Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; coronavirus; severe acute respiratory syndrome coronavirus
Online: 5 July 2020 (10:16:43 CEST)
Background: The information on the difference in clinical characteristics between severe and non-severe cases is limited in some countries including Iran. The objective of this case series is to compare the clinical characteristics, radiologic features, and laboratory findings between COVID-19 severe cases who received the intensive care unit (ICU) care with non-severe cases who did not receive ICU care. Methods: In this retrospective cohort study, 186 laboratory-confirmed patients with COVID-19 diagnosed from 1 March 2020 to 30 March 2020 were investigated. Results: This study population included 186 hospitalized patients with confirmed COVID-19. The median age was 47 years, and 88 (47.31%) were female. Of these patients, 48 were admitted and transferred to ICU. Of 186 patients, 44.62% had medical comorbidities including hypertension and diabetes. The most common clinical manifestation were shortness of breath 86.56%, myalgia 74.19%, and headache. Higher neutrophil counts, CRP, and LDH as well as the lower levels of lymphocytes were the most important laboratory finding among COVID-19 patients. As of April 15, 2020, 33 were still hospitalized. A total of 116 patients (62.70 %) had been discharged, and 36 patients (19.94 %) had died. Of the 48 patients admitted to the ICU, 33.33% have died. Conclusion: In the present study, shortness of breath was the most common clinical symptom, and the mortality rate in patients admitted to the ICU was about 33%, indicating that about one-third of patients with severe illness who admitted to the ICU section died.
ARTICLE | doi:10.20944/preprints202007.0046.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Hantavirus cardiopulmonary syndrome; Hantavirus pulmonary syndrome; extracorporeal membrane oxygenation; transpulmonary thermodilution; high volume hemofiltration; Andes Hantavirus
Online: 5 July 2020 (05:24:11 CEST)
Background: Hantavirus cardiopulmonary syndrome (HCPS) has a high lethality. About two-thirds of the severe cases may be rescued by extracorporeal membrane oxygenation (ECMO). However, about half of the patients supported by ECMO suffer major complications. High volume hemofiltration (HVHF) is a depurative extracorporeal support that provides homeostatic balance allowing hemodynamic stabilization in some critically ill patients. Methods: We implemented HVHF prior to ECMO consideration in the last five severe HCPS patients requiring mechanical ventilation and vasoactive drugs admitted to our intensive care unit. Patients were considered HVHF-responders if ECMO was avoided and nonresponders if ECMO support was needed. Results: The first two patients required ECMO, while the last three did not. Patients had a maximum serum lactate of 8.4 [4.3-14] mMol/L and a lowest cardiac index of 1.76 [1.45-2.9] L/min/m2. Nonresponders were connected later to HVHF, displayed progressive tachycardia and decreasing stroke volume. The opposite was true for HVHF-responders who also received targeted-HVHF compounded by aggressive hyperoncotic albumin, sodium bicarbonate and calcium supplementation plus ultrafiltration to avoid fluid overload. All patients survived, but one of the ECMO patients suffered a vascular complication. Conclusion: HVHF may contribute to support severe HCPS patients avoiding the need for ECMO in some of them. Early connection and targeted-HVHF may increase the chance of success.
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.
Fri, 26 June 2020
ARTICLE | doi:10.20944/preprints202006.0318.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: ventilator; pandemic; ventilation; influenza pandemic; coronavirus; coronavirus pandemic; pandemic ventilator; single-limb; open source; open hardware; COVID-19; medical hardware; RepRap; 3-D printing; open source medical hardware; embedded systems; real-time operating system
Online: 26 June 2020 (17:25:16 CEST)
This study describes the development of an automated bag valve mask (BVM) compression system, which, during acute shortages and supply chain disruptions can serve as a temporary emergency ventilator. The resuscitation system is based on the Arduino controller with a real-time operating system installed on a largely RepRap 3-D printable parametric component-based structure. The cost of the system is under $170, which makes it affordable for replication by makers around the world. The device provides a controlled breathing mode with tidal volumes from 100 to 800 milliliters, breathing rates from 5 to 40 breaths/minute, and inspiratory-to-expiratory ratio from 1:1 to 1:4. The system is designed for reliability and scalability of measurement circuits through the use of the serial peripheral interface and has the ability to connect additional hardware due to the object-oriented algorithmic approach. Experimental results demonstrate repeatability and accuracy exceeding human capabilities in BVM-based manual ventilation. Future work is necessary to further develop and test the system to make it acceptable for deployment outside of emergencies in clinical environments, however, the nature of the design is such that desired features are relatively easy to add with the test using protocols and parametric design files provided.
ARTICLE | doi:10.20944/preprints202006.0310.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Scientific research; Frauds; Reliability; Distrust; Distributed Ledger Technologies
Online: 26 June 2020 (12:18:41 CEST)
Frauds and misconducts have been common in the history of science. Recent events connected to the COVID-19 pandemic have highlighted how the risks and consequences of this are no longer acceptable. Two papers, addressing the treatment of COVID-19, have been published in two of the most prestigious medical journals. In both, the authors declared to have analysed electronic records from a private corporation, which apparently collected data of tens of thousands of patients, coming from thousands of hospitals. Both papers have been retracted a few weeks later. When such events happen, the confidence of the population in scientific research is likely to be weakened. The objective of this paper is to highlight how the current system endangers not only the reliability of scientific research, but also the very foundations of the trust system on which modern healthcare is based. Having shed the light on the dangers of a system without appropriate monitoring, we propose to improve the research process using the promising aspects of the distributed ledger technology which, thanks to the characteristics of immutability, decentralization and transparency, appears among the best solutions to avoid the repetition of the mistakes linked to the recent and past history of research.
Wed, 24 June 2020
ARTICLE | doi:10.20944/preprints202006.0295.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: insurance claims; reproducibility; propensity score; veridical data science; sensitivity analysis
Online: 24 June 2020 (09:51:17 CEST)
Medical insurance claims are becoming increasingly common data sources to answer a variety of questions in biomedical research. Although comprehensive in terms of longitudinal characterization of disease development and progression for a potentially large number of patients, population-based studies using these datasets require thoughtful modification to sample selection and analytic strategies, relative to other types of studies. Along with complex selection bias and missing data issues, claims-based studies are purely observational, which limits effective understanding and characterization of the treatment differences between groups being compared. All these issues contribute to a crisis in reproducibility and replication of comparative findings. This paper offers some practical guidance to the full analytical process, demonstrates methods for estimating causal treatment effects on several types of outcomes common to such studies, such as binary, count, time to event and longitudinally varying repeated measures outcomes, and aims to increase transparency and reproducibility. We provide an online version of the paper with readily implementable code for the entire analysis pipeline to serve as a guided tutorial for practitioners. The online version can be accessed at https://rydaro.github.io/. The analytic pipeline is illustrated using a sub-cohort of patients with advanced prostate cancer from the large Clinformatics TM Data Mart Database (OptumInsight, Eden Prairie, Minnesota), consisting of 73 million distinct private payer insurees from 2001-2016.
ARTICLE | doi:10.20944/preprints202006.0293.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Covid-19; SARS-CoV-2; doxycycline; pentoxifylline; treatment; proposal
Online: 24 June 2020 (09:47:14 CEST)
We are proposing, for any interested investigator, a randomized open clinical trial for mild and mild-to-moderate Covid-19 comparing a treatment regimen with standard of care, and eventually with another investigational regimen, if ongoing or will be implemented. The patients could be hospitalized or ambulatory but not requiring admission to intensive care units and mechanical ventilation. The proposed therapeutic regimen consists of doxycycline (an antimicrobial having also anti-inflammatory properties, probable antioxidant and possible some antiviral effects), and pentoxifylline, a hemorheological compound used in occlusive arterial diseases but also having proven anti-inflammatory properties. Doxycycline is included in the WHO’s list of essential medicine being an effective, safe, widely available, and inexpensive medication and widely accessible. It will be administered at a dosage of 100 mg orally twice daily for ten days. Pentoxifylline, in clinical use since 1972, and also widely accessible, will be given at a dosage of 400 mg orally, also twice daily, for ten days. The primary outcome measures are: 1) Progression of disease to a severe form requiring intensive care admission and mechanical ventilation; 2) Fatality rates and 3) Time to clinical recovery.This proposal was presented to the National Directors and Core Leads meeting of the Canadian Trials Network (CTN) on May 6, 2020. The interventional trial template suggested by CTN was used for designing the trial.
ARTICLE | doi:10.20944/preprints202006.0287.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Covid-19; quality of life; mental health; physical health
Online: 24 June 2020 (09:29:00 CEST)
Introduction:The majority of epidemiological reports focus on confirmed cases of COVID-19. In this study, we aim to assess the health and well-being of adults not infected with Covid-19 after two months of quarantine in Morocco.Materials and methods:Two months after the declaration of quarantine in Morocco following the Covid-19 epidemic, we carried out a descriptive cross-sectional study of 279 Moroccan citizens. We used the Short Form Health Survey (SF-12) as a determinant of quality of life, which is based on eight dimensions of health. The data were collected using an electronic questionnaire distributed online. The participants also indicated their socio-demographic data, their knowledge and practices regarding the Covid-19 pandemic and whether they had chronic health problems.Results:The quality of life of all participants was moderately disrupted during the Covid-19 pandemic with a mental health score (MCS) of 34.49 (± 6.44) and a physical health score (PCS) of 36.10 (± 5.82). Participants with chronic diseases scored lower with 29.28 (± 1.23) in mental health (MCS) and 32.51 (± 7.14) in physical health (PCS). The seriousness of COVID-19 has an impact on the quality of life and health well-being of people and this impact is more marked in patients with chronic health problems.Conclusion: Our results confirm the need to pay attention to the health of people who have not been infected with the virus. Our results also point out that uninfected people with chronic illnesses may be more likely to have well-being problems due to quarantine restrictions.
Tue, 23 June 2020
REVIEW | doi:10.20944/preprints202006.0284.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; RT-PCR; antibody; zoonotic; animal transmission; genomics; asymptomatic fraction; herd immunity
Online: 23 June 2020 (13:30:11 CEST)
Since December 2019, a rapid increase in the number of SARS-CoV-2 (COVID-19) cases was reported worldwide, despite strict infection control and lock down measures. Current paper investigated the actual facts behind this rapid increase in the number of cases. Study of genomic sequence reveals that domestic and wild animals were likely ancestors and zoonotic source for SARS-CoVs, MERS-CoVs, and SARS-CoV-2. Strong evidence suggest that these viruses already existed and replicated in animals and humans during past several decades, exhibiting diverse mutations, evolutions and self-limiting diseases, except during outbreaks. Serious zoonotic reservoir investigations are required to investigate animal transmission of SARS-CoVs and SARS-CoV-2 to limit current pandemic. This might be the reason of increasing number of cases via animals. SARS-CoV-2 has been retrospectively isolated in different studies in August 2019, several months before Wuhan announced. Hence, there is a possibility that viruses existed, went undetected, infecting subclinically, in past several years, and SARS-CoV-2 antigens and neutralizing antibodies may have been present in humans since long time. This might be another reason of increasing number of cases by screening as mass screening and antigen or antibody testing was not carried out in the past years. Randomized controlled trials are required to investigate human to human transmission by touch, as the current evidence is limited with conflicting results. As all SARS-CoVs are basically respiratory viruses, droplet precautions and infection control measures are essential, especially for hospital staff. Increased number of SARS-CoV-2 asymptomatic, or subclinical cases are detected worldwide. This silent phase of transmission can be beneficial for humans. Lack of symptoms eventually lessen virus transmission and reduce the pathogen's long-term survival and provide humoral herd immunity up to several years. Hence, seropositivity with diverse antibodies develops against mutating SARS-CoVs which will confer strong immunity during epidemics. Strategies such as identification, contact tracing and quarantine are costly and practically difficult. Hence, asymptomatic persons can continue their work with droplet precautions and standard infection control procedures, while symptomatic or sick persons can isolate themselves in their homes without the need for strict quarantine until clinical recovery, with reduced hospital visits and minimizing chances of hospital acquired infections. RT-PCR has low sensitivity and specificity, carries a high risk of handling live virus antigens, and requires difficult protocols. As viral load also sharply declines after few days of onset of infection, this technique might overlook infection. Furthermore, SARS-CoV-2 infection may be present in blood when oropharyngeal swabs are negative by RT-PCR. Additionally, RT-PCR usually gives false negative and false positive results and must be interpreted cautiously. This might be again a reason of increasing number of cases by false positive RT-PCR reporting. Moreover, antibodies against SARS-CoVs develop robustly in serum even by reduced amount of antigens. In contrast to RT-PCR, ELISA for diagnosing antibodies against SARS-CoV-2 demonstrates 100% specificity and 100% sensitivity, even in clinically asymptomatic individuals. These antibodies can be used for serologic surveys, monitoring and screening. However, screening tests for SARS-COV-2 should be avoided in unhygienic public places by nasopharyngeal swabs, which carry a high risk of further transmission, co-infection or superinfection. Such highly infectious virus must be isolated and tested in highly sterilized laboratory. Further strict international laws and policies are required to stop the possible spread of experimental viruses, biological warfare and bioterrorism.
ARTICLE | doi:10.20944/preprints202006.0283.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Metabolic Syndrome; Obesity; inflammation; Oxidative Stress; nitrosative stress; biomarkers
Online: 23 June 2020 (11:35:38 CEST)
Purpose: To investigate the alterations in nitro-oxidative stress (OS) and antioxidant status in adolescents with metabolic syndrome (MetS) and whether these alterations occur independently from effects of overweight or obesity.Methods: Blood was collected in 47 adolescents with MetS and 94 adolescents without MetS as assessed with the International Diabetes Federation criteria. The International Obesity Task Force (IOTF) criteria were used to classify the subjects into those with overweight or obesity. We measured nitro-oxidative biomarkers including nitric oxide metabolites (NOx), lipid hydroperoxides (LOOH), and malondialdehyde (MDA), and antioxidant biomarkers, i.e. total radical-trapping antioxidant parameter (TRAP), paraoxonase (PON)-1 activity, thiol (SH-) groups, as well as tumor necrosis factor-α, glucose, insulin, triglycerides, uric acid and high-density lipoprotein cholesterol (HDL-C).Results: Logistic regression analysis showed that increased MDA and NOx and a lowered TRAP/uric acid ratio were associated with MetS. Machine learning including soft independent modeling of class analogy (SIMCA) showed that the top-3 most important features of MetS were increased glucose and MDA and lowered HDL-C. Support vector machine using MDA, glucose, insulin, HDL-C, triglycerides and body mass index as input variables yielded a 10-fold cross-validated accuracy of 89.8% when discriminating MetS from controls. The association between MetS and increased MDA was independent from the effects of overweight-obesity. glucose, insulin, triglycerides and HDL-C.Conclusion: In adolescents, increased MDA formation is a key component of MetS, indicating that increased production of reactive oxygen species with consequent lipid peroxidation and aldehyde formation participate in the development of MetS.
Sun, 21 June 2020
CASE REPORT | doi:10.20944/preprints202006.0282.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; mesenteric vein thrombosis
Online: 21 June 2020 (16:44:51 CEST)
Since its inception in December 2019, Covid-19 has challenged the global scientific community. Some treatments were used in this infection, but doubts still persist regarding the use of medications 1. More severe cases complicate with endothelial dysfunction, excess thrombin synthesis and decreased fibrinolysis which, associated with hypoxemia, lead to a hypercoagulability state 2 and some authors indicate the use of anticoagulants for these 3. For mild cases, doubts remain regarding this indication. We will report the case of a patient with mild symptoms of covid-19, complicated by inferior mesenteric vein thrombosis.
ARTICLE | doi:10.20944/preprints202006.0275.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; COVID-19; real-time RT-PCR; COVID-19 symptoms; COVID-19 hematological findings; Bangladesh
Online: 21 June 2020 (14:47:03 CEST)
Objective: SARS-Cov-2 infection or COVID-19 is a global pandemic. From the time of identification to till, multiple clinical symptoms and parameters have been identified by the researchers of various countries and regions regarding the diagnosis and presentations of COVID-19 disease. In this manuscript, we investigated the primary symptoms and basic hematological presentations of SARS-CoV-2 infection among the Bangladeshi patients. Methodology: We have collected the disease history of mild to moderate degree of COVID-19 patients; hematological and biochemical on admission reports of moderate degree COVID-19 patients. All of them were tested positive for SARS-CoV-2 by RT-PCR in different institutes in Bangladesh. Results: According to this study though COVID-19 patients in Bangladesh commonly presented with fever, cough, fatigue, shortness of breath, and sore throat, but symptoms like myalgia, diarrhea, skin rash, headache, Abdominal pain/cramp, nausea, vomiting, restlessness, and a higher temperature of >1000F have a greater presentation rate and more frequent than other published studies. CRP and Prothrombin time was found to increase in all the patients. Serum ferritin, ESR, SGPT, and D-Dimer were found increased among 53.85%, 80.43, 44%, and 25% patients respectively. 17.39% of the patients had leukocytosis and neutrophilia. 28.26% of patients presented with lymphocytopenia. 62.52% of patients had mild erythrocytopenia. Conclusion: Despite some similarities, our study has evaluated a different expression in presenting symptoms in the case of COVID-19 patients in Bangladesh. CRP, Prothrombin time, serum ferritin, ESR, SGPT, D-Dimer, erythrocytopenia, and lymphocytopenia can be initial diagnostic hematological findings and assessment for prognosis COVID-19 disease. Also, gender variations have a different scenario of clinical and laboratory appearance in this region.
ARTICLE | doi:10.20944/preprints202006.0252.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Salmonella typhi; control; Widal test; incidence
Online: 21 June 2020 (10:23:15 CEST)
Typhoid fever is a communicable disease transmitted by the bacteria Salmonella typhi, related to serotype paratyphi A, B and C. The disease is of a significant health concern in most developing countries especially Cameroon. Objectives: The study aimed at determining the prevalence and associated risk factors of typhoid fever in children ( 0-18 years) attending the “Deo Gratias” hospital in Douala. Method: A hospital base cross sectional study from August to September 2018 was carried out in patients’ age 0-18 years suffering from typhoid fever at the Deo gratias Catholic hospital. Widal slide agglutination test was the diagnostic test used. Positive tested patients were administered questionnaires to evaluate the level of knowledge, attitude and practice toward the disease, as well as their self-management abilities. Data obtained from respondents was analysed by descriptive statistics. One-way ANOVA and means comparison using Tukey’s test (α = 0.05) was performed to check whether the population of respondents differed significantly across risk factor practices. Results were finally presented on bar charts, tables and pie chart. Results: Typhoid fever was more prevalent in females (52.3%) than in males (47.7%), with a high proportion in the ages 5-9 years (38.6%). A significant difference was observed in population of respondents across risk factor practices. Conclusion: Water quality have a great impact on the burden of typhoid fever among children. The identification of risk factors associated to the disease is of great importance in the development of rational control strategies of the disease.
Tue, 9 June 2020
REVIEW | doi:10.20944/preprints202006.0120.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; COVID-19; pathogenesis; children; neonates; immune response; secondary hemophagocytic lymphohistiocytosis; renin-angiotensin system; genetic polymorphisms; ACE2; AGTR2; AGTR1; NOS; lung injury
Online: 9 June 2020 (08:07:40 CEST)
The spread of the infection caused by the new coronavirus SARS-CoV-2 (COVID-19) became pandemic on March 11, 2020. From the time of the first cases (in November 2019, Wuhan, China), to date, a large number of COVID-19 observations have been accumulated in different age groups of patients both in China and abroad. Published scientific data allows us to conclude that children suffer from COVID-19 much less often than adults and tolerate the disease in a milder form, often appear to be asymptomatic. There is currently no final answer why children are less susceptible to this virus; however, scientists are increasingly inclined to consider a complex effect of the immune response and components of the renin-angiotensin system (RAS), which according to recent studies affects not only the cardiovascular system, but is also responsible for the activation of inflammatory reactions. A hypothesis of genetic predisposition to the development of severe forms of COVID-19 has recently been made. We conducted a search for publications in the databases and showed current scientific ideas about COVID-19 pathogenesis and factors influencing the disease development in childhood. Childhood immunity may have several protective features against SARS-CoV-2: immaturity of particular elements of the innate immune response, constitutional lymphocytosis with a shift towards anti-inflammatory Th2-response, as well as "trained" immunity. The influence of renin-angiotensin system reactions in this review is shown from two perspectives: expression of ACE2 receptors and polymorphisms of certain genes of this system. It was established that ACE2 transmembrane protein is not only the entry point for the virus but also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1-7), which has vasodilating properties. Higher ACE2 content in children compared with adults helps maintain balance in the renin-angiotensin system and prevents the development of complications. It was also shown that the presence of certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) could determine the imbalance inside the RAS, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift towards vasoconstrictor, proliferative and profibrotic mechanisms.
Sun, 7 June 2020
ARTICLE | doi:10.20944/preprints202006.0096.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Social Distancing; Pandemics; COVID-19; Digital Healthcare; UHC
Online: 7 June 2020 (15:08:44 CEST)
COVID-19 has been a major issue in most countries throughout the world with 213 countries being affected till date due to the disease. The pandemic has raised concerns over the healthcare facilities available in various countries and question the government decisions made during this period of outbreak. Despite having the best healthcare facilities several countries across Europe and America have found it difficult to contain the disease outbreak questioning the available solutions to contain an area. This paper focuses on presenting information on solutions available to control outbreaks in order to prevent another pandemic occurring in the future. The paper also highlights the strategies and plans implemented by various governments who have been successful in combatting the disease with minimum damage. By using available resources such as technology, scientific innovation and digitalized healthcare this paper focuses on providing solutions which are already available to be utilized in the right manner.
ARTICLE | doi:10.20944/preprints202006.0094.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: CCCP; Mitophagy; Regulatory T cells; Flow cytometry; fluorescence microscopy
Online: 7 June 2020 (15:03:23 CEST)
Objective: To investigate the effects and mechanisms of different concentrations of CCCP on mitophagy in human peripheral blood regulatory T cells. Methods: Tregs were isolated, identified and then grouped, treating with CCCP at a concentration of 2.5 μM, 5 μM, 10 μM, 20 μM and 40 μM for 24h in an incubator. Flow cytometry detected the reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial quality, and fluorescence microscopy observed the co-localization of mitochondria and lysosomes in each group. Results: The purity of CD4+CD25+Tregs was (93.36 ± 1.87) %. With the increase of CCCP concentration, the level of ROS gradually increased, while the MMP decreased gradually. About the mitochondria and lysosome fusion, the fluorescence intensity of orange (yellow) was the highest when the concentration of CCCP was in the range of 5-10 μM while decreased with the CCCP concentration continually increasing. The mitochondrial quality decreased with the increase of CCCP concentration. However, there was no significant difference between groups C, D and E. The mitochondrial quality of groups F and G were significantly lower than that of group E. Conclusions: With the concentration of CCCP gradually increased, the level of ROS in Treg cells increased, and MMP decreased, which promoted the mitophagy, mitochondrial quality maintains homeostasis; When ROS accumulated, and MMP decreased significantly, the mitophagy was inhibited, and the mitochondrial quality was significantly decreased.
Thu, 4 June 2020
REVIEW | doi:10.20944/preprints202006.0041.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; COVID-19; 2019-nCOV; Shedding; Detection
Online: 4 June 2020 (17:34:28 CEST)
There is a new public health crisis threatening the world with the emergence and spread of novel coronavirus (SARS-CoV-2). The outbreak of coronavirus disease 2019 (COVID-19), which originated in Wuhan, China, in December 2019, has been declared a public health emergency of international concern by WHO. Most patients infected with SARS-CoV-2 exhibited symptoms of fever, cough, myalgia, fatigue and shortness of breath. Many infected people may be asymptomatic. It is generally believed that airway exposure to respiratory droplets from an infected patient is the main transmission route of this disease. However, apart from respiratory source, other source specimens like faecal matter and urine could be possible for COVID-19 infectivity. The spreading other routes of the virus has been alarming sign, both for public and health care professionals. Understanding the spreading routes of SARS-CoV-2 is crucial for patient management and defining biosafety strategies for public and health care workers.
Wed, 3 June 2020
ARTICLE | doi:10.20944/preprints202006.0011.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: diabetes mellitus; insulin resistance; inflammation; biomarkers; atherogenicity
Online: 3 June 2020 (05:41:03 CEST)
Background: Type 2 diabetes mellitus (T2DM) is associated with increased atherogenicity and inflammatory responses, which may be related to increased levels of high mobility group box 1 (HMGB1) and Dickkopf-related protein 1 (DKK1). Objective: The role of HMGB1 and DKK1 in T2DM is examined in association with lipid and insulin profiles. Methods: Serum HMGB1 and DKK1 were measured in T2DM with and without hypertension and compared with controls. Results: HMGB1 and DKK1 are significantly higher in T2DM irrespective of hypertension. T2DM was also accompanied by increased atherogenicity indices. HMGB1 and DKK1 are significantly correlated with HbA1c, glucose, indices of insulin resistance, β-cell function, and glucose toxicity, and different atherogenic indices. A large part of the variance in the β-cell index (30.5%) and glucose toxicity (34.8%) was explained by the combined effects of HMGB1 and DKK1 and hypertension. We found that 18.3% of the variance of the atherogenic index of plasma was explained by HMGB1 and DKK1 levels and that 31.2% was explained by glucose toxicity, HMGB1 and body weight. Conclusion: The higher serum HMGB1 and DKK1 levels in T2DM patients and the associations with atherogenicity indicate that low grade inflammation and disorders in the Wnt pathways are associated with T2DM and that both HMGB1 and DKK1 may contribute to increased atherogenicity in T2DM. Moreover, both biomarkers may cause more deficits in β-cell function and increase glucose toxicity leading to the development of more inflammation and diabetic complications. HMGB1 and the Wnt pathways are new drug targets in the treatment of T2DM.
ARTICLE | doi:10.20944/preprints202004.0374.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; coronavirus; infectious disease; infection management; PCR test; mortality; kinetic analysis
Online: 3 June 2020 (05:10:05 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, including developed and developing countries. The changes as a proportion of national population were compared, adjusting by the beginning of test-positive cases increase (BPI) or deaths increase (BDI). Remarkable regional differences of more than 100 fold in NPDP and NPDD were observed. The trajectories of NPDD after BDI increased exponentially within 20 days in most countries. Machine learning analysis suggested that NPDD on 30 days after BDI was the highest in developed Western countries (1180 persons per hundred million), followed by countries in the Middle East (128), Latin America (97), and Asia (7). Furthermore, in Western countries with positive rates of the PCR test of less than 7.0%, the increase in NPDP was slowing-down two weeks after BPI, and subsequent NPDD was only 15% compared with those with higher positive rates, which suggested that the situation of testing might have affected the velocity of COVID-19 spread. The causes behind remarkable differences between regions possibly include genetic factors of inhabitants because distributions of the race and of the observed infection increasing rates were in good agreement globally.
Tue, 2 June 2020
ARTICLE | doi:10.20944/preprints202006.0001.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Copper; transfusion-dependent thalassemia; zinc; oxidative stress; antioxidants; biomarkers
Online: 2 June 2020 (09:21:13 CEST)
Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.Aim of the study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. Methods: This study recruited 60 children with TDT and 30 healthy children aged 3-12 years old.Results: Zinc was significantly higher in TDT children than in control children, whilst copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.
Sun, 31 May 2020
REVIEW | doi:10.20944/preprints202005.0487.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: coronavirus; COVID-19; coronavirus etiology; coronavirus pathogenicity
Online: 31 May 2020 (18:16:48 CEST)
Coronavirus Disease 2019 (COVID-19) is a respiratory illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It is considered to be first reported from Wuhan, Hubei Province, China in December 2019. As of present, there are over 3.7 million identified cases worldwide and more than 259,000 deaths have been reported. This disease, its incubation period, course, complications, and the basis of spread remains a potential question due to variation in the pattern of spread around the globe and relatively fewer number of large-scale studies at present. This literature review aims to study the available data on its spread and incubation period. A literature search using PubMed with regular keywords ‘coronavirus’ and ‘COVID-19’, and Medical Subject Headings (MeSH) search for their etiology and pathogenicity was done with the search builder. The literature search revealed 26,689 studies among which 14 studies were selected for review. Studies were selected after the application of inclusion criteria and exclusion criteria with the removal of duplicates, and careful review for the outcome of interest ‘incubation period’. Among the 14 studies selected for review, there were eight review articles, five case reports, and one comparative study. The current literature review concludes that the mean incubation period for most of the literature falls between five days to 12 days with minimum reported time from known exposure to the onset of a symptom being one day and the maximum reported time from exposure to the onset of a symptom being 18 days.
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.
Sat, 23 May 2020
COMMUNICATION | doi:10.20944/preprints202005.0367.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; COVID-19; viral load; children
Online: 23 May 2020 (10:15:07 CEST)
Background: The question of whether children are less likely to pass on SARS-CoV-2 is important for planning society’s response to the pandemic. A document available on the Charité hospital website has not been formally published but is frequently referred to as supporting the notion that viral loads are similar in children and adults. Methods: The summary data from this document was extracted and used to produce summary statistics for three age groups: younger children (ages up to 11), older children (ages 12 to 19) and adults (ages 20 and above). Viral loads between the two children’s groups and the adult group were compared using Welch’s t test, which only requires group means and standard deviations and which is robust against moderate departures from normality. Findings: Viral loads were significantly lower than in adults for both younger children (p=0.04) and older children (p=0.04). Overall, viral loads were lower in children than adults (p=0.005). Interpretation: For both younger and older children, on average those with detectable SARS-CoV-2 have significantly lower viral loads than adults. Funding: No funding was received for this analysis.
ARTICLE | doi:10.20944/preprints202005.0365.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; smoking; nicotine; nicotinic cholinergic system; inflammation; acetylcholine receptors
Online: 23 May 2020 (10:06:14 CEST)
While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine for other potential interactions between the virus and other cell receptors. Based on the clinical observation of low smoking prevalence among hospitalized COVID-19 patients, we recently identified a “toxin-like” amino acid (aa) sequence on the receptor binding domain of the spike glycoprotein of SARS-CoV-2 (aa 375-390) with homology to a sequence of a snake venom toxin, which could interact with nicotinic acetylcholine receptors (nAChRs). We now present computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 spike glycoprotein and the extracellular domain of the nAChR alpha9 subunit. We identified an interaction between the aa381-386 of the SARS-CoV-2 spike glycoprotein and the aa189-192 of the extracellular domain of the nAChR alpha9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the alpha9 nAChR and alpha-bungarotoxin. A similar interaction was observed between the pentameric alpha7 AChR and the SARS-CoV-2 spike glycoprotein. Our findings support the hypothesis that severe COVID-19 may be associated with disruption of the nicotinic cholinergic system which could be caused by an interaction between SARS-CoV-2 and nAChRs.
ARTICLE | doi:10.20944/preprints202005.0362.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: cross-sectional survey; antibiotic use; antimicrobial resistance; knowledge; brunei
Online: 23 May 2020 (05:54:43 CEST)
Background: Public misconception and demand for the indication of antibiotics could lead to inappropriate prescribing and consumption. Successful treatment can only be achieved when the public and industrial users have knowledge on antibiotic use and resistance. This survey is aimed to assess antibiotic usage and knowledge regarding antibiotics and antimicrobial resistance (AMR) among undergraduate students of Universiti Brunei Darussalam (UBD), public university located in Brunei Darussalam. Methods: A cross-sectional study was performed using a self-administered questionnaire. The questionnaire was adapted from the World Health Organization (WHO) Antibiotic Resistance, Multi-country public awareness survey distributed online. Students at UBD were invited to participate in the online survey through internal email. The questionnaire consisted of 5 sections: demographic information, antibiotic usage, knowledge on antibiotics, antibiotic resistance (AMR) and use of antibiotics in agriculture. Data were analyzed descriptively and appropriate inferential statistics was used accordingly. Cronbach’s alpha was also done to determine the internal consistency. The section on antibiotic use and knowledge showed good internal consistency of Cronbach’s alpha 0.66 and 0.86 respectively. Research ethics approval was obtained from the PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam (UBD). Results: A total of 145 students returned the complete questionnaire. The result of the study found that 50% of the students had good level of knowledge of antibiotic and antimicrobial resistance with a mean total knowledge score of 11.4 out of 14. Respondents reported the use of antibiotic in the past (69%). Many of the students could identify the use of antibiotics for the treatment of bacterial infection. However, there were also students who incorrectly thought that antibiotics can be used for cold and flu (43%) and fever (41%). Moreover, 76% of the respondents mistakenly believed that antibiotic resistance is the result of the body becoming resistant to antibiotics. Only 12% of the respondents were found to have poor knowledge in the study. Conclusions: Misconceptions in regards to the use of antibiotics for conditions related to viral illnesses was noticed among the respondents in our study. Thus, improving knowledge on antibiotics is crucial to address those beliefs.
Fri, 22 May 2020
REVIEW | doi:10.20944/preprints202005.0352.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Health record; electronic health record; e-health record; the history of medicine; the economy of the healthcare system
Online: 22 May 2020 (10:48:18 CEST)
The history of health records (later also called medical records), including ones regarding individual patients, is thousands of years old. It finds it roots in the first ancient civilisations. Up until the 19th century the records’ purpose was mainly an educational one. In the 19th and 20th century they started becoming significant in other roles as well, including those not strictly limited to medicine. In particular, to account for medical procedures, insurance proceeds or legal action. Currently we are living in a revolutionary era when it comes to health records, in which their character has changed from a “paper-based” to an electronic one. This paper presents the development of health records from the ancient to modern times, mainly in Europe and North America. Other cultures and civilisations, including China and India, are not discussed. An analysis of available sources was conducted, inter alia digital versions of manuscripts up to hundreds of years old. The analysis was based on PubMed and Google Scholar (several key words, all the available sources). Sources published in non-international languages (e.g. Dutch) were also investigated. Overall, approximately 600 articles were analysed, 158 of which were used and cited in this paper. The conclusions drawn from the analysis are as follows: (1) Health records, priorly used mostly for educational purposes, for about 100 years now have acquired a fully formal status. (2) We are currently facing the most revolutionary changes regarding the transformation of paper-based records into electronic ones. (3) The consequences of this process include systematic applications of solutions within the area of e-health, which allow us to make medical services more flexible, improve the health of individual patients and entire populations and potentially limit expenditure. (4) In the light of the ongoing COVID-19 pandemic, introducing electronic health records could be beneficial in terms of limiting the potential sources of contamination (physical copies of health records), saving time and resources, and improving the network of communication between medical centres.
REVIEW | doi:10.20944/preprints202005.0350.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Medical documentation; medicine; public health; computer networks; artificial intelligence; AI; smart city
Online: 22 May 2020 (10:43:06 CEST)
This work addresses the problem of the application of artificial intelligence to the creation and maintenance of medical documentation and the use of big data in medicine to support efficient patient diagnosis and treatment. This study covers the latest advances in AI and big data, based on literature reviews and interviews with leading experts in these fields. The following conclusions were obtained: (1) Based on the needs of patients and providers of medical services, and given the latest technological advances, all medical documentation should be digital and the processes of its creation, access, sharing, and consistency checking should by supported by suitably designed AI systems. (2) The knowledge contained in medical documentation constitutes a resource of strategic importance for humanity, with almost unlimited potential. (3) All medical documentation should be anonymised and should be made widely available, just like data and research results in the field of experimental physics. (4) This will accelerate development of new treatments, best practice and help to identify new medical emergencies, such as Covid-19. In practice today, unfortunately, the design of medical record systems is fragmented between institutions and countries, often focusing discussions on narrow technical details, and forcing clinicians to waste time on filling up multiple pages of illness history. This leads to many inefficiencies and lost opportunities and necessitates a fundamentally new approach.
Thu, 21 May 2020
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVI-19; SARS-CoV-2; virus; mutation; polymorphism; genome sequence
Online: 21 May 2020 (04:09:53 CEST)
Background: SARS-CoV-2 infection has spread to over 200 countries since it was first reported in December of 2019. Significant country-specific variations in infection and mortality rate have been noted. Although country-specific differences in public health response have had a large impact on infection rate control, it is currently unclear as to whether evolution of the virus itself has also contributed to variations in infection and mortality rate. Previous studies on SARS-CoV-2 mutations were based on the analysis of ~ 160 SARS-CoV-2 sequences available until mid-February 2020.2, 3, 4, 5 By mid-April, > 550 SARS-CoV-2 sequences had been deposited in GenBank, and over 8,200 in the GISAID database. Methods: We performed a sequence analysis on 474 SARS-CoV-2 genomes submitted to GenBank up to April 11, 2020 by multiple alignment using Map to a Reference Assembly and Variants/SNP identification. The results were verified on a larger scale, 8,126 hCoV-19 (SARS-CoV-2) sequences from GISAID database. Results: We identified 5 recently emerged mutations in many isolates (up to 40%). Our analysis highlights 5 frequent new mutations that have emerged since late February 2020. These mutations are: one each missense (non-synonymous) mutation in orf1ab (C1059T), orf3 (G25563T) and orf8 (C27964T), one in 5’UTR (C241T), one in a non-coding region (G29553A). The final mutation (G29553A) was found to be almost exclusive to the US isolates. The first 3 mutations are non-synonymous, leading to amino acid substitutions in the viral protein sequence. Except for C241T, all the novel mutations identified are absent in the isolates from Italy and Spain in the SARS-CoV-2 genomes deposited in GenBank and GISAID by April 13, 2020. Conclusion: The results of current study indicate that new mutations are emerging as COVID-19 pandemic are spreading to different countries and that geography specific mutants may exist. The findings of current study lay the foundation for further investigation into the impact of SARS-CoV-2 mutations on disease incidence, severity, and host immune response. In addition, it may also provide insights into vaccine development and serological response detection for the virus.
Sun, 17 May 2020
REVIEW | doi:10.20944/preprints202005.0282.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: telehealth; telemedicine; NCOVID-19; technology; management; regulations
Online: 17 May 2020 (08:09:18 CEST)
Telehealth has been playing a progressively major role in the management of the NCOVID-19 crisis. The enforcement of social distancing measures has had the consequence of reduced technology distance in almost every walk of life. In this paper, based primarily on the still unfolding experiences of deploying it during the current situation, we argue that telehealth has finally come of age and that it is time to move it from the peripheries to the center of the 21st century healthcare. To provide a live context to the discussion, several instances of how telehealth strengthened our healthcare systems during the NCOVID-19 crisis are presented.
Thu, 14 May 2020
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; Egypt; Epidemic SIR Model; Pandemic; Flattening the curve
Online: 14 May 2020 (15:12:16 CEST)
Background: Flattening the curve refers to community isolation measures that keep the daily number of disease cases at a manageable level for medical providers. Efforts to completely contain the COVID – 19 have failed. As there is currently no vaccine or specific medication to treat COVID-19, the only way to flatten the curve is through collective action of mitigation efforts. Objectives: The study was carried out with aim to study the effect of mitigation efforts in reducing the overall COVID -19 attack rate and flattening the curve of COVID-19 in Egypt. Methods: Secondary data in the situation reports of WHO, Worldometer and Egyptian MoHP Report about the COVID-19 epidemic in Egypt were analyzed till June 27, 2020. Survival analysis was carried out to determine the cumulative proportional survival of COVID-19. The Susceptible Infected Recovered (SIR) model was used to study the epidemic dynamics of COVID-19 pandemic. Results: In Egypt in the fourth week after exposure β was 0.17 and γ = 0.07. The fraction of infectious individuals will grow exponentially as the exponential growth rate was 0.10, with an epidemic time of 7 days. R in 22 nd June was 0.80 (less than one person infected) where β=0.21 and γ =0.26. There was reduction in the actual overall attack rate at 22nd June of 96 % of its value without intervention with a cumulative proportional survival of 0.89. There was flattening of the curve. Conclusion and Recommendation: Mitigation efforts of Egypt had succeeded in flattening the curve of COVID-19 Pandemic. Even though, strengthening all the mitigation efforts to keep the exposure probability, as well as the transmission rate as low as possible is mandatory for containment of the epidemic.
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.
Tue, 12 May 2020
ARTICLE | doi:10.20944/preprints202005.0212.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Annona squamosa; phytomedicine; proliferation; apoptosis; migration; estrogen receptor; tumor size
Online: 12 May 2020 (12:37:43 CEST)
: Annona squamosa L. is an important medicinal plant used in traditional medicine for the treatment of various diseases. Different parts of A. squamosa L. have various therapeutic effects; however, the anticancer activity of the leaves has not yet been identified. In vitro, MTT, nuclear staining, and LDH assays were used to evaluate cell survival and proliferation in cells exposed to the extracts. The effect of the extracts on cell migration was investigated using a monolayer wound repair assay, and the apoptotic effects were evaluated using flow cytometry. A breast cancer model was used to study the effect of the extract on the tumor size, and the expression of different proliferative and apoptotic markers was evaluated by immunohistochemical analysis. At a concentration of 100 µg/mL, A. squamosa leaf extracts exerted strong antiproliferative and cytotoxic effects against various cell lines. The extracts reduced wound closure and strongly induced apoptosis. In vivo study, rats were sacrificed 24 h after the last injection, and tumor size, as well as the expression of proliferative and apoptotic markers, were observed to be greatly affected by treatment with the extracts. Therefore, A. squamosa leaf extract may be developed as a potential novel drug to treat breast cancer in the future
HYPOTHESIS | doi:10.20944/preprints202004.0348.v3
Subject: Medicine & Pharmacology, General Medical Research Keywords: hydroxychloroquine; COVID-19; pneumonia; prophylaxis; treatment
Online: 12 May 2020 (08:06:55 CEST)
According to current literature and preliminary data, hydroxychloroquine (HCQ) seems potentially effective in the treatment of patients with Covid-19 pneumonia. The concentrations of HCQ in lungs might be well above that of plasma. Most likely, this property of HCQ provides effective drug concentrations in lungs. HCQ has a gradual onset of action in the treatment of rheumatic diseases. This could be valid for the treatment of Covid-19 pneumonia. It was suggested that regular HCQ administration in animals for a certain time might result in gradual accumulation of HCQ in tissues. Reduced perfusion, somewhat distorted architecture of lung tissue, edema and, suggested gradual accumulation of HCQ in lung tissue might cause reduced HCQ concentrations in pneumonic areas of the lungs in Covid-19 pneumonia. Patients with Covid-19 pneumonia and extensive lung involvement might have less HCQ concentrations in their lungs than patients having limited lung involvement. Furthermore, patients with Covid-19 pneumonia and extensive lung involvement might have more viral load than patients having limited lung involvement. That’s why treatment of patients with advanced Covid-19 pneumonia using HCQ might result in treatment failure, however HCQ might be effective in the treatment of patients with mild and moderate Covid-19 pneumonia. Using HCQ in Covid-19 pneumonia prophylaxis seems logical since providing enough accumulation of HCQ in the healthy lungs, before the arrival of the SARS-CoV-2 virus, might prevent Covid-19 pneumonia. However, the purpose of this paper is not to recommend using or not using HCQ for the treatment or for the prophylaxis of Covid-19 pneumonia. The purpose of this paper is only to try to bring a new perspective on the role of HCQ in the treatment or in the prophylaxis of Covid-19 pneumonia. This paper proposes only hypotheses, which need further researches to be confirmed.
Mon, 11 May 2020
ARTICLE | doi:10.20944/preprints202005.0197.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; Vietnam; Epidemiology; control; screening
Online: 11 May 2020 (13:02:32 CEST)
IntroductionThe aim of this study is to describe the epidemiology of all COVID-19 patients in Vietnam and to describe the measures of disease control and prevention implemented. MethodsData were recovered from Wikipedia regarding the 2020 coronavirus pandemic in Vietnam. The period covered was from 23 January to 20 April 2020. Descriptive analysis was stratified by gender, age, country of origin, travel history, clinical symptoms and outcome. A survey of disease control and prevention measures was conducted at the Centre for Disease Control in the Thai Binh province, which is responsible for screening and isolating individuals at high risk of COVID-19. ResultsAs of 20 April 2020, Vietnam had recorded 268 confirmed COVID-19 patients. 55.2% were female. 67.9% were aged 20-49 years and 82.5% were Vietnamese. 60.4% of cases were imported from outside Vietnam. Other cases were acquired in Vietnam by individuals in close contact with imported cases. Only one patient who had not travelled had had no known contact with a confirmed case. 63.1% of patients were asymptomatic. 75.7% of patients were discharged. No deaths were recorded. The Thai Binh CDC surveyed a total of 2,203 persons at risk of COVID-19. 336 persons (15.2%) were isolated at hospitals and 1,411 (64.0%) in dedicated isolation facilities. 16.4% reported at least one respiratory symptom. No positive cases confirmed by RT-PCR have been reported in the Thai Binh province to date. ConclusionThe effect of the systematic screening and isolation strategy made it possible to limit local transmission in Vietnam. Vietnam needs to reinforce diagnostic capacities, prevention measures and provide the necessary epidemiological data on which to base interventions. The wider use of rapid serological tests is also advisable in order to be able to conduct extensive screening in the community.
Sat, 9 May 2020
ARTICLE | doi:10.20944/preprints202005.0163.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; pulsoximeter; Internet of Things; maker culture; medically underserved area
Online: 9 May 2020 (10:55:48 CEST)
Family doctors can have an active role in identifying significant population needs and solutions. During COVID-19 epidemic, patient home monitoring with pulse oximetry has been a key aspect of care of patients. However, pandemics bring shortage medical equipment such as pulse oximetry. Through the local maker community in a matter of days four “smart” pulsoximeters were created and built. Following Internet of Things principles, the pulsoximeters were programmed to transmit recorded data through Wi-Fi, in real time, directly to the doctors. Each protype pulsoximeter served a family doctor during the pandemic. Building instructions were shared in maker-oriented websites, potentially leading to additional small-scale productions.
ARTICLE | doi:10.20944/preprints202005.0156.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; Egypt; epidemic SIR model; pandemic; flattening the curve
Online: 9 May 2020 (08:29:15 CEST)
Background: Flattening the curve refers to community isolation measures that keep the daily number of disease cases at a manageable level for medical providers. Efforts to completely contain the COVID – 19 have failed. As there is currently no vaccine or specific medication to treat COVID-19, the only way to flatten the curve is through collective action of mitigation efforts. Objectives: The study was carried out with aim to study the effect of mitigation efforts in reducing the overall COVID -19 attack rate and flattening the curve of COVID-19 in Egypt. Methods: Secondary data in the situation reports of WHO, Worldometer and Egyptian MoHP Report about the COVID-19 epidemic in Egypt were analysed till April 24, 2020. The Susceptible Infected Recovered (SIR) model was used to study the epidemic dynamics of COVID-19 pandemic. Results: In Egypt in fourth week after exposure β was 0.27 and γ = 0.06. The fraction of infectious individuals will grow exponentially as the exponential growth rate was 0.21, with an epidemic time of 4 days. R in 23 rd April it was 0.18 (less than one person infected) where β=0.07 and γ =0.39. There was reduction in the actual overall attack rate up to 23th April of 70 % of its value without intervention. There was flattening of the curve. Conclusion and Recommendation: Mitigation efforts of Egypt had succeeded in flattening the curve of COVID-19 Pandemic. Even though, strengthening all the mitigation efforts to keep the exposure probability, as well as the transmission rate as low as possible is mandatory for containment of the epidemic.
ARTICLE | doi:10.20944/preprints202005.0152.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Covid-19; personal protective equipment; facemask; odds ratio; Malaysia
Online: 9 May 2020 (08:02:16 CEST)
Background: The COVID-19 transmission has been established to occur through respiratory droplets from coughing and sneezing. Health agencies have strongly recommended the use of facemask as a precaution from cross-transmission. Objective: This study investigated the prevalence of facemask use among visitors to the hospital. This study also investigated the demographic factors contributing to unacceptable facemask practice. Setting: This prospective observational study was done among hospital visitors to a district specialist hospital during COVID-19 pandemic outbreak. Methods: Individuals entering through dedicated entry point were observed for the type, category and practice of wearing personal protective equipment. Inclusion criteria for this study were any individual's ≥ 2 years old entering the treatment facility from selected entry points. Patients were categorized into two groups of acceptable and unacceptable facemask practice. The Pearson chi-square was used to test for differences in investigated variables in the univariate setting and Binary Logistic regression model was used in the multivariate setting. Main Outcome Measure: Prevalence, acceptance practice and odds ratio of unacceptance of facemask use. Results: Among 1652 individuals included in the final analysis, 1574 (96.9%) was observed wearing facemask with 1269 (72.0%) of individuals worn medical-grade facemask. However, among them, only 1397 (88.8%) individuals' facemask practice was acceptable while the reaming 177 (11.2) individuals were perceived with unacceptable facemask practice. Male individuals, Malay ethnic and high risk age group are 1.47 times (Odds Ratio: OR=1.47; 95% CI, 1.06-2.06; p=.023), 2.18 times (OR=2.18; 95% CI, 1.55-3.08; p<.001) and 1.99 times (OR=2.18; 95% CI, 1.42 - 2.77; p<.001) more likely to exhibit unacceptable facemask practice respectively. Conclusion: Extensive use of facemasks coupled with environmental hygiene measures is a public health strategy which can help to mitigate the COVID-19 epidemic impact. However, a targeted comprehensive strategy to improve compliance to proper facemask practice among the high-risk population is needed to achieve maximal protective benefit.
ARTICLE | doi:10.20944/preprints202005.0057.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; treatment; drug; survival; antiviral; hydroxychloroquine
Online: 9 May 2020 (04:45:37 CEST)
Background: Although no specific treatment for COVID 19 has been proven effective yet, some drugs with in vitro potential against SARS-CoV-2 virus have been proposed for clinical use. Hydroxychloroquine has in vitro anti-viral and immunomodulatory activity, but there is no current clinical evidence of its effectiveness on the outcome of the disease. Methods: We enrolled all 18-85 years old inpatients from Central Defense Hospital, Madrid, Spain, who were hospitalised due to COVID-19 and had a definitive outcome (either dead or discharged). We used a statistical survival analysis. Results: We analysed 220 medical records. 166 patients met the inclusion criteria. 48,8 % of patients not treated with HCQ died, versus 22% in the group of 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 between 18 to 85 years hospitalised with COVID-19, hydroxychloroquine treatment with an initial loading dose of 800mg improved patient survival when admitted in early stages of the disease. There was a non-statistically significant trend towards survival in all groups, which will need to be clarified in subsequent studies.
Fri, 8 May 2020
REVIEW | doi:10.20944/preprints202005.0142.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; serology; RT-PCR; lab; clinical
Online: 8 May 2020 (12:26:46 CEST)
COVID-19 was identified in Wuhan, China in in December 2019, and rapidly spread worldwide, being declared global pandemic one month later on 30 January 2020. Since its emergence, COVID-19 has raised global concerns associated with drastic measures that were never adopted in any previous outbreak, to contain the situation as early as possible. The 2019 novel corona virus (2019-nCoV) or SARS-CoV-2 is the causative agent of COVID-19. 2019-nCoV genetic sequence was rapidly identified within few days since the first reported cases and RT-PCR kits became available for COVID-19 diagnosis. However, RT-PCR diagnosis carries a risk of false-negative results, therefore additional serologic test are needed. The most important approach in the battle against COVID-19 is rapid diagnosis of suspicious cases, timely therapeutic intervention and isolation to avoid community spread. In this review, we summarize the clinical scenario that raises suspicion of COVID-19 and available laboratory diagnostics.
Thu, 7 May 2020
ARTICLE | doi:10.20944/preprints202005.0127.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; liver fibrosis; amino acids; insulin resistance
Online: 7 May 2020 (13:29:39 CEST)
Altered amino acid levels have been found in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, it is not clear whether this alteration is due to altered hepatic metabolism or insulin resistance. The aim of this study was to clarify the association among amino acid levels, fatty liver, and liver fibrosis while eliminating the influence of insulin resistance. NAFLD and liver fibrosis were diagnosed using transient elastography and subjects were divided in three groups: normal, NAFLD, and liver fibrosis. To exclude the influence of insulin resistance, the subjects were matched using the homeostasis model assessment of insulin resistance (HOMA-IR). The amino acid serum levels were compared among the groups. Of 731 enrolled subjects, 251 and 33 were diagnosed with NAFLD and liver fibrosis. Although significant differences were observed among the groups in the serum levels of most amino acids, all but those of glutamate and glycine disappeared after matching for HOMA-IR. The multivariate logistic regression revealed that glutamate, glycine, and HOMA-IR were independent risk factors for liver fibrosis. The altered serum levels of most amino acids were associated with insulin resistance, while the increase in glutamate and the decrease in glycine levels were strongly associated not only with insulin resistance, but also with altered liver metabolism in patients with liver fibrosis.
Subject: Medicine & Pharmacology, General Medical Research Keywords: asymmetric； blasts；acute leukemia； allogeneic hematopoietic stem cell transplantation； case report
Online: 7 May 2020 (10:53:42 CEST)
Background: After allogeneic hematopoietic stem cell transplantation (allo-HSCT), acute leukemia relapse is common, and asymmetric bone marrow recurrence hasn’t been reported. Because the anatomical distribution of acute leukemia clones in the bone marrow after allo-HSCT is presumed to be diffuse, bone marrow aspirations are performed in single site. Case presentation: We identified two acute leukemia patients, whose leukemic burden in bilateral bone marrow specimens differed significantly. The first case was a 20-year-old man who was diagnosed with acute myelomonocytic leukemia and received haploidentical allo-HSCT. He had been in complete remission for two years and off immunosuppressive medications for a year, with normal peripheral blood count. Routine bone marrow biopsy of his left posterior iliac bone marrow showed 52% leukemia blasts, while the right side had 0% blasts ten days later. Due to the discordant results, the patient refused further intervention and died of high leukocyte syndrome four months later. The second case was a 23-year-old woman who was diagnosed with acute B lymphoblastic leukemia and received HLA-identical sibling allo-HSCT. Although 62% of blasts were found in her left iliac marrow on day +122, 0 % of blasts were found on a sample obtained from the right iliac crest on day +128. Whole-body 18F-FDG PET/CT scans confirmed that the leukemic infiltration in her bone marrow was asymmetric. Considering the higher leukemic burden on the left, we chose the left posterior iliac crest aspiration for further response evaluation. After chemotherapy combined with donor lymphocyte infusion, she achieved transient hematologic complete remission. She died of septic shock with heart failure at +258 days after allo-HSCT before infusion of anti-CD19 donor chimeric antigen receptor T cells. Conclusions: To our knowledge, these are the first case reports of asymmetric bone marrow infiltration of blasts in acute leukemia patients after allo-HSCT. Bilateral posterior iliac crest aspirations or 18F-FDG-PET/CT scans may help distinguish such distribution. If discordant bone marrow specimens are observed, physicians should restrict future bone marrow studies to the more involved side.
ARTICLE | doi:10.20944/preprints202005.0117.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Coronaviruses; Blockchain Technology; COVID-19; Smart Contracts; Data Exchange; Secure; Distributed Ledger Technology; Healthcare
Online: 7 May 2020 (10:10:00 CEST)
WHO was informed on 31 December 2019 of cases of unknown cause pneumonia in Wuhan City, China. On 7 January 2020 Chinese authorities reported a novel coronavirus as the cause and was temporarily labeled "2019-nCoV." Coronaviruses (CoV) are a wide family of viruses which cause diseases ranging from common cold to more serious illnesses. A novel coronavirus (nCoV) is a new strain not previously found in humans. Countries around the globe have stepped up their surveillance to quickly detect any new 2019-nCoV cases. Blockchain is developing into a safe and efficient network for secure data sharing in applications such as the financial industry, operations management, food industry, energy market, the Internet of Things and healthcare. In this paper, we are using blockchain technology as a mean to share authentic data, tracking of relevant information and help speed up the treatment process. At the same time it will preserve person’s identity. Timely deployment and suitable implementation of the proposed model have the opportunity to curb COVID-19 transmissions and associated mortality, especially in environments with inadequate access to testing facilities. This work will also facilitate in the treatment of other infectious diseases. Smart contract have been designed and implemented using the ethereum blockchain platform which has been presented in this paper. This work would facilitate multiple stakeholders who are involved within the medical system to curb the transmission of this disease.
ARTICLE | doi:10.20944/preprints202005.0113.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; COVID-19; inflammation; smoking; nicotine; hospitalization; adverse outcome
Online: 7 May 2020 (08:52:04 CEST)
Background: The purpose of this study was to examine the prevalence and effects of current smoking on adverse outcomes among hospitalized COVID-19 patients. Methods: We performed a systematic review of the literature (PubMed) for studies published until April 25. Studies were included into the analysis if they satisfied all of the following criteria: 1. To present hospitalized patients with COVID-19. 2. To classify patients into less and more severe disease, irrespective of the severity definition (defined as “adverse ourtcome”). 3. To present data on the smoking status, separately for each severity classification. We identified 18 (from a total of 1398) relevant studies. Pooled current smoking prevalence was compared with the gender-adjusted, population-based expected prevalence by calculating Prevalence Odds Ratio (POR). The association between current, compared to non-current and former, smoking and adverse outcome was examined by calculating Odds Ratio (OR). All analyses were performed using random-effects meta-analysis. Results: Among 6515 patients, 440 of whom were current smokers, the pooled prevalence of current smoking was 6.8% (95%CI: 4.8-9.1%) and the POR was 0.21 (95%CI: 0.16-0.26, P < 0.001). In Chinese studies only, the POR was 0.22 (95%CI: 0.17-0.27, P < 0.001). Current smokers were more likely to have an adverse outcome compared to non-current smokers (OR: 1.53, 95%CI: 1.06-2.20, P = 0.022). However, they were less likely to have an adverse outcome compared to former smokers (OR: 0.42, 95%CI: 0.27-0.74, P = 0.003). Conclusion: An unexpectedly low prevalence of current smoking was observed among hospitalized patients with COVID-19. Hospitalized current smokers had higher odds compared to non-current smokers but lower odds compared to former smokers for an adverse outcome. The possibility that nicotine may have a protective effect in COVID-19 which may be masked by smoking-related toxicity and by the abrupt cessation of nicotine intake when smokers are hospitalized should be explored.
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.
Mon, 4 May 2020
REVIEW | doi:10.20944/preprints202004.0065.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; case fatality rate; Italy; testing; health care system; demographics; comorbidites; epidemiological trends
Online: 4 May 2020 (18:38:16 CEST)
There is much discussion among clinicians, epidemiologists, and public health experts about why case fatality rate from COVID-19 in Italy (at 13.3% as of April 20, 2020, versus a global case fatality rate of 6.9%) is considerably higher than estimates from other countries (especially China, South Korea, and Germany). In this article, we propose several potential explanations for these differences. We suggest that Italy’s overall and relative case fatality rate, as reported by public health authorities, is likely to be inflated by such factors as heterogeneous reporting of coronavirus-related fatalities across countries and the iceberg effect of under-testing, yielding a distorted view of the global severity of the COVID-19 pandemic. We also acknowledge that deaths from COVID-19 in Italy are still likely to be higher than in other equally affected nations due to its unique demographic and socio-economic profile. Lastly, we discuss the important role of the stress imparted by the epidemic on the Italian healthcare system, which weakened its capacity to adequately respond to the sudden influx of COVID-19 patients in the most affected areas of the country, especially in the Lombardy region.
Subject: Medicine & Pharmacology, General Medical Research Keywords: coronavirus; COVID-19; public health intervention; revive economy; disease severity; epidemiological model and R0
Online: 4 May 2020 (15:08:26 CEST)
We previously proposed a public intervention framework concept that would allow people to resume personal and economic activities. We showed that intervention measures are used in a quantitative scale to reduce transmission probabilities and disease severity. In this article, we systematically examine the origin, assumptions, performance and limitations of epidemiological models from different views used in past review. We found that nearly all model assumptions fail to hold or are remote from reality; R0 does not exit or has no utility in guiding treatment options; personalized intervention measures are vitally important to COVID-19 due to its transmission characteristic; and current epidemiological models are unable to accurately assess the true benefits of personalized intervention measures. We suggest that poor performance of the models are attributed to flawed assumption that health/disease properties can be treated as transferable properties. The flaw creates a fiction that disease properties such as infection probabilities and death risks can be transferred from any vulnerable persons to anyone in the population and thus severely limit societal ability to fight the pandemic. We finally show that the benefits of personalized mitigation measures could be determined directly by using variable Ri values for infected persons (or nodes) together assessment of death rate and disability rate; the attempt of avoiding the disease by defeating all potential transmission probabilities is unrealistic; but mitigating disease severity for specific persons is more feasible and reliable. A most reliable strategy for reviving economy is using personalized protective measures and improving person health before effective vaccine is available.
Sun, 3 May 2020
HYPOTHESIS | doi:10.20944/preprints202005.0039.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Exercise; Angiotensin-converting enzyme; SARS-CoV-2; COVID-19; Ecology
Online: 3 May 2020 (08:45:12 CEST)
We hypothesize that the reason severe COVID-19 is closely linked to a limited number of conditions such as obesity, hypertension, older age and diabetes is that these conditions are characterized by a pro-inflammatory state in general and an angiotensin converting enzyme-1-bias in particular. We review recent evidence that this pro-inflammatory state can be reversed via regular exercise and a healthy diet. Studies are suggested that could test this hypothesis.
REVIEW | doi:10.20944/preprints202005.0029.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; Cytokine Storm; Lung Injury; Thalidomide; Anti-inflammatory Drug
Online: 3 May 2020 (07:31:53 CEST)
The new pandemic coronavirus disease 2019 (COVID-19) is a worldwide threatening health issue. Early progression of this disease starts in the lung airways with an exaggerated inflammation, triggered by the viral infection and characterized by a “cytokine storm” that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs, Thalidomide, a historically emblematic controversial molecule that harbors an FDA approval for treating Erythema Nodosum Leprosum (ENL) and multiple myeloma (MM). Based on only one-case report of positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Conversely, the absence of any substantial, promising evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases might cause a significant obstacle for carrying on clinical studies. In this review, we will discuss the theoretical effectiveness of this drug in attenuating inflammatory complications that are encountered in patients with COVID-19 while pinpointing the lack of evidence that is needed to move forward with this drug.
Sat, 2 May 2020
ARTICLE | doi:10.20944/preprints202005.0016.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; elderly; proton pump inhibitors; antipsychotics; metformin; oral antidiabetics
Online: 2 May 2020 (15:48:33 CEST)
Background: COVID-19 is a disease of the elderly as 95% of deaths related to COVID-19 occur in people over 60 years of age. Despite the urgent need for a preventive treatment there are currently no serious leads, other than the vaccination. Objective: To find a preventive treatment of COVID-19 in elderly patients. Design: Retrospective case-control study. Setting: Robertsau Geriatric Hospital of the University Hospitals of Strasbourg, France. Patients: 179 elderly patients who had been in contact with the SARS-CoV-2, of whom 89 had tested RT-PCR-positive (COVID-pos) for the virus and 90 had tested RT-PCR-negative (COVID-neg). Measurements: Treatments within 15 days prior to RT-PCR (including antihypertensive drugs, antipsychotics, antibiotics, nonsteroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), paracetamol, anticoagulant, oral antidiabetics (OADs), corticosteroids, immunosuppressants), comorbidities, symptoms, laboratory values, and clinical outcome were all collected using the electronic patient record. Results: COVID-pos patients more frequently had a history of diabetes (P=.016) and alcoholism (P=.023), a lower leukocyte count (P=.014) and a higher mortality rate– 29.2% versus 14.4% – (P=.014) when compared to COVID-neg patients. Patients on PPIs were 2.3 times less likely (odds ratio [OR] = 0.4381, 95% confidence interval [CI] [0.2331, 0.8175], P=.0053) to develop COVID-19 infection, compared to those not on PPIs. No other treatment decreased or increased this risk. COVID-19 patients on antipsychotics (P=.0013) and OADs (P=.0166) were less likely to die. Limitations: retrospective study. Conclusion: PPIs treatment lowered the risk of development of COVID-19 infection, and antipsychotics and OADs decreased the risk of mortality in geriatric patients. If further studies confirm this finding, PPIs could be used preventatively in the elderly in this pandemic context. Moreover, OADS and antipsychotics should be tested in clinical trials.
Thu, 30 April 2020
REVIEW | doi:10.20944/preprints202004.0540.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: cholinergic anti-inflammatory pathway; novel coronavirus; SARS-CoV-2; COVID-19; meta-analysis; Cytokine Release Syndrome; nicotine; smokers
Online: 30 April 2020 (17:01:38 CEST)
SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It produces severe acute respiratory disease (COVID-19), which is fatal in many cases, characterised by cytokine release syndrome (CRS). According to the World Health Organization (WHO), those who smoke are likely to be more vulnerable to infection. Here, in order to clarify the epidemiologic relationship between smoking and COVID-19, we present a systematic literature review until 28 April 2020 and a meta-analysis. It includes 18 recent COVID-19 clinical and epidemiological studies based on smoking patient status from 720 initial studies in China, USA, and Italy. The percentage of hospitalised current smokers was 7.7% (95%CI: 6.9-8.4) in China, 2.3% (95%CI: 1.7-2.9) in the USA and 7.6% (95%CI: 4.2-11.0) in Italy. These percentages were compared to the smoking prevalence of each country and statistically significant differences were found in them all (p <0.0001). By means of the meta-analysis, we offer epidemiological evidence showing that smokers were statistically less likely to be hospitalised (OR=0.18, 95%CI: 0.14-0.23, p<0.01). CRS and exacerbated inflammatory response are associated with aggravation of hospitalise patients. In this scenario, we hypothesise that nicotine, not smoking, could ameliorate the cytokine storm and severe related inflammatory response through the cholinergic-mediated anti-inflammatory pathway.
Tue, 28 April 2020
BRIEF REPORT | doi:10.20944/preprints202004.0482.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVI-19; SARS-CoV-2; virus; mutation; polymorphism; genome sequence
Online: 28 April 2020 (07:36:18 CEST)
SARS-CoV-2 infection has spread to over 200 countries since it was first reported in December of 2019. Significant country-specific variations in infection and mortality rate have been noted. We performed a sequence analysis of 474 SARS-CoV-2 genomes submitted to GenBank up to April 11 and identified 5 recently emerged mutations in many the isolates (up to 40%). This finding was verified on a larger scale using the GISAID database with 8,008 SARS-CoV-2 sequences. Our analysis highlights 5 frequent new mutations that have emerged since late February 2020. These mutations are: one each missense (non-synonymous) mutation in orf1ab (C1059T), orf3 (G25563T) and orf8 (C27964T), one in 5’UTR (C241T), one in a non-coding region (G29553A). The final mutation (G29553A) was found to be almost exclusive to the US isolates. The first 3 mutations are non-synonymous, leading to amino acid substitutions in the viral protein sequence. Except for C241T, all the novel mutations identified are absent in the isolates from Italy and Spain. Although the clinical significance of these mutations is currently unclear, the findings lay the foundation for further study into the impact of SARS-CoV-2 mutations on disease incidence, severity, and host immune response. In addition, it may also provide insights into vaccine development and serological response detection for the virus.
Sun, 26 April 2020
ARTICLE | doi:10.20944/preprints202004.0466.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; coronavirus; ACE2; bioinformatics analysis; drug prediction
Online: 26 April 2020 (03:14:50 CEST)
Recently, the outbreak of coronavirus disease 2019 (COVID-19) is threatening human health globally. There is a dire need to find potential therapeutic agents. Angiotensin converting enzyme 2 (ACE2), as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered as potential therapeutic target in COVID-19 pandemic. Here, our bioinformatics analysis revealed that the biological function of ACE2 was correlated with regulation of blood pressure and mediation of SARS-CoV-2 entry into host cells. Ten ACE2 cooperative proteins were identified by using STRING with a high score. ACE2 expressed highly in the small intestine, testis, and kidney. The level of ACE2 expression in tumor tissues varies in different types of cancers compared with that in normal tissues. It was worth noting that the expression level of ACE2 in the tumor has no effect on patient survival. MiRNA hsa-miR-942-5p, and three transcription factors (TFs) including Signal transducer and activator of transcription 4 (STAT4), Estrogen related receptor α (ESRRA), and Signal transducer and activator of transcription 3 (STAT3) were selected as novel ACE2 regulators. Moreover, nine potential therapeutic drugs were predicted by two online databases. Thus, our research may expand the overall view of ACE2 in COVID-19 treatment.
Sat, 25 April 2020
ARTICLE | doi:10.20944/preprints202004.0463.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: diabetes mellitus; insulin resistance; cytokines; adaptor proteins; CLNK
Online: 25 April 2020 (11:32:48 CEST)
Type 2 diabetes mellitus (T2DM) is an endocrine illness associate with various changes in the immune system and adaptor protein levels. Cytokine dependent hematopoietic cell linker (CLNK) is an adapter protein that regulates immune receptor signaling and acts as a regulator of the receptor signaling of T-cells and natural killer T-cell. The role of CLNK in T2DM is not studied previously. In the present study, serum CLNK level was measured and correlated with some sociodemographic and insulin resistance (IR) parameters. This is achieved by performing measurement of CLNK and insulin parameters (glucose, insulin, and HbA1c in addition to the calculation of the functions of IR (HOMA2IR), insulin sensitivity (HOMA%S), and beta-cell function (HOMA%B)) in 60 T2DM patients and 30 controls. The results indicated a significant increase (p=0.025) in serum CLNK in patients group in comparison with the controls. Multivariate generalized linear model (GLM) analysis revealed no significant effect of age, BMI, and sex on the CLNK level. The results of tests for between-subjects showed that the CLNK affects diagnosis significantly (F=7.445, p=0.008, partial η2 =0.081) and its effect is approximately the same as the effect of insulin (F=8.107, p=0.006, partial η2 =0.087). The correlation study showed a highly significant positive correlation between CLNK and the duration of disease (rho=0.420, p<0.001). It can be concluded that the increase CLNK in T2DM revealing the role of the adaptor proteins level in the nature of disease. Elevation of CLNK level may be used as a predictor for diabetes complications, which needs more investigations.
BRIEF REPORT | doi:10.20944/preprints202004.0452.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: respiratory failure; stethoscope; ultrasound; COVID-19
Online: 25 April 2020 (02:31:18 CEST)
The current Covid-19 pandemic has hugely disrupted the delivery of routine and established medical care. Patients can develop a wide range of clinical signs and symptoms from a cough and fever to severe respiratory failure. There is an ongoing argument on a concise investigative pathway to ensure the safety of all healthcare workers. The stethoscope can help with any clinical respiratory assessment but the risk of cross infection is high. Computer tomography should not be routinely performed. There is a potential place for lung ultrasound but outcomes are not yet determined.
Thu, 23 April 2020
REVIEW | doi:10.20944/preprints202004.0416.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: citation classics; top-cited articles; antibiotics; bibliometric analysis; antibacterial; antimicrobials
Online: 23 April 2020 (15:20:39 CEST)
Citation frequencies represent the most significant contributions in any respective field. This bibliometric analysis aimed to identify and analyze the 100 most-cited publications in the field of antibiotics and to highlight the trends of research in this field. “All databases” of Clarivate Analytics' Web of Science was used to identify and analyze the 100 publications. The articles were then cross-matched with Scopus and Google Scholar. The frequency of citation ranged from 940 to 11051 for the Web of Science, 1053 to 10740 for Scopus, and 1162 to 20041 for Google Scholar. Five hundred thirteen authors made contributions to the ranked list, and Robert E.W. Hancock contributed in six articles, which made it to the ranked list. Sixty-six scientific contributions originated from the United States of America. In contrast, five publications were linked to the University of Manitoba, Canada, that was identified as the educational organization, which made the most contributions (n=5). According to the methodological design, 26 of the most cited works were review-type closely followed by 23 expert opinions/perspectives. Eight articles were published in Nature journal, making it the journal with the most scientific contribution in this field. Correlation analysis between the publication age and citation frequency was found statistically significant (P = .012).
Wed, 22 April 2020
ARTICLE | doi:10.20944/preprints202004.0397.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: coronavirus; COVID-19; SARS-CoV-2; pandemic; public health intervention; lockdown; resurgence; forecasting; mathematical modelling; SEIR model
Online: 22 April 2020 (08:48:16 CEST)
The outbreak of coronavirus disease 2019 (COVID-19) was identified in Wuhan, China, in December 2019. As of April 17, 2020, more than 2 million cases of COVID-19 have been reported worldwide. Northern Italy is one of the world’s centers of active coronavirus cases. In this study, we predicted the spread of COVID-19 and its burden on hospital care under different conditions of social distancing in Lombardy and Emilia-Romagna, the two regions of Italy most affected by the epidemic. To do this, we used a Susceptible-Exposed-Infectious-Recovered (SEIR) deterministic model, which encompasses compartments relevant to public health interventions such as quarantine. A new compartment L was added to the model for isolated infected population, i.e., individuals tested positives that do not need hospital care. We found that in Lombardy restrictive containment measures should be prolonged at least until early July to avoid a resurgence of hospitalizations; on the other hand, in Emilia-Romagna the number of hospitalized cases could be kept under a reasonable amount with a higher contact rate. Our results suggest that territory-specific forecasts under different scenarios are crucial to enhance or take new containment measures during the epidemic.
COMMUNICATION | doi:10.20944/preprints202004.0093.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; virus, bioaerosol; social distancing; aerodynamic size; infection
Online: 22 April 2020 (05:54:48 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 or treatment, resulted in the decision of multiple governments to enact measures of social distancing. Thus, it is of general interest to consider the validity of the proposal for keeping a social distancing of at least 2 m from other persons to avoid the spread of COVID-19. The exposure to the bioaerosol can result in the deposition of the pathogen in the respiratory tract of the host causing disease and an immunological response. In the atmospheric context, the work evaluates the effect of aerodynamic diameter (size) of particles in carrying RNA copies of the novel coronavirus. A SARS-CoV-2 carrier person talking, sneezing, or coughing at distance of 2 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 from 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.
Tue, 21 April 2020
HYPOTHESIS | doi:10.20944/preprints202004.0348.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: hydroxychloroquine; COVID-19; pneumonia; prophylaxis; treatment
Online: 21 April 2020 (13:40:04 CEST)
According to current literature and preliminary data, hydroxychloroquine (HCQ) seems potentially effective in treating patients with Covid-19 pneumonia. The concentrations of the HCQ in lungs might be well above that of plasma. Most likely, this property of HCQ provides effective drug concentrations in lungs. HCQ has a gradual onset of action in the treatment of rheumatic diseases. This could be valid for the treatment of Covid-19 pneumonia. Reduced perfusion, somewhat distorted architecture of lung tissue, edema and, gradual accumulation of HCQ in lung tissue might reduce HCQ concentrations in pneumonic areas of the lungs in Covid-19 pneumonia. Patients having extensive lung involvement might have less HCQ concentrations in their lungs than patients having limited lung involvement. Furthermore, patients having extensive lung involvement might have more viral load than patients having limited lung involvement. That’s why HCQ might be more effective in the treatment of mild and moderate Covid-19 pneumonia cases and might not be effective in advanced cases. Using HCQ in Covid-19 prophylaxis seems logical since providing enough accumulation of HCQ in the healthy lungs before the arrival of the SARS-CoV-2 virus, might prevent Covid-19 pneumonia. However,the purpose of this paper is not to recommend using or not using HCQ for the treatment or for the prophylaxis of Covid-19 pneumonia. The purpose of this paper is only to try to bring a new perspective on the role of HCQ in the treatment or in the prophylaxis of Covid-19 pneumonia. This paper proposes only hypotheses, which need further researches to be confirmed.
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.
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, 20 April 2020
REVIEW | doi:10.20944/preprints202004.0361.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; pandemic; asymptomaticspread; early-stage COVID-19 mitigation
Online: 20 April 2020 (06:18:33 CEST)
Early-stage interventions in a potential pandemic are important to understand as they can make the difference between runaway exponential growth that is hard to turn back and stopping the spread before it gets that far. COVID-19 is an interesting case study because there have been very different outcomes in different localities. These variations are best studied after the fact if precision is the goal; while a pandemic is still unfolding less precise analysis is of value in attempting to guide localities in the early stages to learn lessons of those that preceded them. I examine two factors that could differentiate strategy: asymptomatic spread and differences in use of the Bacillus Calmette-Guerin (BCG) tuberculosis vaccine. These differences point to the possibility of alternative strategies to prevent COVID-19 from entering the runaway phase. The most promising is testing all contacts of anyone who has tested positive, not only those who are symptomatic. Should this demonstrate asymptomatic transmission, then all contacts of anyone who tests positive should be isolated and tested, and only released from quarantine when it is clear that they are past incubation and not positive.
REVIEW | doi:10.20944/preprints202004.0355.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: vitamin D; ACE2; diabetes; cardiovascular disease
Online: 20 April 2020 (01:37:43 CEST)
Coronavirus disease (COVID-19) is an infectious disease caused by a new virus which causes respiratory illness. Older adults and people who have previous chronic medical conditions are at higher risk for more serious complications from COVID-19.Hypovitaminosis D is attributed to the increased risk of lung injury and acute respiratory distress syndrome (ARDS) as well as diabetes, Cardiovascular event and associated comorbidities, which are the main causes of severe clinical problem in COVID-19 patients. Considering the protective role of vitamin D through modulating the innate and adaptive immune system as well as inhibition of Renin Angiotensin System (RAS), vitamin D supplementation might boost the immune system of COVID-19 patients and reduce severity of the disease in vitamin D deficient individuals.
ARTICLE | doi:10.20944/preprints202004.0354.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: machine learning; computer-assisted reporting; RadLex®; natural language processing; contextual reporting; The Alberta Stroke Programme Early CT Score (ASPECTS)
Online: 20 April 2020 (01:31:44 CEST)
Objectives: Studies evaluating machine learning (ML) algorithms on cross-lingual RadLex® mappings for developing context-sensitive radiological reporting tools are lacking. Therefore, we investigated whether ML-based approaches can be utilized to assist radiologists in providing key imaging biomarkers – such as The Alberta stroke programme early CT score (APECTS). Material and Methods: A stratified random sample (age, gender, year) of CT reports (n=206) with suspected ischemic stroke was generated out of 3997 reports signed off between 2015-2019. Three independent, blinded readers assessed these reports and manually annotated clinico-radiologically relevant key features. The primary outcome was whether ASPECTS should have been provided (yes/no: 154/52). For all reports, both the findings and impressions underwent cross-lingual (German to English) RadLex®-mappings using natural language processing. Well-established ML-algorithms including classification trees, random forests, elastic net, support vector machines (SVMs) and boosted trees were evaluated in a 5 x 5-fold nested cross-validation framework. Further, a linear classifier (fastText) was directly fitted on the German reports. Ensemble learning was used to provide robust importance rankings of these ML-algorithms. Performance was evaluated using derivates of the confusion matrix and metrics of calibration including AUC, brier score and log loss as well as visually by calibration plots. Results: On this imbalanced classification task SVMs showed the highest accuracies both on human-extracted- (87%) and fully automated RadLex® features (findings: 82.5%; impressions: 85.4%). FastText without pre-trained language model showed the highest accuracy (89.3%) and AUC (92%) on the impressions. Ensemble learner revealed that boosted trees, fastText and SVMs are the most important ML-classifiers. Boosted trees fitted on the findings showed the best overall calibration curve. Conclusions: Contextual ML-based assistance suggesting ASPECTS while reporting neuroradiological emergencies is feasible, even if ML-models are restricted to be developed on limited and highly imbalanced data sets.
Sun, 19 April 2020
HYPOTHESIS | doi:10.20944/preprints202004.0348.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: hydroxychloroquine; COVID-19; pneumonia; prophylaxis
Online: 19 April 2020 (13:41:42 CEST)
According to current literature and preliminary data, hydroxychloroquine (HCQ) seems potentially effective in treating patients with Covid-19 pneumonia. The concentrations of the HCQ in the lungs might be well above that of plasma. Most likely, this property of HCQ provides effective drug concentrations. HCQ has a gradual onset of action in the treatment of rheumatic diseases. This could be valid for the treatment of Covid-19 pneumonia. Reduced perfusion, somewhat distorted architecture of lung tissue and edema might reduce HCQ accumulation in pneumonic areas of the lungs in Covid-19 pneumonia. Patients having extensive lung involvement might have less HCQ concentrations in their lungs than that of patients having limited lung involvement. Furthermore, patients having extensive lung involvement might have more viral load than that of limited lung involvement. That’s why HCQ might be more effective in the treatment of mild and moderate Covid-19 pneumonia cases and might not be effective in advanced cases. Using HCQ in Covid-19 prophylaxis seems logical since providing enough accumulation of HCQ in the healthy lungs before the arrival of the SARS-CoV-2 virus, might prevent Covid-19 pneumonia. The purpose of this paper is not to recommend using or not using HCQ for the treatment or for the prophylaxis of Covid-19 pneumonia. The purpose of this paper is only to try to bring a new perspective on the role of HCQ in the treatment or in the prophylaxis of Covid-19 pneumonia. This paper proposes only hypotheses, which need further researches to be confirmed.
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.
REVIEW | doi:10.20944/preprints202004.0331.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; associated comorbidities; treatment; ACE2 inhibitors; Type 2 diabetes
Online: 19 April 2020 (05:42:22 CEST)
The Corona Virus Disease 2019 (COVID-19) outbreak is becoming pandemic with the highest mortality in people with associated comorbidities. These RNA viruses containing four structural proteins usually use spike protein to enter the host cell. It has been demonstrated that Angiotensin Converting Enzyme 2 (ACE2) ,as a part of renin-angiotensin-aldosterone system (RAAS), acts as a host receptor for the virus which is the main target of therapeutic approaches. However, medications acting on RAAS can lead to serious complications especially in people with diabetes and hypertension. To avoid this, other potential treatment modalities should be used in COVID-19 patients with associated comorbidities.
REVIEW | doi:10.20944/preprints202004.0325.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; artificial intelligence; AI; blockchain; epidemic; pandemic; machine learning; deep learning; coronavirus; SARS-CoV-2
Online: 19 April 2020 (04:44:37 CEST)
The beginning of 2020 has seen the emergence of coronavirus outbreak caused by a novel virus called SARS-CoV-2. The sudden explosion and uncontrolled worldwide spread of COVID-19 show the limitations of existing healthcare systems to timely handle public health emergencies. In such contexts, innovative technologies such as blockchain and Artificial Intelligence (AI) have emerged as promising solutions for fighting coronavirus epidemic. On the one hand, blockchain can combat pandemics by enabling early detection of outbreaks, protecting user privacy, and ensuring reliable medical supply chain during the outbreak tracking. On the other hand, AI provides intelligent solutions for identifying symptoms caused by coronavirus for treatments and supporting drug manufacturing. Motivated by these, in this paper we present an extensive survey on the use of blockchain and AI for combating coronavirus (COVID-19) epidemics based on the rapidly emerging literature. First, we introduce a new conceptual architecture which integrates blockchain and AI specific for COVID-19 fighting. Particularly, we highlight the key solutions that blockchain and AI can provide to combat the COVID-19 outbreak. Then, we survey the latest research efforts on the use of blockchain and AI for COVID-19 fighting in a wide range of applications. The newly emerging projects and use cases enabled by these technologies to deal with coronavirus pandemic are also presented. Finally, we point out challenges and future directions that motivate more research efforts to deal with future coronavirus-like epidemics.
Thu, 16 April 2020
BRIEF REPORT | doi:10.20944/preprints202004.0275.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; ARDS; PEEP; mechanical ventilation; transpulmonary pressure
Online: 16 April 2020 (13:24:29 CEST)
With the emergence of COVID-19 we are confronted with a new clinical picture of acute respiratory distress syndrome in the intensive care unit. In the majority of patients, the respiratory mechanics are very different from the “normal” ARDS patient. We measured transpulmonary pressure and dead space ventilation to assess the effects of high and low PEEP levels on lung compliance and ventilation-perfusion mismatching. Advanced respiratory mechanics were assessed in 14 patients. Compared to ARDS patients, lung compliance was relatively high (61 ± 5 mL/cmH2O). COVID-19 patients had high dead space ventilation and gas exchange impairment (Bohr 52 ± 3%; Enghoff modification 67 ± 2%; ventilatory ratio 2.24 ± 0.23). we show that higher PEEP levels decrease lung compliance and in most cases increase dead space ventilation, indicating that high PEEP levels probably cause hyperinflation in patients with COVID-19. We suggest using prone position for an extended period of time, and apply lower PEEP levels as much as possible.
HYPOTHESIS | doi:10.20944/preprints202004.0269.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; pandemic; antibiotics; immune response; mitochondria; epidemiology; health policy
Online: 16 April 2020 (12:14:30 CEST)
Italian, Spanish, French vs German, Austrian or Norwegian COVID-19 tracks? Antibiotics might have a partial impact on COVID-19 death rates in various countries. Our working hypotheses based on recent publications is that that antibiotics may be a major factor that negatively affects patients’ immune system during viral infections. We are all aware that there is no specific and effective medical treatment for COVID-19 so far. However, we know that our immune system is the only efficient weapon that fights against this syndrome right now. In fact, antibiotics are very often prescribed to prevent secondary infections following an antiviral immune response. Various antibiotic therapies have also been commonly applied to support COVID-19 treatments in China and Italy. Unfortunately, the frequent antibiotic off-site targets include mitochondria that are genetically and evolutionary closely linked to bacteria. Mitochondria are multifunctional organelles responsible for bioenergetics in nearly all our cells, acting as signaling hubs in antiviral and antibacterial immune responses. Several studies have demonstrated that mitochondria are vulnerable to antibacterial treatments, interrupting their physiology. Inhibition of these processes by antibiotics might render the immune system less capable of fighting acute COVID-19 viral infections. Some antibiotics, including those prescribed for COVID-19 in Wuhan, have been shown to inhibit the synthesis of mitochondrial DNA. The question is whether antibiotics support such a treatment or weaken patient immune responses in this case. This hypothesis should be evaluated based on comparative clinical data that seem to be unavailable at the moment. Possibly the COVID-19 risk group should be extended to all patients being treated with antibiotics, including those who finished antibiotic therapies days up to several months before SARS-CoV-2 infection. We therefore urge health service response groups to evaluate the impact of antibiotics on COVID-19 recovery vs death retrospective data. We would like to motivate international, national and local health authorities to share available clinical treatment data, discuss and optimize treatment strategies.
ARTICLE | doi:10.20944/preprints202004.0266.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; mild patients; quarantine facility; video-consultation; living and treatment support center
Online: 16 April 2020 (08:23:06 CEST)
With the outbreak of coronavirus disease 2019 (COVID-19), there is a need for efficient management of patients with mild or no symptoms, which account for the majority. The aim of this study is to introduce the structure and operation protocol of a living and treatment support centre (LTSC) operated by Seoul National University Hospital in South Korea. The existing accommodation facility was converted into a 'patient centre' where patients was isolated. A few Medical staff here performed medical tests and responded to emergencies. Another part of the LTSC was 'remote monitoring centre'. In this center, patients’ self-measured vital signs and symptoms were monitored twice a day, and the medical staff staying here provided video-consultation via a smartphone. During the 3 weeks from March 5 to March 26, 2020, 113 patients were admitted and treated. LTSC could be an efficient alternative to hospital admission in pandemic situation like COVID-19.
Wed, 15 April 2020
ARTICLE | doi:10.20944/preprints202004.0243.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: vitamin C; ascorbic acid; ascorbate; pneumonia; community acquired pneumonia; oxidative stress; protein carbonyls; hypovitaminosis C; vitamin C deficiency
Online: 15 April 2020 (10:12:26 CEST)
Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the intensive care unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and haematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, a marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs 56 ± 24 µmol/L, P <0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs 24 ± 14 µmol/L, P = 0.02). The total pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (P < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples form 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (P = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Due to the important roles that vitamin C plays in the immune system, low vitamin C status is possibly both a cause and a consequence of the disease. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease oxidative stress and aid in their recovery.
Tue, 14 April 2020
REVIEW | doi:10.20944/preprints202004.0160.v2
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; ACE; ACE2; Angiotensin II; Bradykinin; RAS inhibitors; ACE inhibitors; AT1 receptor blockers; Losartan; Bradykinin Antagonists; Ang II loading; Giapreza; Icatibant.
Online: 14 April 2020 (14:34:43 CEST)
As the world grapples with a pandemic with various and expanding epicenters, a flurry of medical and scientific activity has gained speed and momentum in a race to halt COVID-19. A controversial topic has been the connection between COVID-19 and the Renin-Angiotensin system (RAS). COVID-19, like Sars before it, enters by way of the Angiotensin Converting Enzyme 2 (ACE2). ACE2 is ubiquitously expressed in many tissues in the body serving as the doorway by which the virus can enter and spread causing inflammatory havoc. Demographic evidence coming out of China and other locations make it clear that the elderly and those suffering cardiovascular complications such as hypertension etc are most at risk. The connection to RAS and the demographic nature of the data coming out has led many to advance hypothesis, recommendations and even therapies based on existing RAS inhibitors and other components of the renin-Angiotensin system. It is pertinent to review the literature in the context of our understanding of the renin-angiotesnin system to allow better judgements to be made as well as lines of research initiated advancing a quick resolution to COVID-19. Covid-19 appears invincible as if dipped in the river Styx, but even Achilles had a vulnerable heel. Understanding the homeostatic balance that the coronavirus disrupts, we can discover the arrow in corona’s heel.
ARTICLE | doi:10.20944/preprints202004.0218.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: type 2 diabetes mellitus; walking speed; sarcopenia
Online: 14 April 2020 (08:45:26 CEST)
Diabetes is a risk factor for mild cognitive impairment (MCI) and dementia. However, how the clinical characteristics of type 2 diabetic patients with MCI are linked to sarcopenia and/or its criterion remain to be elucidated. Japanese patients with type 2 diabetes mellitus were categorized into the MCI group for MoCA-J (the Japanese version of the Montreal cognitive assessment) score <26, and into the non-MCI group for MoCA-J ≥26. Sarcopenia was defined by a low skeletal mass index along with low muscle strength (handgrip strength) or low physical performance (walking speed <1.0 m/s). Univariate and multivariate-adjusted odds ratio models were used to determine the independent contributors for MoCA-J <26. Among 438 participants, 221 (50.5%) and 217 (49.5%) comprised the non-MCI and MCI groups, respectively. In the MCI group, age (61 ± 12 vs. 71 ± 10 years, p < 0.01) and duration of diabetes (14 ± 9 vs. 17 ± 9 years, p < 0.01) were higher than those in the non-MCI group. Patients in the MCI group exhibited lower hand grip strength, walking speed, and skeletal mass index, but higher prevalence of sarcopenia. Only walking speed (rather than muscle loss or muscle weakness) was found to be an independent determinant of MCI after adjusting for multiple factors, such as age, gender, BMI, duration of diabetes, hypertension, dyslipidemia, smoking, drinking, eGFR, HbA1c, and history of coronary heart diseases and stroke. In subgroup analysis, a group consisting of male patients aged ≥65 years, with BMI <25, showed a significant OR for walking speed. This is the first study to show that slow walking speed is a sole determinant for the presence of MCI in patients with type 2 diabetes. It was suggested that walking speed is an important factor in the prediction and prevention of MCI development in patients with diabetes mellitus.
REVIEW | doi:10.20944/preprints202004.0217.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; Indigenous Tribes; Co-morbidities; Corona Virus; Navaho
Online: 14 April 2020 (08:43:11 CEST)
Introduction The COVID-19 virus was initially reported in Dec 2019 as the causative agent of a pneumonia breakout in Wuhan China. This virus rapidly spread from China to Europe and the East Coast of the United States eventually reaching the South West United States and indigenous tribes in mid -March. Since, then the indigenous tribes have been devasted by the virus which the Governor of New Mexico has likened as an existential threat. Methodology A PubMed search was performed utilizing the words: Navajo Indian, Indigenous Indian, 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: Navajo’s and other indigenous peoples may have elevated levels of ACE2 receptors in their lungs and other tissues allowing greater susceptibility to the COVID-19 virus. Increased levels of diabetes and protein nutrition are directly related to increased morbidity and mortality in this group while obesity, COPD, and heart diseas are not. The increased morbidity and mortality is exasperated by an inability to test for COVID-19 Conclusion: The infectivity rate of Navaho’s on the reservation is 22 times higher than the national average with a death rate near 4%. Comorbidites account for some of the increased morbidity and mortality while lack of access to adequate health care unnecessarily magnifies the poor outcome. The threat to indigenous tribes in the Southwest of COVID-19 is dire.
Sun, 12 April 2020
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, 10 April 2020
ARTICLE | doi:10.20944/preprints202004.0166.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: osteopathic manipulation; cranial osteopathy; reproducibility; osteopathic medicine
Online: 10 April 2020 (03:26:52 CEST)
Background and Objectives: The techniques directed to the cranial field in osteopathy are the most questioned due to the lack of scientific evidence. In osteopathic practice, manual palpation is essential and, therefore, measuring reliability is fundamental. The objective of study is to assess the reliability and validity of osteopathic treatment depending on experience. Materials and Methods: A cross-sectional study of reliability and validity was conducted. For measurements, a strain gauge was placed on the sphenobasilar synchondrosis of the skull base, and three maneuvers (lateral compression, anteroposterior compression and compression maneuver of the mastoids) were repeated 25 times each by osteopaths with different time of experience (5-10 years, 1-5 years, <1 year). Measurement averages were computed for each of the three maneuvers to verify the average effect of each group in comparison to that of the Gold Standard (GS) (>10 years of experience). Data were analyzed to check for inter- and intra-observer reliability using intra-class correlation coefficients (ICC). Results: Reliability and validity in 5-10 experience of observer 1 and observer 2 in the tree maneuvers was excellent (p<0.001) against GS. Poor or enough reproducibility and concordance were observed in osteopaths with less experience. Conclusion: Experience of osteopaths determines the efficacy of cranial maneuvers in osteopathic treatment for patients’ rehabilitation.
Thu, 9 April 2020
REVIEW | doi:10.20944/preprints202004.0160.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Covid-19; ACE2; AT1; AT2; Angiotensin; ACE; ACE inhibitors; Angiotensin Receptor Blockers
Online: 9 April 2020 (14:48:21 CEST)
As the world grapples with a hot pandemic with various and expanding epicenters, a flurry of medical and scientific activity has gained speed and momentum in a race to halt Covid-19. Due to the urgency of the situation, publication peer review has been speeded up to get information published and turn the gears of research in search for a cure. A hot and controversial topic has been the connection between Covid-19 and the Renin-angiotensin system (RAS). Covid-19, like Sars before it, enters by way of the Angiotensin Converting Enzyme 2 (ACE2). ACE2 is ubiquitously expressed in many tissues in the body serving as the doorway by which the virus can enter and spread causing inflammatory havoc. Demographic evidence coming out of china and other locations make it clear that the elderly and those suffering cardiovascular complications such as hypertension etc are most at risk. The connection to RAS and the demographic nature of the data coming out has led many to advance hypothesis, recommendations and even therapies based on existing RAS inhibitors and other components of the renin-angiotensin system. It is pertinent to review the literature in the context of our understanding of the renin-angiotesnin system to allow better judgements to be made as well as lines of research initiated advancing a quick resolution to Covid-19.
CASE REPORT | doi:10.20944/preprints202004.0134.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; multi-dose BCG; beta cells regeneration; improved C-peptide; serendipity
Online: 9 April 2020 (05:03:24 CEST)
Diabetes mellitus (DM) is one of the major risk factors for COVID-19 complications as it is one of the chronic immune-compromising conditions especially if patients have uncontrolled diabetes, poor HbA1c &/or irregular blood glucose levels. Diabetic patient’s mortality rates with COVID-19 are higher than cardiovascular or cancer patients. Recently Bacillus Calmette–Guérin (BCG) has shown successful results in reversing diabetes in both rats and clinical trials based on different mechanisms from aerobic glycolysis to Beta cells regeneration. BCG is a multi-face vaccine that has been used extensively in protection from TB and leprosy and has been repositioned for treatment of bladder cancer, diabetes & multiple sclerosis. Recently, the COVID-19 epidemiological study confirmed that universal BCG vaccination reduced morbidity and mortality in certain geographical areas. Countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies that have shown low numbers of reported COVID-19 cases. Some countries have started clinical trials that included a single dose BCG vaccine as prophylaxis from COVID-19 or an attempt to minimize its side effects. This proposed research aims to use BCG vaccine as a double-edged weapon countering both COVID-19 & diabetes, not only as protection but also as therapeutic vaccination. The work includes a case study of regenerated pancreatic beta cells based on improved C-peptide & PCPRI laboratory findings after BCG vaccination for a 9 years’ patient. The patient was re-vaccinated based on a negative tuberculin test & no scar at the site of injection of the 1st BCG vaccination at birth. Furthermore, the authors in the present article described a prospective BCG multi-dose clinical study in full details that they will apply in case of acceptance of their submitted grant & the ethical committee approval. The aim of the clinical study is to check if double dose BCG (4 weeks apart) will show a significant difference in the protection of health care professionals in Egypt. The authors suggest and invite the scientific community to take into consideration the concept of direct BCG re-vaccination (after 4 weeks) because of the reported gene expressions & exaggerated innate immunity consequently. As the diabetic MODY-5 patient (mutation of HNF1B, Val2Leu) was on low dose Riomet® while eliminating insulin gradually, a simple analytical method for metformin assay was recommended to ensure its concentration before use as it is not approved yet by the Egyptian QC labs.
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.
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, 6 April 2020
REVIEW | doi:10.20944/preprints202004.0071.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS CoV; macrophage activation syndrome; cytokine storm; immunology
Online: 6 April 2020 (16:22:42 CEST)
Introduction: The COVID-19 pandemic is a global crisis, the number of cases and deaths are on a steep incline. This article reviews the possible immunological mechanisms which underlie the disease pathogenesis by looking at the behaviour of previous coronaviruses not only in humans but also other mammals which possibly act as reservoir hosts. Observations: A key aspect of this coronavirus as well as the previous SARS CoV seems to be the importance of host immune response in the pathology and clinical severity of illness caused by them. A hyperactive innate immune state in combination with an exhausted adaptive immune response are possible determinants of severe illness. Conclusion: There is a possibility that the current SARS CoV 2 has immune evasive tactics similar to SARS CoV in its repertoire, since they share a 76% homology. These might have been learnt behaviour from long periods of persistence in their reservoir hosts and they may be the reason behind the dysregulated immune response evoked in humans. That in turn is highly likely to be one of the factors which govern disease severity. With this in mind we want to bring the medical community’s attention to a ‘hit early, hit hard’ intervention as a possible strategy to modify the course of the disease and bring down the numbers of severe sufferers.
REVIEW | doi:10.20944/preprints202004.0065.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; case fatality rate; Italy; testing; health care system; demographics; comorbidites; epidemiological trends
Online: 6 April 2020 (15:17:12 CEST)
There is much discussion among clinicians, epidemiologists, and public health experts about why case fatality rate from COVID-19 in Italy (at 12.1% as of April 2, 2020, versus a global case fatality rate of 5.2%) is considerably higher than estimates from other countries (especially China, South Korea, and Germany). In this article, we propose several potential explanations for these differences. We suggest that Italy’s overall and relative case fatality rate, as reported by public health authorities, is likely to be inflated by such factors as heterogeneous reporting of coronavirus-related fatalities across countries and the iceberg effect of under-testing, yielding a distorted view of the global severity of the COVID-19 pandemic. We also acknowledge that deaths from COVID-19 in Italy are still likely to be higher than in other equally affected nations due to its unique demographic and socio-economic profile. Lastly, we discuss the important role of the stress imparted by the epidemic on the Italian healthcare system, which weakened its capacity to adequately respond to the sudden influx of COVID-19 patients in the most affected areas of the country, especially in the Lombardy region.
ARTICLE | doi:10.20944/preprints202004.0063.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: SARS-CoV-2; COVID-19; Pandemic geographical distribution; Epidemic forecasting; Weather conditions; Climatic zones.
Online: 6 April 2020 (14:11:52 CEST)
This paper investigates whether the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) pandemic – also known as COronaVIrus Disease 19 (COVID-19) – could have been favored by specific weather conditions. It was found that the 2020 winter weather in the region of Wuhan (Hubei, Central China) – where the virus first broke out in December and spread widely from January to February 2020 – was strikingly similar to that of the Northern Italian provinces of Milan, Brescia and Bergamo, where the pandemic has been very severe from February to March. The similarity suggests that this pandemic worsens under weather temperatures between 4°C and 11°C. Based on this result, specific isotherm world maps were generated to locate, month by month, the world regions that share similar temperature ranges. From January to March, this isotherm zone extended mostly from Central China toward Iran, Turkey, West-Mediterranean Europe (Italy, Spain and France) up to the United State of America, coinciding with the geographic regions most affected by the pandemic from January to March. It is predicted that next spring, as the weather gets warm, the pandemic will likely worsen in northern regions (United Kingdom, Germany, East Europe, Russia and North America) while the situation will likely improve in the southern regions (Italy and Spain). However, in autumn, the pandemic could come back and affect the same regions again. The Tropical Zone and the entire Southern Hemisphere, but in restricted southern regions, could avoid a strong pandemic because of the sufficiently warm weather during the entire year. Google-Earth-Pro interactive-maps are provided as supplements.
COMMUNICATION | doi:10.20944/preprints202004.0062.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; FDA approved drugs; High Throughput Virtual Screening; Sincalide; Pentagastrin.
Online: 6 April 2020 (14:09:04 CEST)
In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.
ARTICLE | doi:10.20944/preprints202004.0049.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Covid-19; epidemic in Italy; statistical forecast
Online: 6 April 2020 (11:28:31 CEST)
We statistically investigate the Coronavirus Disease 19 (hereinafter Covid-19) epidemics, which is particularly invasive in Italy. We show that the high apparent mortality (or Case Fatality Ratio, CFR) observed in Italy, as compared with other countries, is likely biased by a strong underestimation of infected cases. To give a more realistic estimate of the mortality of Covid-19, we use the most recent estimates of the IFR (Infection Fatality Ratio) of epidemic, based on the minimum observed CFR, and furthermore analyse data obtained from the ship Diamond Princess, a good representation of a ‘laboratory’ case-study from an isolated system in which all the people have been tested. From such analyses we derive more realistic estimates of the real extension of the infection, as well as more accurate indicators of how fast the infection propagates. We then point out from the various explanations proposed, the dominant factors causing such an abnormal seriousness of the disease in Italy. Finally, we use the deceased data, the only ones estimated to be reliable enough, to predict the total number of infected people and the interval of time when the infection in Italy could stop.
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.
Wed, 25 March 2020
COMMUNICATION | doi:10.20944/preprints202003.0366.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; coronavirus; temperature; humidity; solutions
Online: 25 March 2020 (04:00:09 CET)
This article investigates whether the weather has any role in spreading the COVID-19 and how that knowledge can be used to arrest this fast spreading disease. It highlights that Temperature and Humidity both are extremely important for transmitting the virus- temperature being the stronger factor. A dry, cool environment is the most favourable state for spread of the virus. In fact, high temperature environment significantly reduces the risk from the virus. Regulating Temperature and Humidity level can provide drastic results to stop and arrest the outbreak. Some urgent solutions are proposed based on that knowledge. The novelty of such approach is- it can be applied overnight and implemented immediately across the globe. It is very cost effective and practically without side effects. No vast amount of funding is required to adopt these measures. These actions are likely to reduce the spread of the disease dramatically and it is expected that these measures will be implemented on an emergency basis worldwide.
Tue, 24 March 2020
ARTICLE | doi:10.20944/preprints202003.0361.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; SARS-CoV-2; pathogenicity model; diagnosis; progression prediction; poikilosis
Online: 24 March 2020 (14:43:24 CET)
A novel strategy is presented for reliable diagnosis and progression prediction of diseases with special attention to COVID-19 pandemy. A plan is presented for how the model can be implemented worldwide in healthcare and how novel treatments and targets can be detected. The idea is based on poikilosis, pervasive heterogeneity and variation at all levels, systems and mechanisms. Poikilosis in diseases can be taken account in pathogenicity model, which is based on distribution of three independent condition measures – extent, modulation and severity. Pathogenicity model is a population or cohort-based description of disease components. Evidence-based thresholds can be applied to the pathogenicity model and used for diagnosis as well as for early detection of patients in risk of developing the most severe forms of the disease. Analysis of patients with differential course of disease can help in detecting biomarkers of diagnostic and prognostic significance. A practical and feasible plan is presented how the concepts can be implemented in practice. Collaboration of many actors, including the World Health Organization and national health authorities, will be essential for success.
Mon, 23 March 2020
HYPOTHESIS | doi:10.20944/preprints202003.0319.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: COVID-19; coronavirus; SARS-CoV-2; respiratory illness; pneumonia; I4R approach; immune system; inflammation; immune boosting interventions
Online: 23 March 2020 (00:33:02 CET)
The current global pandemic of coronavirus disease 2019 (COVID-19) caused by the coronavirus SARS-CoV-2 has already had a major adverse impact on the world due to the exponentially increasing deaths due to the disease and the extreme actions taken by the world community to prevent its spread. It is important to explore novel methods of reducing the illnesses and fatality rates of the coronavirus-infected patients. Since the weakness of the immune system is one of the major contributing factors for the illnesses caused by such viruses, and since inflammation is a major contributing factor for the mortality of COVID-19 patients, interventions that boost the immune system and/or are anti-inflammatory may reduce the COVID-19 incidence and the mortality due to the disease. A large variety of interventions are known to improve the immune response and/or reduce inflammation. However, all the interventions would not be applicable or acceptable to everyone and so the interventions would need to be individualized based on individual circumstances and preferences. This approach, known as “Individualized Interventions to Improve the Immune Response”, or the I4R approach, should be studied in pilot clinical trials urgently, in order to potentially reduce the harm caused by the current coronavirus pandemic.
Fri, 20 March 2020
HYPOTHESIS | doi:10.20944/preprints202002.0147.v3
Subject: Medicine & Pharmacology, General Medical Research Keywords: new coronavirus; 2019-nCoV; superinfection therapy (SIT); apathogenic dsRNA virus; interferon-dependent antiviral genes; broad-spectrum antiviral treatment; clinically tested.
Online: 20 March 2020 (09:31:54 CET)
The transmission characteristic of COVID-19 is of similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the 1918 pandemic influenza. The virus is now in more than 100 countries and on nearly all continents. The World Health Organization (WHO) declared the COVID-19 outbreak a pandemic. There is no current evidence from random clinical trials (RCTs) to recommend any specific anti-COVID-19 treatment for patients with suspected or confirmed COVID-19 infection. In order to mitigate the impact of the COVID-19 outbreak, here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated viruses might interact in co-infected patients. During SIT, the patient benefit from superinfection with an apathogenic dsRNA virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). Importantly, the epidemiological efficacy of a similar strategy to SIT had already been successfully tested in large controlled trials. Standard live orally administered enterovirus vaccines that stimulate the production of endogenous interferon of the host mitigated the seasonal outbreaks of influenza and other associated acute respiratory infections in 152,042 individuals without adverse reactions.
Thu, 19 March 2020
ARTICLE | doi:10.20944/preprints202003.0291.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: co-infection; coronavirus disease 2019; COVID-19; influenza
Online: 19 March 2020 (02:00:47 CET)
Background: On late December 2019, a viral pneumonia known as coronavirus disease 2019 (COVID-19), was originated from China and spread very rapidly in the world. Therefore, COVID-19 became a global concern and health problem. Methods: We presented four patients in this study. They were selected from patients who presented with pneumonia symptoms and were suspicious for COVID-19 and referred to the intended centers for COVID-19 diagnosis and management of Shiraz University of Medical Sciences in the south of Iran. Two nasopharyngeal and oropharyngeal throat swab samples were collected from each patient and tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection by real-time reverse-transcriptase–polymerase-chain-reaction (RT-PCR), and also samples were sent for influenza viruses and all the respiratory panel. Results: In the present report, four patients were diagnosed in the starting days of COVID-19 disease in our center in south of Iran with co-infection of SARS-CoV-2 and influenza virus. Conclusions: This co-infection of COVID-19 and influenza highlights the importance of considering SARS-CoV-2 PCR assay regardless of other positive findings for other pathogens in the primary test during the epidemic.
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.
Subject: Medicine & Pharmacology, General Medical Research Keywords: magnetic resonance imaging; emergency departments; utility
Online: 17 March 2020 (04:01:04 CET)
Most pathologies in emergency departments(EDs) can be detected with using non-invasive, extremely safe magnetic resonance imaging (MRI). MRI is highly sensitive to abnormality, so when compared to Computed Tomography(CT), a negative MRI far exceeds the value of a negative CT. This was a retrospective cohort study comparing resource utilization between September 2016 and September 2017 in a university hospital ED. Descriptive statistics are presented with frequency, percentage, mean, standard deviation, minimum and maximum values. A chi-square analysis was conducted to examine the relationships. Analyses were conducted using the SPSS 22.0 package program. In the ED, MRI is available 24/7. MRI was performed on 954 (479 female, 475 male) patients. A total of 212 cranial, 604 diffusion, 57 lumbar, 40 cervical, 38 dorsal, two abdominal, and one orbital MRIs were performed. In most groups, the average age was over 40, and the age distribution was similar (p = 0.12). There was no significant sex difference except for lumbar MRI. Lumbar MRI and diffusion MRI groups were admitted to the hospital mostly in the day hours (p = 0.03); in other groups, night and day admissions were almost the same. Neuroimaging takes the majority part of MRI examinations in our ED.
Sun, 8 March 2020
Subject: Medicine & Pharmacology, General Medical Research Keywords: humans; infection control; therapy; coronavirus; immunoglobulins; drug therapy; therapeutic use; corticosteroid
Online: 8 March 2020 (17:04:19 CET)