 eligible participants were randomly assigned either calorie restriction (CR) or CRF. Both dietary intervention groups were further divided into two age groups: ≤45 and >45 years. The changes in MetS severity, inflammatory status, iron status, and red blood cell fatty acid profile were evaluated. Seventy-one participants completed the trial. Both dietary interventions significantly ameliorated MetS and improved the participants’ inflammatory status. CR significantly increased total iron binding capacity, whereas CRF increased hepcidin levels. Furthermore, CRF significantly increased the n-6/n-3 and arachidonic acid/docosahexaenoic acid ratios. In conclusion, CR and CRF improved the anthropometric and MetS characteristics of early-middle aged women, including body weight, blood glucose levels, triglyceride levels, as well as the scores for the homeostasis model assessment of insulin resistance and quantitative insulin sensitivity cheque index. Dietary intervention was more effective in >45-year-old women than ≤45-year-old women.
Fri, 27 October 2017
ARTICLE | doi:10.20944/preprints201710.0169.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: Schizophrenia; bipolar; psychosis; depression; polygenic risk score; diagnosis; RDoC
Online: 27 October 2017 (11:58:11 CEST)
In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genetic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing the potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study, an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. Within the DSM-IV framework, we compare two broad diagnostic groups: one consisting of predominantly affective and one of predominantly psychotic disorders. Depressive, manic, and psychotic symptoms as well as global functioning over time were analyzed. Furthermore, we explore the effects of polygenic risk scores for schizophrenia on diagnostic group membership and address their effects on non-participation in follow-up visits. While phenotypic results show differences in both current psychotic and manic symptoms, depressive symptoms did not vary between both groups. Polygenic risk scores for schizophrenia significantly explained part of the variability of the diagnostic group. Furthermore, there was a trend that a higher polygenic loading for schizophrenia was associated with attrition. Because of its unique properties, the PsyCourse study presents a prime resource for the interrogation of complex genotype-phenotype relationships.
Mon, 18 September 2017
HYPOTHESIS | doi:10.20944/preprints201709.0081.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: sarcoidosis; monocytes; cancer; neoplasia; vitamin D; 25-hydroxyvitamin D3; 1,25-hydroxyvitamin D3; etiology; spontaneous remission of cancer; vitamin D side effects
Online: 18 September 2017 (14:21:11 CEST)
The cause of sarcoidosis is unknown, and vitamin D is contraindicated to treat the condition. We therefore ask what causes sarcoidosis and why vitamin D can be dangerous for those so afflicted. We propose a contrary hypothesis: sarcoidosis is a physiological process of defense against cancer that requires the substrate vitamin D. We tested this hypothesis, finding many case reports involving sarcoidosis and cancer—further cases of cancer mimicry by sarcoidosis. Several reports describe spontaneous healing of cancer in the presence of sarcoidosis. In the context of the granulomas of sarcoidosis, monocytes are the site of vitamin D release. Furthermore, active vitamin D can control cancer cells by using the vitamin D receptors of the nucleus. That granulomas consistently do not caseate is explained as a confrontation with human molecules and the cancer cells’ complete absorption. The striking fact that granulomas of sarcoidosis mostly lack cancerous cells is interpreted as a result of a well-functioning sarcoidosis process. We view the typical sarcoidosis monocytic synthesis of active vitamin D as a successful defense against cancer: a theory we call the “endogenous program organizing cancer apoptosis” (EPOCA).
Mon, 13 April 2020
REVIEW | doi:10.20944/preprints202003.0001.v2
Subject: Medicine & Pharmacology, Other Keywords: emerging coronavirus; 2019-nCoV; SARS-CoV-2; COVID-19; diagnosis; vaccines; therapy; one health
Online: 13 April 2020 (02:29:00 CEST)
In the past decades, several new diseases have emerged in new geographical areas, with pathogens including Ebola, Zika, Nipah, and coronaviruses (CoVs). Recently, a new type of viral infection has emerged in Wuhan City, China, and initial genomic sequencing data of this virus does not match with previously sequenced CoVs, suggesting a novel CoV strain (2019-nCoV), which has now been termed as severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Although Coronavirus disease 2019 (COVID-19) is suspected to originate from an animal host (zoonotic origin) followed by human-to-human transmission, the possibility of other routes such as food-borne transmission should not be ruled out. Compared to diseases caused by previously known human CoVs, COVID-19 shows less severe pathogenesis but higher transmission competence, as is evident from the continuously increasing number of confirmed cases globally. Compared to other emerging viruses such as Ebola virus, avian H7N9, SARS-CoV, or MERS-CoV, SARS-CoV-2 has shown relatively low pathogenicity and moderate transmissibility. Codon usage studies suggest that this novel virus may have been transferred from an animal source such as bats. Early diagnosis by real-time PCR and next-generation sequencing has facilitated the identification of the pathogen at an early stage. Since, no antiviral drug or vaccine exists to treat or prevent SARS-CoV-2, potential therapeutic strategies that are currently being evaluated predominantly stem from previous experience with treating SARS-CoV, MERS-CoV, and other emerging viral diseases. In this review, we address epidemiological, diagnostic, clinical, and therapeutic aspects, including perspectives of vaccines and preventive measures that have already been globally recommended.
Tue, 6 September 2016
REVIEW | doi:10.20944/preprints201609.0022.v1
Subject: Medicine & Pharmacology, Psychiatry & Mental Health Studies Keywords: Pervasive developmental disorder; Autism spectrum disorder (ASD); brain network; Theory of Mind (ToM); Music Therapy (MT); therapeutic effect
Online: 6 September 2016 (11:53:58 CEST)
Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. Evidence based studies have reported the extensive therapeutic application of music on various part of the brain in a nonverbal child with autism through hearing or making music.Hence we hypothesized that MT intervention can improve the communication capacity in people with ASD, than customary neurorestoration therapy alone.
Wed, 11 March 2020
COMMUNICATION | doi:10.20944/preprints202003.0184.v1
Subject: Medicine & Pharmacology, Other Keywords: SARS-CoV-2; diagnosis; antibody; serology; screening
Online: 11 March 2020 (10:40:09 CET)
Until now, viral RNA detection is almost the only way to confirm the infection of SARS-CoV-2 in practice. But varied reasons lead to the low sensitivity by RNA detection, which proposes serious challenge to disease control. We tested the performance of detecting total antibody(Ab) and IgM antibody in serum by the methods of chemiluminescence, Enzyme Linked Immunosorbent Assay(ELISA), and colloidal gold. Data showed that the sensitivity and specificity for total Ab and IgM detection were high by all the three methods, and compared with IgM, the sensitivity was higher for total Ab detection. Evidence from studies showed viral RNA testing combining with serological testing could increase the sensitivity of diagnosis, while remaining the high specificity. Specific serolody test for SARS-CoV-2 has great value for clinical practice and public health.
Fri, 27 April 2018
ARTICLE | doi:10.20944/preprints201804.0349.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: bacterial infections; sensitivity; specificity; immature granulocytes; Latvia; child; sepsis
Online: 27 April 2018 (06:09:47 CEST)
Background: Detection of small proportion of serious bacterial infections (SBI) with potentially life threating course in a large group of children with fever admitted to emergency department (ED) is still complicated. Measurement of immature granulocytes (IG) percentage may be used as a marker of bacterial infections. The aim of the study was to evaluate whether the IG percentage is a useful additional predictive marker of SBI. Methods: This study included 258 children with febrile infections admitted to the ED. Clinical follow-up, microbiological and radiological tests were used as reference standards for the definition of SBI. Study population was categorized into two groups: (i) infected patients with no suspicion of SBI (n = 75); (ii) patients with suspicion of SBI (n = 183). IG percentage, white blood cell count (WBC) and C-reactive protein (CRP) levels were analyzed from the first routine blood samples at hospital admission. Results: A statistically significant difference in IG percentage levels was observed in children with SBI and those without - the mean IG percentage was 1.2% for the SBI group, 0.3% for those without SBI. The cutoff level of IG percentage to predict SBI was 0.45 (84% specificity, 66% sensitivity, 90% positive predictive value). We combine variables and evaluate their additive values. The sensitivity of WBC to detected SBI improved from 74% to 85% when IG percentage was added to the prediction models. When CRP, WBC and IG percentage were combined, the sensitivity to predict SBI increased to 93%, the specificity to 86%. (95% CI 77–93%). Receiver operator characteristic analysis to predict SBI showed an area under the curve (AUC) of 0.80 for IG percentage. Conclusion: Addition of IG percentage to traditionally used markers of SBI as WBC and CRP may help to identify children with serious bacterial infections. Furthermore IG percentage can be rapidly obtained from the traditional full blood count without any extra sampling and costs.
Sat, 9 May 2020
REVIEW | doi:10.20944/preprints202005.0160.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: Sars-Cov2; Covid-19; Children; Kawasaki disease; toxic shock syndrome
Online: 9 May 2020 (09:01:24 CEST)
In the end of April nearly 100 cases of children aged between 6 month and 9 years with Kawasaki like disease were reported (mostly in Europe) probably linked to COVID-19. With the increasing awareness of this condition the number of cases reported is increasing worldwide. We aim to sum up the known data about this new entity based on published data (in a case report, a series of 8 cases and in newspapers and society statement) and using our knowledge of classical Kawasaki disease. It seems to be a post infectious disease with an onset between 2-4 weeks after the infection, probably in genetically predisposed children aged between 6 month to 17 years. A very rough estimation of incidence based on current data from Bergamo, Italy, and New York State and a lot assumption is between 0.016% (95% CI:0.013-0.02%) - 0.31% (95% CI: 0.2-0.47%) of infected children. Clinical signs overlaps with Kawasaki disease in some children, but another feature is prominent gastrointestinal manifestations. For the 9 detailed patients most had incomplete presentation for Kawasaki disease (with a mean 1.7 (+/-1.2) criteria per patient for the 5 non fever criterion) and only one had a classical form. In some cases, presentation is closer to toxic shock syndrome or isolated myocarditis. Persistent fever seems to be constant and biological exploration are consistent with inflammation (elevated CRP, ferritin and D-Dimers). Management is described as supportive and children seem to improve rapidly, but can require cardiac or respiratory support. In date of 11 may 2020 there is 4 deaths confirmed linked to these new entities (1 in UK and 3 in New York). Paediatricians and general practitioners need to be aware of these possible evolution following COVID-19 infection. However it seems to be rare and children are probably still spared from most morbidities and mortality linked to COVID-19 infection .There are need of published detailed cohorts to better delineate these entities.
Mon, 23 March 2020
REVIEW | doi:10.20944/preprints202003.0343.v1
Subject: Medicine & Pharmacology, Other Keywords: coronavirus; 2019-nCoV; SARS-CoV-2; animal coronaviruses; COVID-19; bat coronavirus; zoonoses; epidemiology; transmission; diagnosis; antivirals; prevention and control
Online: 23 March 2020 (07:19:35 CET)
After the appearance of first cases of ‘pneumonia of unknown origin’ in the Wuhan city, China, during late 2019, the disease progressed fast. Its cause was identified as a novel coronavirus, named provisionally 2019-nCoV. Subsequently, an official name was given as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) by the International Committee on Taxonomy of Viruses (ICTV) study group. The World Health Organization (WHO) named the Coronavirus disease-2019 as COVID-19. The epidemics of COVID-2019 have been recorded over 113 countries/territories/areas apart from China and filched more than 4292 humans, affecting severely around 1,18,326 cases in a short span. The status of COVID-2019 emergency revised by the WHO within 42 days from Public Health International Emergency (January 30, 2020) to a pandemic (March 11, 2020). Nonetheless, the case fatality rate (CFR) of the current epidemic is on the rise (between 2-4%), relatively is lower than the previous SARS-CoV (2002/2003) and MERS-CoV (2012) outbreaks. Even though investigations are on its way, the researchers across the globe have assumptions of animal-origin of current SARS-CoV-2. A recent case report provides evidence of mild COVID-2019 infection in a pet dog that acquired COVID-2019 infection from his owner in Hong Kong. The news on travellers associated spread across the globe have also put many countries on alert with the cancellation of tourist visa to all affected countries and postponement of events where international visits were required. A few diagnostic approaches, including quantitative and differential real-time polymerase chain reaction assays, have been recommended for the screening of the individuals at risk. In the absence of any selective vaccine against SARS-CoV-2, re-purposed drugs are advocated in many studies. This article discourse the current worldwide situation of COVID-2019 with information on virus, epidemiology, host, the role of animals, effective diagnosis, therapeutics, preventive and control approaches making people aware on the disease outcomes.
Mon, 28 November 2016
REVIEW | doi:10.20944/preprints201611.0138.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: computational imaging; midsagittal plane; inter-hemispheric fissure; symmetry analysis; neuroimaging
Online: 28 November 2016 (02:03:34 CET)
Brain is the most complex organ in the human body and it is divided into two hemispheres - left and right hemispheres. Left hemisphere is responsible for control of right side of our body whereas right hemisphere is responsible for control of left side of our body. Brain image segmentation from different neuroimaging modalities is one of the important parts in clinical diagnostic tools. Neuroimaging based digital imagery generally contain noise, inhomogeneity, aliasing artifacts, and orientational deviations. Therefore, accurate segmentation of brain images is a very difficult task. However, the development of accurate segmentation of brain images is very important and crucial for a correct diagnosis of any brain related diseases. One of the fundamental segmentation tasks is to identify and segment inter-hemispheric fissure/mid-sagittal plane, which separate the two hemispheres of the brain. Moreover, the symmetric/asymmetric analyses of left and right hemispheres of brain structures are important for radiologists to analyze diseases such as Alzheimer's, Autism, Schizophrenia, Lesions and Epilepsy. Therefore, in this paper we have analyzed the existing computational techniques used to find brain symmetric/asymmetric analysis in various neuroimaging techniques (MRI/CT/PET/SPECT), which are utilized for detecting various brain related disorders.
Wed, 16 October 2019
ARTICLE | doi:10.20944/preprints201910.0178.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: essential oils; Bartonella henselae; persisters; stationary phase; antimicrobial activity
Online: 16 October 2019 (05:18:55 CEST)
Bartonella henselae is a fastidious Gram-negative intracellular bacterium which can cause cat scratch disease, endocarditis in humans and animals as well as other complications, leading to acute or chronic infections. The current treatment for Bartonella infections is not very effective due to antibiotic resistance and also persistence. To develop better therapies for persistent and chronic Bartonella infections, in this study, with the help of SYBR Green I/PI viability assay, we performed a high-throughput screening of an essential oil library against stationary phase B. henselae. We successfully identified 32 essential oils that had high activity, including four essential oils extracted from Citrus plants, three from Origanum, three from Cinnamomum, two from Pelargonium and two from Melaleuca, as well as frankincense, ylang ylang, fir needle, mountain savory (winter), citronella, spearmint, elemi, vetiver, clove bud, allspice and cedarwood essential oils. The minimal inhibitory concentration (MIC) determination of these 32 top hits indicated they were not only active against stationary phase non-growing B. henselae but also had good activity against log phase growing B. henselae. The time-kill curve by drug exposure assay showed 13 active hits, including essential oils of oregano, cinnamon bark, mountain savory (winter), cinnamon leaf, geranium, clove bud, allspice, geranium bourbon, ylang ylang, citronella, elemi and vetiver, could eradicate all stationary phase B. henselae cells within 7 days at the concentration of 0.032% (v/v). Two active ingredients, carvacrol and cinnamaldehyde, of oregano and cinnamon bark essential oils, respectively, were shown to be very active against stationary phase B. henselae such that they were able to eradicate all the bacterial cells even at the concentration ≤ 0.01% (v/v). Our finding of active essential oils may help to develop more effective treatments for persistent Bartonella infections.
Mon, 26 September 2016
ARTICLE | doi:10.20944/preprints201609.0093.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: metastatic breast cancer; taxanes; eribulin; observational study
Online: 26 September 2016 (11:39:32 CEST)
Taxanes have been shown to be the most effective treatment for recurrent or metastatic breast cancer. However, for patients pretreated with taxanes, more active and possibly less toxic drugs are needed. In this retrospective study, we investigated on the effectiveness and safety of eribulin mesylate in 91 taxane-refractory subjects, extracted from the ESEMPIO database, which included 497 metastatic breast cancer patients treated with eribulin allover the Italy. This analysis included only those patients who have shown disease progression while receiving taxane therapy (primary refractory), or those who achieved a response followed by progression while still on therapy (taxane failure). Overall, 41/91 patients (45.2%) showed a clinical benefit; 1 complete response (2.2%) and 16 partial responses (17.6%) were observed. The median progression free survival was 3.1 months (95% CI: 2.8–3.5) and the median overall survival was 11.6 months (95% CI: 8.7–16.7). With regard to toxicity, 53 patients (58%) experienced asthenia/fatigue, 23 (25%) showed peripheral neurotoxicity, 18 (20%) alopecia, 12 (13%) mild constipation and 27 (30%) neutropenia. The toxicity related to the treatment led to eribulin dose reduction in 19 (21%) and discontinuation in 9 (10%) patients, respectively. In conclusion, this study suggests that eribulin is effective and well tolerated also in taxane-refractory patient.
Wed, 21 September 2016
ARTICLE | doi:10.20944/preprints201609.0074.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: hepatocellular carcinoma; hepatitis B virus X protein; Notch1 pathway; ERK; AKT
Online: 21 September 2016 (09:49:13 CEST)
Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.
Mon, 9 March 2020
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Novel coronavirus pneumonia; COVID-19; SARS-CoV-2; Pathology; Critical patient
Online: 9 March 2020 (10:31:10 CET)
Background Critical patients with novel coronavirus pneumonia ( COVID-19) have worse outcome and high mortality. However, the histopathology of critical patient with COVID-19 remains undisclosed. Methods We performed the whole lung biopsy, and described the pathological changes of critical COVID-19 patient done with transplant by HE staining, immunohistochemistry and special staining observed under the microscopy. Findings The whole lungs displayed diffuse congestive appearance and partly haemorrhagic necrosis on gross examination. The haemorrhagic necrosis was prominently present in outer edge of the right lower lung. The cut surfaces of the lung displayed severe congestive and haemorrhagic changes. The main pathological changes showed massive pulmonary interstitial fibrosis, and partly hyaline degeneration, variable degrees of hemorrhagic pulmonary infarction. Small vessels hyperplasia, vessel wall thickening, lumen stenosis, occlusion and microthrombosis formation. Focal monocytes, lymphocytes and plasma cells infiltrating into pulmonary interstitium. Bronchiolitis and alveolitis with proliferation, atrophy, desquamation and squamous metaplasia of epithelial cells. Atrophy, vacuolar degeneration, proliferation, desquamation and squamous metaplasia in alveolar epithelial cells. Alveolar cavity congestion was prominent, and contained mucus, edema fluid, desquamated epithelial cells, and inflammatory cells. We also found several multinucleate giant cells and intracytoplasmic viral inclusion bodies. Special stains including Masson stain, sirius red staining, reticular fibers staining indicated massive pulmonary interstitial fibrosis. Immunohistochemistry showed positive for immunity cells including CD3, CD4, CD8, CD20, CD79a, CD5, CD38 and CD68. Interpretation We demonstrate the pathological findings of critical patient with COVID-19, which might provide a deep insight of the pathogenesis and severity of this disease.
Thu, 9 March 2017
REVIEW | doi:10.20944/preprints201703.0052.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: mucositis; radiotherapy; chemotherapy; pathophysiology; management; melatonin
Online: 9 March 2017 (04:46:30 CET)
The current treatment for cervico-facial cancer involves radio and/or chemotherapy. Unfortunately, cancer therapies can lead to local and systemic complications such as mucositis, which is the most common dose-dependent complication in the oral cavity and gastrointestinal tract. Mucositis can cause a considerably reduced quality of life in cancer patients already suffering from physical and psychological exhaustion. However, melatonin, whose role in the treatment of mucositis has recently been investigated, offers an effective alternative therapy in the prevention and/or management of radio and/or chemotherapy-induced mucositis. This review focuses on the pathobiology and management of mucositis in order to improve the quality of cancer patients’ lives.
Wed, 11 January 2017
REVIEW | doi:10.20944/preprints201701.0057.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: osteoarthritis; rheumatoid arthritis; medicinal plants; herbs
Online: 11 January 2017 (07:56:32 CET)
Chronic joint inflammatory disorders such as osteoarthritis and rheumatoid arthritis have in common an upsurge of inflammation, and oxidative stress, resulting in progressive histological alterations and disabling symptoms. Currently used conventional medication (ranging from pain-killers to biological agents) is potent, but frequently associated with serious, even life-threatening side effects. Used for millennia in traditional herbalism, medicinal plants are a promising alternative, with lower rate of adverse events and an efficiency frequently comparable with that of conventional drugs. Nevertheless, their mechanism of action is in many cases elusive and/or uncertain. Even many of them have been proved effective in studies done in vitro or on animal models, there is a scarcity of human clinical evidence. The purpose of this review is to summarise the available scientific information on these joint-friendly medicinal plants, which have been already tested in human studies: Arnica montana, Boswelliaspp., Curcuma spp., Equisetum arvense, Harpagophytumprocumbens, Salix spp., Sesamumindicum, Symphytumofficinalis, Zingiberofficinalis, Panaxnotoginseng, Whitaniasomnifera.
Thu, 6 February 2020
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: 2019-nCoV; epidemiology; causes; prevention and control; review
Online: 6 February 2020 (08:54:11 CET)
The 2019-nCoV has been identified as the cause of an outbreak of respiratory illness in Wuhan, Hubei Province, China beginning in December 2019. This epidemic had spread to 19 countries with 11,791 confirmed cases, including 213 deaths, as of January 31, 2020. The World Health Organization declared it as a Public Health Emergency of International Concern. This study analyzed and discussed 70 research articles published until January 31, 2020 for a better understanding of the epidemiology, causes, clinical diagnosis, prevention and control of this virus. Studies thus far have shown origination in connection to a seafood market in Wuhan, but specific animal association has not been confirmed. The reported symptoms include fever, cough, fatigue, pneumonia, headache, diarrhea, hemoptysis, and dyspnea. Preventive measures such as masks, hand hygiene practices, avoidance of public contact, case detection, contact tracing, and quarantines are effective for reducing the transmission. To date, no specific antiviral treatment is proven effective, hence, infected people primarily rely on symptomatic treatment and supportive care. Although these studies had relevance to control a public emergency, more research need to be conducted to provide valid and reliable ways to manage this kind of public health emergency in both short- and long- term.
Fri, 28 February 2020
ARTICLE | doi:10.20944/preprints202002.0447.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2; ACE2; RGD; Spike protein; therapeutic drugs
Online: 28 February 2020 (16:26:53 CET)
Pneumonia caused by a new coronavirus SARS-CoV-2 has caused serious harm to people's lives and health in Wuhan, China. By February 26, 2020, over 80,000 people were infected and 2,814 died from the infection. The initial route of infection is the binding of the spike protein (S protein) of the virus to the angiotensin-converting enzyme 2 (ACE2). From bioinformatics analysis, we found that the S protein of SARS-CoV-2 produced an evolutionary mutation of K403R compared with the S protein of SARS-CoV, forming an adjacent RGD motif at the interaction surface. As the RGD motif is considered as a ligand for many cell surface integrins, we proposed that the binding of S protein of SARS-CoV-2 with integrins may facilitate the infection process of the virus. Therefore, high-throughput virtual screening was performed by choosing the key residues of S protein interface of SARS-CoV-2 and the adjacent RGD motif as potential binding site, to search for the potential agents targeting interaction of S protein of SARS-CoV-2 with both ACE2 and integrins as potential therapeutic drugs. Various libraries including the FDA-approved drugs etc. were screened, and Nadide, Losartan, 9'''-Methyllithospermate B and Leonurine etc. were identified as representative potential drugs candidate for COVID-19.
Tue, 2 August 2016
ARTICLE | doi:10.20944/preprints201608.0011.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: curcumin; furazolidone; oxidative stress; DNA damage; mitochondrial pathway
Online: 2 August 2016 (05:59:38 CEST)
Furazolidone (FZD) is a synthetic nitrofuran with the antiprotozoal and antibacterial activity. The proper mechanism of FZD induced toxicity is still unclear. This study aimed to investigate the protective effect of curcumin on FZD induced oxidative stress, DNA injury and apoptosis in human hepatocyte L02 cells. The results showed that curcumin treatment significantly ameliorated FZD induced cytotoxicity, characterized by decreasing the production of reactive oxygen species (ROS) and malondialdehyde, as well as increasing superoxide dismutase, catalase activities and glutathione contents. Moreover, curcumin pretreatment significantly inhibited FZD induced the loss of mitochondrial membrane potential, the activation caspase-9 and -3 and apoptosis. Comet assay showed that curcumin attenuated FZD induced DNA injury in a dose-dependent manner. Correspondingly, curcumin markedly reversed the up-regulation of p53, Bax, caspase-9 and -3 mRNA expressions and the down-regulation of Bcl-2 mRNA (all p<0.05 or 0.01). These results reveal that curcumin protects against FZD induced oxidative stress, DNA injury and cell apoptosis via inhibiting oxidative stress and mitochondrial pathway, which may be attributed to ROS scavenging and anti-oxidative ability of curcumin. Importantly, our study highlights that curcumin may be a potential way to prevent FZD-mediated oxidative DNA injury and apoptosis in human or animals.
Mon, 29 August 2016
ARTICLE | doi:10.20944/preprints201608.0225.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: circular RNAs (circRNAs); circulating circRNA; type 2 diabetes mellitus (T2DM); pre-diabetes; microarray analysis; biomarker
Online: 29 August 2016 (13:37:38 CEST)
The purpose of current study was to investigate the expression characteristic of circular RNAs (circRNAs) in peripheral blood of type 2 diabetes mellitus (T2DM) patients and their potentials as diagnostic biomarkers for pre-diabetes and T2DM. In present study, the circRNAs in the peripheral blood from 6 healthy individuals and 6 T2DM patients were collected for microarray analysis. The results indicated that there were 489 differentially expressed circRNAs, of which 78 were upregulated and 411 were downregulated in the T2DM group. Then we selected 5 circRNAs as the candidate biomarkers under a stricter screening criteria and further verified them in another cohort (control group, n=20; pre-diabetes group, n =20; T2DM group; n=20). 3 of the 5 circRNAs presented upregulated expression in the experimental groups, including 2 circRNAs of the T2DM group that had higher expression than the pre-diabetes group. Hsa_circ_0054633 was identified to have the largest area value under the carve (AUC). In another independent cohort (control group, n=60; pre-diabetes group, n=63; T2DM group, n=64), the diagnostic capacity of hsa_circ_0054633 was tested. The results showed that the AUC for the diagnosis of pre-diabetes was 0.751(95% confidence interval=[0. 666-0.835], P＜0.001) while it was 0.793 ([0.716-0.871], P＜0.001) for the diagnosis of T2DM. After including the risk factors of T2DM, the AUC increased to 0.841 ([0.773-0.910], P <0.001) and 0.834 ([0.762-0.905], P <0.001), respectively. Hsa_circ_0054633 presented a certain diagnostic capability for pre-diabetes and T2DM.
Tue, 21 April 2020
ARTICLE | doi:10.20944/preprints202004.0374.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; coronavirus; infectious disease; infection management; PCR test; mortality; kinetic analysis
Online: 21 April 2020 (05:42:47 CEST)
Global differences in changes in the numbers of population-adjusted daily test-positive cases (NPDP) and deaths (NPDD) by COVID-19 were analyzed for 49 countries. The changes per population of a hundred million were compared, adjusting by the beginning of test-positive cases increase (BPI) or deaths increase (BDI). Notable regional differences of more than 100 times in NPDP and NPDD were observed. The trajectories of NPDD after BDI increased exponentially within 20 days in most countries. A machine learning analysis suggested that NPDD on 30 days after BDI was the highest in Western countries (1180), followed by the Middle East (128), Latin America (97), and then Asia (7), and furthermore that, NPDD in Western countries with a positive rate of the PCR test of less than 7.0% attenuated to only 15%. The cause behind differences between regions might be complex, however, investigation of the host genetic factors would be warranted. The lower positive rate would be caused by aggressive testing policy and associated with longer lag times between BPI and BDI. Our analysis suggested that the positive rate need to be 7% or less by extensive tests to reduce deaths effectively. As the number of infected people is growing rapidly, earlier expansion of the test capacity is indispensable.
Mon, 26 September 2016
ARTICLE | doi:10.20944/preprints201608.0165.v2
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Pueraria mirifica; mammary gland; uterus; carcinogenesis; estrogenic activity; Donryu rat
Online: 26 September 2016 (09:25:39 CEST)
Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in uterus weight. Secondly, a 4 week PM application to non-operated rats at a dose of 3% after 7,12-dimethylbenz[a]anthracene (DMBA) initiation resulted in significant elevation of cell proliferation in the mammary glands. In a third experiment, postpubertal administration of 0.3% (200 mg/kg body weight (b.w.)/day) PM to 5-week-old non-operated animals for 36 weeks following initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG), respectively, resulted in significant increase of mammary adenocarcinoma incidence. A significant increase of endometrial atypical hyperplasia multiplicity was also observed. Furthermore, PM at doses of 0.3% and, more pronouncedly, of 1% induced dilatation, hemorrhage and inflammation of the uterine wall. In conclusion, postpubertal long-term PM administration to Donryu rats exerts estrogenic effects in the mammary gland and uterus, and at a dose of 200 mg/kg b.w./day was found to promote mammary carcinogenesis initiated by DMBA.
Tue, 13 September 2016
CASE REPORT | doi:10.20944/preprints201609.0045.v1
Subject: Medicine & Pharmacology, Other Keywords: eosinophilic pneumonia; lung nodules; dyspnea; eosinophils
Online: 13 September 2016 (04:04:39 CEST)
Chronic eosinophilic pneumonia (CEP) is an idiopathic disorder characterized by an abnormal and marked accumulation of eosinophils in the interstitial and alveolar spaces of the lung. Idiopathic chronic eosinophilic pneumonia is reported to comprise anywhere from 0-2.5% of cases within the registries of interstitial lung disease. Diagnosis is based on the clinical constellation of symptoms, characteristic radiographic findings and peripheral blood or BAL eosinophilia, in the absence of infection or drug-induced eosinophilia. There is no consensus on the dose and duration of treatment, but most authors recommend initial doses of prednisone at 0.5–1 mg/kg/day with gradual tapering of the dose for total treatment duration of 6–12 months.
Mon, 2 March 2020
ARTICLE | doi:10.20944/preprints202002.0220.v2
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: coronavirus; COVID-19 pneumonia; pathology; SARS-CoV-2
Online: 2 March 2020 (01:34:58 CET)
There is currently a lack of pathologic data on the novel coronavirus (SARS-CoV-2) pneumonia, or COVID-19, from autopsy or biopsy. Two patients who recently underwent lung lobectomies for adenocarcinoma were retrospectively found to have had COVID-19 at the time of surgery. These two cases thus provide important first opportunities to study the pathology of COVID-19. Pathologic examinations revealed that, apart from the tumors, the lungs of both patients exhibited edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, and multinucleated giant cells. Hyaline membranes were not prominent. Since both patients did not exhibit symptoms of pneumonia at the time of surgery, these changes likely represent an early phase of the lung pathology of COVID-19 pneumonia.
Tue, 20 September 2016
ARTICLE | doi:10.20944/preprints201609.0073.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: diabetes mellitus, molecular docking, thin layer chromatography, alpha amylase, ellagic acid
Online: 20 September 2016 (16:13:12 CEST)
Diabetes mellitus is the fifth deadliest disease in the developing countries. Even with all the research and new drugs available, combating diabetes is still challenging. There are successes in finding new cost effective drugs without side effects, even if not perfect. In our investigation we studied binding mechanism of secondary metabolite of T. chebula in silico. It was observed that three compounds out of 16 have a higher binding affinity for the target proteins. Ellagic acid showed highest binding affinity with alpha amylase, beta glucosidase and alpha glucosidase with lesser binding energies -4.5kcal/mol, -5.36kcal/mol and -4.48kcal/mol respectively. Arjungenin has lesser binding energy of 4.77 kcal/mol with glucokinase while luteoline has binding energy of -7.25kcal/mol for enzyme glycogen synthase kinase. These entire compounds interacted with non-covalent interaction. Petroleum ether extract showed the significant alpha amylase inhibitory activity i.e. 51.22% as compared to standard drug (65.99%).TLC analysis revealed the presence of total 9 compounds in different plant extracts one of them might be a lead compound which could be further exploited for the development of novel safer and potent antidiabetic drug.
Tue, 13 February 2018
ARTICLE | doi:10.20944/preprints201802.0091.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cancer; lung cancer; leukemia; Daphne; Thapsia; daphnane diterpenes
Online: 13 February 2018 (07:08:47 CET)
Although several plant-derived drug groups (vinca alkaloids, taxanes, podophyllotoxin derivatives and camptothecins) continue to be widely used in cancer therapy, the anticancer potential of the Plant Kingdom remains largely unexplored. In this work, we have carried out a random screening for selective anticancer activity of 57 extracts from 45 plants collected in Grazalema Natural Park, an area in the South of Spain of high plant diversity and endemism. Using lung cancer cells (A549) and lung non-malignant cells (MRC-5), we found that several extracts were more cytotoxic and selective against the cancer cell line than the standard anticancer agent cisplatin. Five active extracts were further tested in cancer and normal cell lines from other tissues, including three skin cell lines with increasing degree of malignancy. An extract from the leaves of Daphne laureola L. (Thymelaeaceae) showed a striking potency and selectivity on lung cancer cells and leukemia cells; the IC50 values against these cancer cells were approximately 10000-fold lower than against the normal cells. Daphnane-type diterpene orthoesters may be responsible for this highly selective anticancer activity.
Fri, 23 December 2016
ARTICLE | doi:10.20944/preprints201612.0121.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: antibacterial activity, cinnamon, honey, checkerboards method, synergistic activity
Online: 23 December 2016 (18:37:59 CET)
Propionibacterium acnes and Staphylococcus epidermidis are the major skin bacteria that cause the formation of acne. The present study was conducted to investigate antibacterial activity of ethanolic extract of cinnamon bark, honey and their combination against acne bacteria. The antibacterial activity of extract of cinnamon bark and honey were investigated against P. acnes and S. epidermidis using disc diffusion method. Minimum Inhibitory Concentration (MIC) and minimal bactericidal concentration (MBC) were performed using Clinical and Laboratory Standard Institute (CLSI) methods. The interaction combination between extract of cinnamon bark and honey was determined by using a checkerboards method. The results showed that he MIC of extract of cinnamon bark and honey against P. acne were 256 µg/mL and 50% v/v, respectively, while against S. epidermidis were 1024 µg/mL and 50% v/v, respectively. The MBC of extract of cinnamon against P. acnes and S. epidermidis were more than 2048 µg/mL, whereas the MBC for honey against P. acnes and S. epidermidis were 100%. The combination of cinnamon bark extract and honey against against P. acnes and S. epidermidis, showed additive activity with the FICI value 0.625. Therefore, the combination of extract of cinnamon bark and honey has potential activity against acne causing bacteria.
Tue, 25 February 2020
ARTICLE | doi:10.20944/preprints202002.0378.v1
Subject: Medicine & Pharmacology, Other Keywords: Coronavirus Disease 2019; SARS-CoV-2; clinical features; laboratory; outcomes; epidemic.
Online: 25 February 2020 (12:19:14 CET)
Introduction: An epidemic of Coronavirus Disease 2019 (COVID-19) begun in December 2019 in China, causing primary concern. Among raised questions, clinical, laboratory, and imaging features have been partially characterized in some observational studies. No systematic reviews have been published on this matter. Methods: We performed a systematic review of the literature with meta-analysis, using three databases to assess clinical, laboratory, imaging features, and outcomes of confirmed cases of COVID-19. All the observational studies, and also case reports, were included. The case reports were analyzed separately. We performed a random-effects model meta-analysis to calculate the pooled prevalence and 95%CI. Measures of heterogeneity, including Cochran’s Q statistic, the I2 index, and the τ2 test, were estimated and reported.Results: 660 articles were retrieved. After screening by abstract and title, 27 articles were selected for full-text assessment. Of them, 19 were finally included for qualitative and quantitative analyses. Additionally, 39 case report articles were included and analyzed separately. For >656 patients, fever (88.7%, 95%CI 84.5-92.9%), cough (57.6%, 40.8-74.4%) and dyspnea (45.6%, 10.9-80.4%) were the most prevalent clinical manifestations. Among the patients, 20.3% (95%CI 10.0-30.6%) required ICU, with 32.8% presenting ARDS (95%CI 13.7-51.8), 6.2% (95%CI 3.1-9.3) with shock and 13.9% (95%CI 6.2-21.5%) with a fatal outcome.Discussion: COVID-19 is a new clinical infectious disease, causing considerable compromise, especially in patients with comorbidities, requiring ICU in at least a fifth of them and sometimes with fatal outcomes. Additional research is needed to elucidate factors that may mediate the pathogenesis of the severe and fatal associated disease.
Wed, 7 September 2016
REVIEW | doi:10.20944/preprints201609.0029.v1
Subject: Medicine & Pharmacology, Other Keywords: HLA; type 1 diabetes; ethnicity; screening; haplotype
Online: 7 September 2016 (12:49:02 CEST)
Aims/Hypothesis): Type 1 diabetes is an immune-mediated disease with destruction of the pancreatic β-cells, a process that is conditioned by multiple genes and other factors. HLA counts as the major susceptibility gene. Significant variations in HLA genetic susceptibility to type 1 diabetes between Caucasians, African and Asian and other ethnic groups may have led to the variation in incidence of type 1 diabetes globally. Type 1 diabetes is characterized upon HLA identification. In this chapter we discuss global variations in genetic susceptibility of HLA with regard to type 1 diabetes globally with a particular attention to Arab population. Methods): Haplotype configuration of HLA class I A, B, C and Class II –DR/DQ/DP were studied in Caucasians, African and Asian and in Arab population to see if that is responsible for the exponential rise in the rate of type 1 diabetes. Results): Although Arabs have one of the highest global incidence and prevalence rates of type 1 diabetes, unfortunately, there is a dearth amount of information regarding HLA genetic susceptibility to type 1 diabetes in the Arab world. HLA haplotype configurations contribute to its risk value. However, out of an insufficient present study there are examples of misjudgment of HLA risk according to HLA alleles rather than haplotypes. Conclusion): To date HLA outlooks for the characterization of type 1 diabetes. There is an ethnicity difference in HLA characteristics which is responsible for variation in type 1 diabetes. Although Arab population have contributed heavily in the rise of burden of type 1 diabetes, however, there is significantly a dearth amount of studies on HLA in Arab population. Obviously, any future prediction, prevention or cure of the disease will be based on the HLA genetics. There is a dire need for a systematic screening of HLA for Arab population with type 1 diabetes, identification of Arab HLA-risk values and identify those who are prone to get the disease.
Tue, 7 February 2017
REVIEW | doi:10.20944/preprints201702.0020.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: alpha-synuclein; Parkinsons disease; dementia with Lewy bodies; multiple system atrophy; tunelling nanotube; glymphatic system; cell-to-cell spread
Online: 7 February 2017 (03:24:21 CET)
Intracellular aggregates of the alpha-synuclein protein result in cell loss and dysfunction in Parkinson’s disease and atypical parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as alpha-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby alpha-synuclein aggregates in turn mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of alpha-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of alpha-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunnelling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which alpha-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease.
Fri, 20 December 2019
CASE REPORT | doi:10.20944/preprints201912.0264.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: glioblastoma; brain tumor; paleolithic diet; ketogenic diet; paleolithic ketogenic diet; metabolic therapy; intestinal permeability; cancer treatment
Online: 20 December 2019 (06:36:16 CET)
Studies in animal models have suggested that the ketogenic diet may be effective in the treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far, failed to show benefits in cancer survival or in any other hard clinical endpoints of the disease. This paper presents a case report of a patient with glioblastoma multiforme. The patient had initially been treated with standard oncotherapy including surgery, radiotherapy and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the glioblastoma seven months later. Subsequently, the patient refused radiotherapy and chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy. Following the adoption of the PKD, progression of the disease has been completely halted. At the time of writing, the patient has remained in remission for 38 months, is without side-effects and experiences an excellent quality of life without the use of any drugs.
Fri, 28 October 2016
REVIEW | doi:10.20944/preprints201610.0125.v1
Subject: Medicine & Pharmacology, Other Keywords: herbal medicinal products; food supplements; botanicals; normative; phytotherapy; Italian pharmaceutical market; parapharmaceuticals
Online: 28 October 2016 (08:06:07 CEST)
The Italian herbal products market is the most prosperous in Europe. The proof is represented by the use of these products in several marketing categories, ranging from medicine to nutrition and cosmetics. Market and legislation in Italy are at the same time cause and consequence of this peculiar situation. In fact, the legislation on botanical food supplements in Italy is very permissive and at the same time the market shows an overall satisfaction of users and strong feedback in terms of consumption, which brings a widening use of medicinal plants, formerly the prerogative of pharmaceuticals, to other fields such as nutrition. This review summarizes the market and normative panorama of herbal products in Italy, highlighting the blurred boundaries of health indications, marketing authorizations and quality controls between herbal medicines and non pharmaceutical products, such as food supplements, cosmetics and other herbal-based “parapharmaceuticals”.
Sun, 23 February 2020
ARTICLE | doi:10.20944/preprints202002.0308.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: SARS-CoV-2; COVID-19; 3CL protease; molecular docking; molecular dynamics and simulations
Online: 23 February 2020 (02:17:46 CET)
The SARS-CoV-2 was confirmed to cause the regional outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China. The 3C-like protease (3CLpro), an essential enzyme for viral replication, is a valid target to compacts SARS-CoV and MERS-CoV. In this research, an integrated library consisting of 1000 compounds from Asinex Focused Covalent (AFCL) library and 16 FDA-approved protease inhibitors were screened against SARS-CoV-2 3CLpro. Top compounds with significant docking scores and making stable interactions with catalytic dyad residues were obtained. The screening results in identification of compound 621 from AFCL library as well as Paritaprevir and Simeprevir from FDA-approved protease inhibitors as potential inhibitors of SARS-CoV-2 3CLpro. The mechanism and dynamic stability of binding between the identified compounds and SARS-CoV-2 3CLpro were characterized using 50 nanoseconds (ns) molecular dynamic (MD) simulation approach. The identified compounds are potential inhibitors worthy of further development as SARS-CoV-2 3CLpro inhibitors/drugs. Importantly, the identified FDA-approved therapeutics could be ready for clinical trials to treat infected patients and help to curb the COVID-19.
Tue, 30 August 2016