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.
CONCEPT PAPER | doi:10.20944/preprints202005.0149.v1
Subject: Medicine & Pharmacology, Other Keywords: oxidative stress; calcification; signal transduction; vitamin D; cancer mutations; microbiota; quantum phenomena
Online: 9 May 2020 (04:44:30 CEST)
The leading cause and foremost reason for mortality and morbidity in the world is a group known as Noncommunicable Diseases. The best approach to treat them is to evaluate and control the risk factors. There are shared by all these diseases leading to the existence of some meeting points behind all of them. There should be some key to acquire conditions that modify the cells homeostasis and impaired the cell physiology developing different diseases. Physics try to explain the nature of the phenomena that surround us, at first, at the level of our macroscopic perception. Quantum physics studied the atomic and subatomic particles and revolutionized the reality perception with paradoxical and weird concepts. Heisenberg's uncertainty principle established that it is not possible to determine the two characteristic properties of particles with accuracy; measurement affects the system and change it. Subatomic particles have a wave-particle duality that could be in a coherence statement, also can pass through high-energy barriers. Two subatomic particles are entangled, something happening over here can have an instantaneous effect over there, no matter how far away there are. All these concepts have tried to apply to biology and life sciences, especially when classical physics fails to give an accurate description. Quantum biology is behind photosynthesis, mitochondrial respiration, enzyme activity, the sense of smell, animal migration, heredity's fidelity, and consciousness. We can apply all these concepts to diseases pathogeny. So, we describe quantum phenomena in oxidative stress, calcification, signal transduction, vitamin D production, cancer mutations, and microbiome induced pathology. I want to propose that medicine also can be explained by applying quantum physics concepts. It is a new, hard to believe, and an incredible path to be built, but we need to open the treatment options to our patients with new perspectives.
Fri, 8 May 2020
HYPOTHESIS | doi:10.20944/preprints202005.0144.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19, SARS-CoV-2, pyridoxal 5'-phosphate, pyridoxine, vitamin B6, immune response, IL-6, TNF, type I interferon, lymphopenia, blood clotting, coagulopathy, cytokine storm, sphingosine-1-phosphate, kynurenine, inflammasome, serine hydroxymethyltransferase 2 (SHMT2), hypertension, angiotensin
Online: 8 May 2020 (12:36:03 CEST)
Although most cases of COVID-19 are paucisymptomatic, severe disease is characterized by immune dysregulation, with a decreased type I interferon response, increased inflammatory indicators, surging IL-6, IL-10 and TNFα suggestive of cytokine storm, progressive lymphopenia, and abnormal blood clotting. Factors determining susceptibility to severe disease are poorly understood, although mortality correlates with increasing age and co-morbidities including diabetes and cardiovascular disease (CVD). Pyridoxal 5'-phosphate (PLP) tends to be insufficient in populations particularly vulnerable to COVID-19, including the elderly, the institutionalized, and people with diabetes and CVD, and PLP becomes further depleted during infection and inflammation. In turn, low PLP results in immune imbalance, as PLP is an essential cofactor in pathways regulating cytokine production, in particular type I interferons and IL-6, and in lymphocyte trafficking and endothelial integrity. Furthermore, normalizing PLP levels attenuates abnormalities in platelet aggregation and clot formation. Finally, PLP insufficiency induces excess secretion of renin and angiotensin, and hypertension. In inflammatory disease, pharmacological doses of PLP decrease circulating TNFα, IL-6 and D-dimer, and animal studies demonstrate that supplemental PLP shortens the duration and severity of viral pneumonia. Severe COVID-19 manifests as an imbalance in the immune response and the clotting system. Pharmacological PLP supplementation may therefore mitigate COVID-19 symptoms by alleviating both the immune suppression underlying viral spread and the pathological hypersecretion of inflammatory cytokines, as well as directly bolstering endothelial integrity and preventing hypercoagulability.
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.
ARTICLE | doi:10.20944/preprints202005.0125.v1
Online: 7 May 2020 (13:17:59 CEST)
Background: Accreditation is a qualitative assessment aimed at technical-professional quality, but above all, at organizational and measurable aspects through process and outcome checks. Method: There are few references in the literature relating to the accreditation and improvement of the quality and safety of care and treatment in the field of primary care. Clinical Governance must also be applied and certified in the field of primary care. Results: An accreditation system for general medicine is proposed based on a new dynamic model and implement that meets different requirements and assessed on the basis of indicators. Discussion: In the current Italian health system, accreditation of health structures is addressed only to public hospitals and private structures and to providers of services and services, however primary care. GPs / PLS do not have quality and safety guarantee systems or models or systems or public or private accreditation certifications with the SSR and SSN. Conclusion: Given the fundamental importance in the NHS of primary care of MG / PLS as the main and fundamental provider of services to the patient in all his socio-welfare and clinical needs, it is considered essential to think and implement an accreditation system extended to the territorial general practice as already present and in place for all affiliated and provider structures on behalf of the NHS.
ARTICLE | doi:10.20944/preprints202003.0389.v2
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: Parkinson’s disease; physical activity; sedentary way; non-motor symptoms; apathy; dopaminergic therapy
Online: 7 May 2020 (13:05:08 CEST)
Physical activity (PA) is a factor that may have an influence on the symptoms of Parkinson’s disease (PD). The aim of this study was to identify the potential determinants of spontaneous PA in the PD patient group. 134 PD patients aged 65.2±9.2 years, Hoehn-Yahr scale ≤ 4, Mini Mental State Examinaton (MMSE) ≥ 24 were examined. For the study purposes, the authors analyzed: age, sex, education, history of PD, dopaminergic treatment, the severity of PD symptoms using Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn-Yahr scale. Additionally all participants were evaluated through a set of scales for specific neuropsychiatric symptoms including: depression, anxiety, apathy, fatigue and sleep disorders. An analysis of linear regression was used with backward elimination. In the total explanatory model, 12% of the variability in activity (R2=0.125; F(16.133)=2.185; p<0.01), the significant predictor was starting therapy with the dopamine agonist (DA) (β= 0.420; t= 4.068; p=0.000), which was associated with a longer duration of moderate PA. In the total explanatory model, for more than 13% of the variance in time spent sitting (R2=0.135; F(16.130)=2.267; p<0.01), the significant predictors were secondary education and the results of the UPDRS. The patients with secondary and vocational education, those starting treatment with DA and those with a less severe degree of Parkinson’s symptoms (UPDRS) spent less time sitting in a day. It is possible to identify determinants of spontaneous PA. It may elucidate consequences in terms of influence on modifiable conditions of PA and the proper approach to patients with unmodifiable PA factors.
Subject: Medicine & Pharmacology, Cardiology Keywords: acute coronary syndromes; myocardial infarction; STEMI; Covid-19, infectious disease; respiratory infections; pathophysiology; percutaneous coronary intervention; thrombolysis; drug treatment
Online: 7 May 2020 (12:49:39 CEST)
Since association between myocardial infarction (MI) and respiratory infections has been described for influenza-viruses and other respiratory viral agents, understanding possible physiopathological links between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and acute coronary syndromes (ACS) is of the greatest importance. First data suggest an underestimation of ACS cases all over the world, but acute MI still represents a major cause of morbidity and mortality worldwide and should not be overshadowed during the coronavirus disease (Covid-19) pandemic. No common consensus regarding the most adequate healthcare management policy for ACS is currently available. Indeed, important differences have been reported between the measures employed to treat ACS in China during the first disease outbreak and what currently represents clinical practice across Europe and the USA. This review aims to discuss: pathophysiological links between MI, respiratory infections, and Covid-19; epidemiological data related to ACS at the time of the Covid-19 pandemic; what emerged so far from several catheterization labs and coronary care units all over the world, in order to shed some light on the current strategies for optimal management of ACS patients with confirmed or suspected SARS-CoV-2 infection.
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.
HYPOTHESIS | doi:10.20944/preprints202004.0233.v2
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; SARS-CoV-2; Streptoccoci; Pneumococci; Haemophilus influenzae; Hib; Prevenar; vaccination; lactoferrin
Online: 7 May 2020 (05:48:34 CEST)
Two conundrums have puzzled COVID-19 investigators: 1) morbidity and mortality is rare among Infants and young children and 2) rates of morbidity and mortality exhibit very large variances across nations, locals and even within cities. These differences correlate with rates of Haemophilus influenzae type B (Hib) and pneumococcal vaccination, which are almost universal among infants and vary widely by geography among adults and the elderly. The higher the rate of vaccination, the lower the COVID-19 morbidity and mortality. Vaccination rates with other vaccines, including BCG and poliovirus, do not correlate with COVID-19 risks. Notably, both Hib and pneumoccoci are common co-infections with influenza and coronaviruses and are associated with more severe disease and risk of death. Whether the vaccines simply protect against COVID-19 complications, directly protect against COVID-19 infection by inducing cross-reactive immunity, or are markers for some other types of protection such as availability of better healthcare, is not yet known. What is known is that improving coverage rates of Hib and pneumococcal vaccination has significantly lowered severe morbidity and mortality in influenza epidemics and might have similar efficacy for mitigating coronavirus outbreaks. If infants and children are valid indicators, the beneficial effects might be very significant. The possibility that anti-viral proteins in milk (e.g., lactoferrin) protect against COVID-19 is also explored.
ARTICLE | doi:10.20944/preprints202005.0104.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: COVID-19; dental care; infection control; universal precautions; aerosol
Online: 7 May 2020 (05:21:20 CEST)
Dental services are significantly impacted by the COVID-19 pandemic. Almost all dental procedures carry a high infection risk for providers and patients due to spread of aerosols. As a consequence, national public health agencies, and dental professional associations have issued guidelines for enhanced infection control, personal protection equipment and limiting care to urgent or emergency services. However, there is no dental service concept for disaster preparedness or response that might be applied. Similarly, pathways to care provision in a post-pandemic future are missing. We propose Safe Aerosol-free, Emergent Dentistry (SAFE Dentistry) as one approach to dental services during and emerging from pandemics. The concept’s starting point is the identification of the most common patient needs. The next step is to replace common treatments relating to the most common needs with alternative interventions with less infection risk because they do not generate aerosols. SAFE Dentistry is innovative, safe, and responds to the requirements of a pandemic and post-pandemic emergence where the risk of disease transmission remains high. SAFE Dentistry thereby ensures continuity of dental services while protecting providers and patients from infectious pathogens. Moreover, SAFE Dentistry allows dental service providers to remain operational and generate income even under pandemic conditions. Implementation and policy options for SAFE Dentistry include universal availability without co-payments by patients and a uniform bundled payment scheme for providers to simplify budgeting, reimbursement and to provide easier administration during a pandemic. Adaptations and adjustments of the concept are possible and encouraged, as long as the principle of avoiding aerosol-generation is maintained.
Wed, 6 May 2020
ARTICLE | doi:10.20944/preprints202005.0102.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: marine natural products; Laurencia; brominated sesquiterpenes; antimycobacterial; nontuberculous mycobacteria; tuberculosis
Online: 6 May 2020 (15:32:53 CEST)
Marine environments represent a great opportunity for the discovery of compounds with a wide spectrum of bioactive properties. Due to the privileged conditions of natural selection, marine natural products are subject to overcome the pressure put on identify novel drugs; not only in the case of newly discovered bioactive metabolites, but also in those previously known. Since drug resistance has caused an increase in infections caused by tuberculous and nontuberculous Mycobacteria, the re-evaluation of known bioactive metabolites has been suggested as a means to address this problem. In this sense, this study presents an evaluation of in vitro effect of laurinterol (1) and aplysin (2), two brominated sesquiterpenes isolated from Laurencia johnstonii against nine Mycobacterium tuberculosis strains and six nontuberculous mycobacteria. Laurinterol (1) exhibited good anti-tuberculous activity, especially against nontuberculous mycobacteria, being remarkable the effect against M. abscessus with MIC values lower than the reference drug imipenem. This study provides further evidence for the antimycobacterial activity of some sesquiterpenes from L. johnstonii, that can be considered an interesting lead compound for the discovery of novel antimycobacterial molecules to treat NTM infections.
ARTICLE | doi:10.20944/preprints202005.0098.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: breast cancer; snake venom; cytotoxin II; recombinant protein; apoptosis; cell cycle progression; cytotoxicity
Online: 6 May 2020 (15:12:05 CEST)
Breast cancer (BC) is among the leading causes of mortality from cancer in women. Many of the available anticancer drugs have various side effects. Therefore, researchers are seeking novel anticancer agents particularly from natural compounds and in this regard, snake venom is still one of the main sources of drug discovery. Previous studies showed potential anticancer effects of Cytotoxin II (CTII) from Naja naja oxiana against the different types of cancers. In this study, a pET-SUMO-CTII vector was transformed into SHuffle® T7 Express, an Escherichia coli strain, for recombinant protein expression (rCTII) and the cytotoxic effects of this protein was assessed in MCF-7 cells. The flow cytometry assay was applied to measure the apoptosis and cell cycle. Also, mRNA levels of the Bax, Bcl2, P53, caspase-3, caspase-8, caspase-9, caspase-10, matrix metalloproteinases (MMP)-3, and MMP-9 were analyzed by quantitative real-time PCR to determine the underlying cellular pathways affected by rCTII. The results of this study showed that treatment with 4 µg mL-1 of rCTII enhanced apoptosis through the intrinsic and extrinsic pathways. Also, the increase of the cells' proportion in the sub-G1 phase as well as a reduction in S phase was observed. In addition, the expression of MMP-3 and MMP-9 was decreased in the treated group in comparison to the control group that may contribute to the reduced migratory ability of tumor cells. These experimental results indicate that rCTII has anti-proliferative potential, and so this protein could be a potential drug for BC therapy in combination with other drugs.
BRIEF REPORT | doi:10.20944/preprints202003.0338.v3
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Severe Acute Respiratory Syndrome Coronavirus-2; (soluble) ACE2; eosinophil; asthma; IL-10; Lung fibrosis; hypercapnic acidosis; hypoxia; infarction; hypertension; cardiac dysfunction; respiratory distress; coagulopathy; Angiotensin; renin; Ang (1-7); Ang (1-9); Mas receptor; AT2 receptor
Online: 6 May 2020 (04:40:25 CEST)
The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent the establishment of positive feedback loops triggered by COVID-19 in some predisposed subjects. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, it is hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the zinc metalloprotease ACE2 and its downstream pathway for SARS-CoV-2 patients. Of even more interest, metal (zinc) chelators and renin inhibitors (both FDA approved drugs) may also work alone or in combination in inhibiting the positive feedback loops, initially triggered by COVID-19 and subsequently sustained by hypoxia independently on viral trigger, when both arms of renin-angiotensin system (ACE2 and ACE) are upregulated, leading to critical, advanced and untreatable stages of the disease.
Tue, 5 May 2020
REVIEW | doi:10.20944/preprints202005.0089.v1
Subject: Medicine & Pharmacology, Other Keywords: access to medicines; access to antibuotics; impact of access to medicines on public health; problems associated with access; use; abuse of antibiotics resistance; aware; Africa
Online: 5 May 2020 (17:03:07 CEST)
Access to medicines is one of the essential problems in Public Health of low- and middle-income countries (LMICs). The World Health Organization (WHO) defines access to medicines as the possibility of "having continuously accessible and affordable medicines in public or private health facilities that are within a kilometer of the place of residence." Access to medicines, as defined by the WHO, is not fully guaranteed in many LMICs and even in many regions of high-resource countries. The WHO identifies several factors as determinants of limitations in the access to medicines: rational selection, affordable prices, sustainable financing, and reliable health services. The action on these factors makes it possible to improve universal access to medicines with consequent improvement in Public Health. Adequate access to antibiotics and vaccination will avoid a large part of the deaths caused by infectious diseases in the LMICs. However, the emergence of resistance and the difficulties in vaccination campaigns due to socio-political or cultural problems make it challenging to fight many easily treatable infectious diseases. The use and abuse of antibiotics are inevitably associated with the appearance of resistances that make them ineffective. Thus, whereas limited access to antibiotics raises mortality rates from infectious diseases, generalized open access to them ends up eliminating their clinical value. Moreover, the contraction of research in this field for many years has reduced the success in discovering new drugs. Additionally, local market regulations, inadequate selection, inaccessible prices, especially for those of second and third-generation, inefficient health systems, and difficulties of administration and control of prescription compliance, especially in the case of combined therapies, are additional obstacles to universal access to antibiotics. In order to simultaneously improve access to antibiotics and keep resistances under control, it is necessary to develop training and education activities at different social levels (from patients to various Health Care Providers) to complement the national or supranational strategic plans.
REVIEW | doi:10.20944/preprints202005.0085.v1
Subject: Medicine & Pharmacology, Cardiology Keywords: COVID-19; HAPE; high-altitude; tolerance to hypoxia; oxygen transport triad; Cov-2; SARS; pneumonia; ventilators; EPO
Online: 5 May 2020 (15:26:05 CEST)
The critical hypoxia in COVID-19 patients during this pandemic, has taken away many lives all around the globe. The mechanism has been poorly understood and initially, word got around that it was a SARS (Severe Acute Respiratory Syndrome) pneumonia. The atypical images in lung computerized axial tomography (CAT) scans were alarming. This immediately alerted everyone including poor countries to purchase lacking sophisticated ventilator equipment. However, in some countries, even 88% of the patients on ventilators lost their lives. New observations and pathological findings are gradually clarifying the disease. What seems evident is that it is not only one disease but several, with different responses in different countries and different altitudes. The critical hypoxia and «gasping» present in some patients are not totally understood. It was mentioned that it could be like a High-Altitude Pulmonary Edema (HAPE). Hereby, as high-altitude medicine and hypoxia physiology specialists, we compare the pathophysiology with that of high-altitude exposure in order to understand the mechanisms involved. Some differences in lung radiological images along with transmission and viral attack mechanisms are discussed. The oxygen transport triad used at high-altitude can be applied on this pathology in order to propose even the use of erythropoietin (EPO) early in the treatment. The immune system is the most important long-term survival tool, so we suggest a short-term strategy: the use of special Earth open-circuit astronaut-resembling suits with effective outside air filtering re-breathing mechanisms in order to return to work and daily activities, without contamination risk. Thereby, the curve can be flattened without quarantine and the economy could recover.
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: circulating microRNA; biomarker; Parkinson’s disease; real-time PCR
Online: 5 May 2020 (12:19:15 CEST)
Blood Circulating miRNAs are proposed as promising biomarkers for many diseases, including Parkinson’s disease (PD). In this study, plasma circulating miRNAs expression were assessed in three independent sets with totally 151 PD, 21 Multiple system atrophy (MSA) and 138 healthy controls using high-throughput real-time PCR. 485 plasma miRNAs expression were assessed in an initial screening set of 78 PD and 78 normal controls and 7 most-differentially expressed miRNAs were selected as potential biomarkers. Following duplication test with 27 PD and 15 controls was to evaluate the performance of 7 candidate miRNAs and found 3 miRNAs (miR-320a, miR-133b, miR-221-3p) discriminate PD from controls with 74.1% sensitivity and 86.7% specificity. Moreover, miR-221-3p and miR-205 predict early PD from control and miR-205 negatively correlated with disease progression. In the third test, 4 identified miRNAs (miR-320a, miR-133b, miR-221-3p, miR-205) were evaluated in a new cohort with 46 PD, 21MSA and 45 healthy controls. As expected, the elevated miR-133b and miR-221-3p were validated to distinguish PD from controls with 82.6% sensitivity and 88.9% specificity. There was no significant difference on miR-221-3p expression between MSA and controls. Combination of up-regulated miR-133b and miR-221 has potential to serve as a noninvasive biomarker for PD diagnosis.
ARTICLE | doi:10.20944/preprints202005.0077.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: centromere protein F (CENPF); Estrogen Receptor beta; Lung Adenocarcinoma (LUAD); WGCNA package; non-small cell lung cancer (NSCLC)
Online: 5 May 2020 (12:08:59 CEST)
The signal transduction pathways of estrogen receptors (ER) mainly includes gene pathway and non-gene pathway. Studies have shown that the gene pathway of ER is related with the expression of nuclear proteins, and this is the key issue for our current research. With the GEO database analysis, Human centromere protein F (CENPF) is highly expressed in adenocarcinoma of lung (LUAD), and the co-expression of CENPF and ERβ was found in the nucleus of LUAD cells. Meanwhile, CENPF and ERβ2/5 were related with T stage and poor prognosis (P<0.05). Knockdown of CENPF gene significantly inhibited the biological effects of LUAD cells, the tumor growth of mice and the expression of ERβ2/5 (P<0.05). Further, group experiments showed that knockdown CENPF inhibits biological effects of LUAD cells mediated by ERβ pathway. All the results indicated that both CENPF and ERβ2/5 play important roles in the progression of LUAD, and knockdown of CENPF can inhibit the progression of LUAD by inhibiting the expression of ER2/5. Thus, the development of inhibitors against ERβ2/5 subtype and CENPF remained more effective in improving the therapeutic effect of LUAD.
Subject: Medicine & Pharmacology, Nutrition Keywords: Momordica; anti-microbial; photochemical; secondary metabolites
Online: 5 May 2020 (10:17:34 CEST)
Momordica species (Family Cucurbitaceae) are cultivated throughout the world for their edible fruits, leaves, shoots and seeds. Among the species of the genus Momordica, there are three selected species that are used as vegetable, and also for medicinal purposes inter alia Momordica charantia L. (Bitter melon), Momordica foetida Schumch. Et Thonn. (Bitter cucumber) and Momordica balsamina L. (African pumpkin). The three species are reputed to possess anti-diabetic, anti-microbial, anthelmintic bioactivity, abortifacient, anti-bacterial, anti-viral, and also play chemo-preventive functions as they are rich in vitamins as well as both primary and secondary metabolites which possess anti-microbial activities. The fruits and leaves of Momordica species consist of nutritional composition rich in primary metabolites; energy releasing biomolecules, proteins, fibres, minerals (calcium, iron, magnesium, zinc), beta-carotene, foliate and ascorbic acid. The extracts from Momordica species are used for the treatment of a variety of diseases and ailments. Several studies have suggested that Momordica species extracts can lower blood sugar and treat Diabetes mellitus due to its hypoglycemic properties. The crop can also be used to treat other diseases including diarrhea, bleeding gums, piles and hemorrhoids; respiratory problems, leukemia, melanoma, liver cancer, skin infections, and solid sarcomas.
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; RT-PCR test; pre-test probability; positive rate
Online: 5 May 2020 (06:04:41 CEST)
Several articles have reported that the low number of COVID-19 cases in Japan is attributed to the small number of diagnostic RT-PCR tests performed. The criticism is based on the low number of the tests performed, and they suspected there would be more potential cases in Japan. The use of pre-test probability among tested subjects is proposed in order to evaluate of the sufficiency of test availability instead of the number of the tests. The pre-test probability means the average probability, i.e., ‘suspicion level’, of having coronavirus among the tested subject in a country. The higher pre-test probability is regarded as less sufficient opportunity of the tests, and the test availability could be evaluated by the pre-test probability. Thus, potential problems of underestimation of COVID-19 cases by insufficient amount of the test would be clear by using pre-test probability. The comparison of the pre-test probability could be replaced with that of the positive rate of the test because of the linear relationship between them under the assumption of common sensitivity and specificity. Japan shows the third lowest rate (8.6%), and is considered that the considerably sufficient number of the tests have been performed. In conclusion, the positive rate of the test as a surrogate index of the pre-test probability is useful to evaluate the sufficiency of test amount instead of the number of the tests performed. In present, the potential problem of underestimation by insufficient test availability would be less serious in Japan.
HYPOTHESIS | doi:10.20944/preprints202005.0061.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: SARS-CoV-2; COVID-19; Lysosomotropism; Chloroquine
Online: 5 May 2020 (04:29:48 CEST)
The COVID-19 pandemic is one of the largest challenges in medicine and health care worldwide in recent decades, and it is infecting and killing increasing numbers of people every day. In this paper, we discuss the possible relationships among lysosomotropism, increasing lysosomal pH, and the SARS-CoV-2 infection and disease process, and we deduce a possible approach for treatment and prophylaxis. Lysosomotropism is a biological characteristic of small molecules, such as (hydroxyl)chloroquine, amitriptyline, NB 06, or sertraline, which is present in addition to intrinsic receptor-mediated or enzymatic pharmacological effects. Lysosomotropic compounds affect prominent inflammatory messengers, such as IL1B, CCL4, CCL20, and IL6, as well as cathepsin L dependent viral entry (fusion) into host cells. Therefore, this heterogeneous group of compounds is a promising candidate for the prevention and treatment of SARS-CoV-2 infections, as well as influenza A infections and cytokine release syndrome (CRS) triggered by bacterial or viral infections. Patients who have already taken medications with lysosomotropic compounds for other pre-existing conditions may benefit from this treatment in the COVID-19 pandemic. Increased lysosomal pH levels play an important role in the disease process in common skin disorders, such as psoriasis and atopic dermatitis, thus suggesting that affected individuals might benefit from their particular conditions in the COVID-19 pandemic. We suggest data analysis of patients with these diseases, and who are treated with lysosomotropic compounds, and, if the results are promising, subsequent clinical testing of off-label therapy with clinically approved lysosomotropic compounds in the current COVID-19 pandemic and future influenza A pandemics.
REVIEW | doi:10.20944/preprints202005.0059.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: Fascia; fascial connectivity, myofascial meridians; myofascial chains
Online: 5 May 2020 (03:53:34 CEST)
Introduction: Musculoskeletal dysfunctions happen to be the most common reason for referral to physiotherapy and manual therapy services. Therapists may use several articular and/or soft tissue concepts/approaches to evaluate and treat such dysfunctions that may include integration of myofascial system. Despite the research in this area spanning more than three decades, the role played by fascia has not received its duly deserved attention, owing to the lack of definitive research evidence. The concept of ‘fascial connectivity’ evolved two decades ago from a simple anatomical hypothesis called ‘myofascial meridians’. Since then it has been widely researched, as conceptually it makes more sense for functional movements than ‘single-muscle’ theory. Researchers have been exploring its existence and role in musculoskeletal dysfunctions and clinicians continue to practice based on anecdotal evidence. This narrative review attempts to gather available evidence, in order to support and facilitate further research that can enhance evidence based practice in this field. Methods: A search of most major databases was conducted with relevant keywords that yielded 272 articles as of December 2019. Thirty five articles were included for final review with level of evidence ranging from 3b to 2a (as per Center of Evidence Based Medicine’s scoring). Results: Findings from cadaveric, animal and human studies supports the claim of fascial connectivity to neighboring structures in the course of specific muscle-fascia chains that may have significant clinical implications. Current research (level 2) supports the existence of certain myofascial connections and their potential role in the manifestation of musculoskeletal dysfunctions and their treatment. Conclusion: Although these reviews and trials yield positive evidence for the objective reality/existence of fascial connectivity and continuity, several aspects need further exploration and in-depth analysis, which could not be evidenced entirely in this review. Manual and physical therapists may utilize the concept of fascial connectivity as a convincing justification to deal with clinical problems, but need to remain vigilant that functional implications are still being investigated.
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
ARTICLE | doi:10.20944/preprints202004.0308.v4
Subject: Medicine & Pharmacology, Other Keywords: Covid-19; SARS-Cov-2; mortality rate; cancer; cardiovascular disease; respiratory disease; diabetes; kidney diseases
Online: 4 May 2020 (18:51:36 CEST)
Covid-19 has given a halt to all the activities in the world. Europe was most affected, followed by the United States of America. It has taken more than 225,000 lives until now. In this study, we have assessed the severity of Covid-19 by analyzing the mortality rate of Covid-19 and other chronic diseases. The Covid-19 data and “death rate” data caused by other diseases were downloaded from the world health organization (WHO) website. A normalized method was used to see the mortality rate of Covid-19 in comparison to other diseases. The deaths caused by Covid-19 in April 2020 have overtaken the average number of deaths caused by Cancer, Cardiovascular diseases, and other diseases in Belgium, Spain, France, Italy, the UK, and Ireland. Covid-19 was found to be strongly correlated with non-communicable respiratory diseases and Cancer with correlation coefficients 0.73 and 0.70 respectively. The severity of Covid-19 in the USA was moderate. The severity of Covid-19 in Asian countries was found to be low. Europe showed the highest diversity in the mortality rate of Covid-19. On average, except for a few European countries, Cardiovascular diseases, cancer, and non-communicable respiratory diseases were still more lethal and caused more deaths than Covid-19.
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/preprints202005.0037.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: FFAR2; FFAR3; microbiota; gut; immune; SCFA
Online: 3 May 2020 (08:32:51 CEST)
Abstract: Role of gut microbiome in human health is becoming apparent. The major functional impact of gut microbiome is transmitted through the microbial metabolites that are produced in the gut and interact with host cells either in the local gut environment or get absorbed in the circulation to impact distant cells/organs. Short chain fatty acids (SCFAs) are the major microbial metabolites that are produced in the gut through fermentation of non-digestible fibers. SCFAs are known to function through various mechanism, however, their signaling through free-fatty acid receptor 2 and 3 (FFAR2/3; type of G-coupled protein receptors) is new therapeutic approach. FFAR2/3 are widely expression in diverse cell types in human and mice, and functions as sensors of SCFAs to change several physiological and cellular functions. FFAR2/3 modulates neurological signaling, energy metabolism, intestinal cellular homeostasis, immune response and hormone synthesis. FFAR2/3 functions through Gi and/or Gq signaling, that is mediated through specific structural features of SCFAs-FFAR2/3 bindings and modulating specific signaling pathway. In this review, we discussed the wide-spread expression and structural homologies between human and mice FFAR2/3, and their role in different human health conditions. This information can unlock opportunities to weigh the potential of FFAR2/3 as drug target to prevent human diseases.
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
REVIEW | doi:10.20944/preprints202005.0021.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: anti-IgLON5 disease; sleep disorders; tau protein accumulation; immunotherapy; neurodegenerative diseases
Online: 2 May 2020 (16:26:03 CEST)
The objective of this review is to do an overview about the current knowledge of Anti Iglon5 Syndrome, a disease that was first described in 2014. The IgLON proteins are a family of cell adhesion molecules and the presence of antibodies against IgLON5 are crucial for diagnosis of Anti IgLON5 Syndrome. This syndrome has an expanded clinical spectrum that involves prominent sleep disorder, progressive bulbar dysfunction, gait instability with abnormal eye movements reminiscent and cognitive deterioration sometimes associated with chorea. The main neuropathological finding is the neuronal loss with hyperphosphorylated tau (p-Tau) protein accumulation at hypothalamus, brainstem tegmentum, hippocampus, periaqueductal gray matter, medulla oblongata and upper cervical cord. The exact pathogenesis is still unclear and involves a neurodegenerative process and autoimmune response. The early diagnosis is important to avoid unnecessary tests and prevent complications. Important resources for diagnosis are the antibody testing of serum and CSF for IgLON5-IgG. The mortality of anti IgLON5 syndrome is high and new studies published described a good response to immune therapy. However, the response to immune therapy depends of some clinical and analytical characteristic. In addition, future studies are needed to thoroughly study the aspects of pathogenesis and treatment of this important pathological syndrome.
ARTICLE | doi:10.20944/preprints202005.0020.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; , 2019-nCoV; Heparin; Ivermectin; Spike Shielding
Online: 2 May 2020 (16:21:32 CEST)
The disease of COVID-19 comprises the most serious against human health worldwide with a high rate of virulence and mortality. The disease is caused by the 2019-nCoV virus from the beta coronavirus family. The virus makes use of its surface glycoprotein named S protein or spike to enter the human cells. The virus attached to its receptor named angiotensin-converting enzyme 2 on host cells surface via its receptor-binding domain and its fusion is mediated by cleavage at S2' site that is carried out by surface protease. Vaccines or drugs interfering with S protein binding or cleavage sites could be considered as drugs to get rid of the infection. In the current work and though docking and molecular dynamic experiments we have checked more than 100 drugs with high enough molecular weights for their shielding potency toward S protein binding sites and processing S2' sites. Our results indicate the shielding potency of: fidaxomicin > ivermectin > heparin > azithromycin > clarithromycin > eryhthromycin > niclosamide > ritonavir. Considering affluent reports regarding the complex disturbance in the immune system and multi-organ involvement in the disease there is no single or binary drug regime for cure expectedly and instead, we claim the multi-drug regime should be the choice in this context. Accordingly, we suggest our extracted drugs as an adjuvant for clinical trials.
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.
ARTICLE | doi:10.20944/preprints202005.0014.v1
Subject: Medicine & Pharmacology, Other Keywords: HIV/AIDS; community health worker; clinical trial; informed consent; HIV positive; STI
Online: 2 May 2020 (13:45:36 CEST)
Aim: The overall aim of the study was to assess the reasons and experiences of participants involved in Antibody Mediated Prevention (AMP) HIV prevention clinical trial at University of North Carolina (UNC) Project, Lilongwe, Malawi. We determined the participants’ reasons for participating in HIV Prevention clinical trials; and the experiences of participants in HIV Prevention clinical trials. Methods: We adopted the qualitative cross-sectional study method. Data were collected using in-depth interviews (IDIs). Purposive sampling was used to select 12 study participants who consented to take part in the study. All participants were the ones taking part in the AMP HIV prevention study at the UNC Project. Data analysis was done concurrently with data collection using content analysis. Results: Individuals were motivated to participate in HIV research due to a range of perceived benefits. These included personal, health, and financial benefits. Participants' research experiences and their continued participation in HIV research were influenced by the research clinic context and the nature of their interactions with research staff. Conclusion: When the clinical trial study participants’ expectations are met through what they experience in the study, the chances of them adhering to the study visits and procedures are high. Even for those who did not have any expectations prior to the study, feeling welcomed and being able to open up to the study staff encouraged their continued participation. In the end, this outweighed the negative comments made by the people in their communities or their friends
COMMUNICATION | doi:10.20944/preprints202005.0011.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; mathematical model; detection ratio; testing; fatality
Online: 2 May 2020 (12:51:26 CEST)
In attempting to predict the further course of the novel coronavirus (COVID-19) pandemic caused by SARS-CoV-2, mathematical models of different types are frequently employed and calibrated to reported case numbers. Among the major challenges in interpreting these data is the uncertainty about the amount of undetected infections, or conversely: the detection ratio. As a result, some models include assumptions about the percentage of detected cases among total infections while others completely neglect undetected cases. Here, we illustrate how model projections about case and fatality numbers vary significantly under varying assumptions on the detection ratio. Uncertainties in model predictions can be significantly reduced by representative testing, both for antibodies and active virus RNA, to uncover past and current infections that have gone undetected thus far.
REVIEW | doi:10.20944/preprints202005.0010.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: bone metastasis; breast cancer; radiotherapy; diagnostic imaging; radiobiologic response; target therapy
Online: 2 May 2020 (12:48:23 CEST)
The standard of care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment in case of symptomatology onset. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive disease presentations are even more common, leading to a change of paradigm of focal treatments. In fact, acknowledgement of behaviour of disease in these setting of patients is carrying aim of radiotherapy towards modalities with radical intent. The aim of this literature review is to analyse available clinical data regarding disease behaviour, imaging, radiotherapy and chemo-radiotherapy integration outcomes for understanding bone metastasis from breast cancer and the potential impact of targeting it.
REVIEW | doi:10.20944/preprints202005.0003.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: Anti-platelets; Anti-rheumatic drugs; Bisphosphonates; Oral anticoagulants; Oral contraceptives; Vitamin K antagonist
Online: 2 May 2020 (11:50:24 CEST)
More than 15,000 prescriptions and over the counter drugs are available according to the US Food and Drug Administration website. Moreover, several herbal medicines and dietary supplements are readily available to add to the list of possible drugs, which can potentially cause adverse drug interactions. These are a pressing concern for all as they can interfere with many dental procedures. Additionally, the number of geriatric patients seen in routine dental practice has increased over time. This implies that there are more patients with multiple diseases and health conditions like hypertension, diabetes, problems associated with the cardiovascular, renal and gastrointestinal systems, arthritis, osteoporosis, etc. All these require patients to be on certain medications. Furthermore, advancement in the dental field has led to more complex dental procedures (implants, grafts) being carried out in a general dental practice. These advanced and slightly more invasive treatments require the use of certain drugs before, during and after the treatment like local anesthetics, vasoconstrictors, anxiolytics, analgesics and antibiotics. All of these can possibly interact with medications a patient is already taking and can also interfere with the current dental treatment and create complications. This article aims to provide necessary information about commonly encountered systemic diseases and associated treating medications, their mechanism of action, possible complications and their management. The classes of drugs discussed include anti-platelet agents, vitamin K antagonists, novel oral anticoagulants, bisphosphonates, disease-modifying anti-rheumatic drugs and oral contraceptives.
Thu, 30 April 2020
ARTICLE | doi:10.20944/preprints202004.0543.v1
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: Coronavirus; COVID-19; SARS-CoV-2; Pandemic; Paramedic; Infection prevention and control; Aerosols; Aerosol Generating Procedures; Novel virus; Wellbeing
Online: 30 April 2020 (17:20:55 CEST)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes the new Coronavirus disease (COVID-19). The symptoms range from mild to severe with a higher incidence of severe cases seen in patients with risk factors such as older age and comorbidities. COVID-19 is mainly spread through the inhalation of respiratory droplets from coughing or sneezing or via contact with droplet-contaminated surfaces. Paramedics should be aware that some aerosol generating procedures (AGPs) may put them at a higher risk of contracting the virus via possible airborne transmission. The use of remote triage clinical assessment is likely to increase as a result of the pandemic. There is no curative drug treatment for the virus and some medications may exacerbate its effects or make patients more susceptible to it. Paramedics should accept that feeling stressed by the pandemic is a natural response. Official guidelines and advice are evolving continually as the evidence on SARS-CoV-2 and COVID-19 grows. Paramedics should keep up to date with the latest clinical guidance from their employers.
REVIEW | doi:10.20944/preprints202004.0541.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: humanized mice; human immune system; preclinical oncology model; metastasis model; immunotherapy; efficacy; safety
Online: 30 April 2020 (17:10:32 CEST)
Metastases cause high mortality in several cancers and immunotherapies are expected to be effective in the prevention and treatment of metastatic disease. However, only a minority of patients benefit from immunotherapies. This creates a need for novel therapies that are efficacious regardless of the cancer types and metastatic environments they are growing in. Preclinical immuno-oncology models for studying metastases have long been limited to syngeneic or carcinogenesis-inducible models that have murine cancer and immune cells. However, the translational power of these models has been questioned. Interactions between tumor and immune cells are often species-specific and regulated by different cytokines in mice and humans. For increased translational power, mice engrafted with functional parts of human immune system have been developed. These humanized mice are utilized to advance understanding the role of immune cells in the metastatic process, but increasingly also to study the efficacy and safety of novel immunotherapies. From these aspects, this review will discuss the role of immune cells in the metastatic process and the utility of humanized mouse models in immuno-oncology research for metastatic cancers, covering several models from the perspective of efficacy and safety of immunotherapies.
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.
ARTICLE | doi:10.20944/preprints202004.0539.v1
Online: 30 April 2020 (16:50:03 CEST)
With the pandemic of Corona Virus [Covid-19], another infectious disease such as dengue neglected In Indonesia. Since the majority of resources, both human and capital, are focusing more on Covid-19, it is still essential to also manage dengue as it is still becoming a threat to the community. This paper aims to predict the number of cases of dengue in Kupang, East Nusa Tenggara, which can help the government to plan for dengue program activities. The result shows the forecast that dengue will remain high for the whole year. With the stay at the home approach to preventing COVID19, chances to get dengue virus increased. Maintaining a clean environment, reduction of breeding sites, and other protective measurements against dengue transmission is very important to perform.
ARTICLE | doi:10.20944/preprints202004.0527.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Radiation oncology; COVID-19; Radiation therapist COVID-19 policy; Radiation oncology departmental Policy
Online: 30 April 2020 (11:02:58 CEST)
Abstract: This brief policy is written after experience treating COVID-19 positive radiation therapy patients to reduce risk to therapy staff and patients in radiation oncology department. It is important to prioritize the safety of staff and non-infected patients while ensuring the continuation of radiation oncology services. Radiation therapists have sustained contact with covid-19 patients in an enclosed vault. Protocols for correct disinfecting of equipment and room and therapists following methods for less transmission of virus is crucial. This policy covers prevention methods from COVID-19 transmission from patient to patient, patient to staff, staff to patient and staff to staff as follows A.Risk reduction by screening and preparing staff and rooms B.Radiation Therapist Policy for COVID-19 positive patient with CCC (Critical Cancer Care)
REVIEW | doi:10.20944/preprints202004.0525.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: COVID-19; evolution of SARS-CoV-2; replication; emerging disease 2019 and diagnostic tools
Online: 30 April 2020 (10:39:54 CEST)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an etiologic agent of the respiratory disease in humans that is known as coronavirus disease 2019 (COVID19). The first outbreak of the disease was initially documented in Wuhan, Hubei Province, China in late December 2019 where people had experienced SARS pneumonia-like symptoms with unknown etiology. Since then it has been observed that COVID-19 positive patients have been showing mild to severe upper respiratory illness symptoms. The type of virus is known to make its transfer from animals to humans and for the concerned virus; researchers have claimed its origin from bat coronavirus at whole-genome level with a 96 % sequence identity. The COVID-19 virus is very contagious and communicable in nature and has been spread throughout the globe since its first outbreak in China. On March 9, 2020, WHO declared it as a Pandemic, and within a month it was already reported to have shown its presence in 213 countries and territories or areas. As of April 29, 2020, this novel virus infected 3,218,183 people and caused 228,029 mortalities worldwide with a variable mortality rate from 3-13 % across the planet and also varied by age and gender. Diagnosis of the disease is a key component in understanding and controlling the spread of the virus and several techniques have been devised including RT-PCR, ELISA, and sequencing-based approaches. To cure COVID-19 patients as of now we do not have proven to be a safe and effective treatment. Therapeutic options currently under investigation in various parts of the world. However, there are various effective therapeutic targets to repurpose the present antiviral therapy for developing potential interventions against SARS-CoV-2. Boosting the immune system can also help to prevent and spread of COVID-19 using various medication and exercises. In this review, our goal to summarize and discussed the present scientific advancements to fight against this novel pandemic.
ARTICLE | doi:10.20944/preprints202004.0519.v1
Subject: Medicine & Pharmacology, Sport Sciences & Therapy Keywords: Palliative Care; Physical Therapy; End-of-Life Care; Non-pharmacological Intervention; Physiotherapy
Online: 30 April 2020 (08:42:54 CEST)
Abstract The aim of this research is to conduct a systematic review analysing the role of the physiotherapy interventions in palliative care. PRISMA as a critical appraisal tool was utilised for the selection of the research articles. The inclusion criteria were based on the year of publication, ease of availability, language, geographical location, and study type. To ensure the credibility, databases such as Elsevier, Proquest, and EBSCO Host were used to filter the grey content. Data published in the past ten years (2009-onwards) was only included to ensure the selection of the most recent interventions used by the physiotherapists. A total of 11 articles were selected which determined that physiotherapy interventions involving breathing exercises, aerobic exercises, manual therapies, and educational awareness were critical to promoting the functional capability and empower the patients.
Wed, 29 April 2020
ARTICLE | doi:10.20944/preprints202004.0308.v3
Subject: Medicine & Pharmacology, Other Keywords: Covid-19; SARS-Cov-2; mortality rate; cancer; cardiovascular disease; respiratory disease; diabetes; kidney diseases
Online: 29 April 2020 (13:37:39 CEST)
Covid-19 has given a halt to all the activities in the world. Europe was most affected followed by the United States of America. It has taken more than 200,000 lives till now. In this study, we have assessed the severity of Covid-19 by analyzing the mortality rate in Covid-19 and other diseases to see the severity of Covid-19 and other chronic diseases. The Covid-19 data and “death rate” data caused by other diseases were downloaded from the world health organization (WHO) website. A normalized period based method was used to see the mortality rate of Covid-19 in comparison to other diseases. The deaths occurred by cardiovascular diseases, cancer, and respiratory diseases were more in number than the Covid-19 caused deaths in the 45 days period where most of the Covid-19 deaths had taken place. The severity of Covid-19 in the USA was moderate. The severity of Covid-19 in Asian countries was found to be at a low. Europe showed the highest diversity in the mortality rate of Covid-19. Cardiovascular diseases, cancer, and non-communicable diseases were still more lethal and caused more deaths than Covid-19.
ARTICLE | doi:10.20944/preprints202004.0509.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: nodal peripheral T-cell lymphomas; peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS); ALK-negative anaplastic large-cell lymphoma (ALCL/ALK-); Angioimmunoblastic T-cell lymphoma (AITL); diagnosis; prognosis; GATA3 gene expression
Online: 29 April 2020 (12:48:00 CEST)
Background: Nodal peripheral T-cell lymphomas (nPTCLs) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in the clinical practice. Accurate biomarkers to refine the different subtypes of nPTCLs and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA3 gene expression, and its capability to discriminate the different subtypes of nPTCLs. Patients and Methods: From 2000 to 2017, 80 patients with nPTCLs were eligible for GATA3 gene expression analysis that was assessed retrospectively by quantitative real time PCR (qRT-PCR) of neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE). Results: Median age was 49 years old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years. Of them, 36.3% were classified as PTCL/NOS, 31.2% ALK-negative ALCL, 21.2% ALK-positive ALCL and 11.3% AITL. The majority of cases had advanced stage (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA3 gene expression level was 0.49% (range 0 – 7.07) in all cohort, it was 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL/NOS and 0.67% for AITL. The difference of GATA3 gene expression among distinct variants of nPTCLs was statistically significant (p < 0.001). GATA3 gene expression levels ≥ 0.71% discriminate PTCL/NOS from ALK-negative ALCL and AITL with sensitivity of 62% and specificity of 80.3%. GATA3 gene expression levels ≥ median was associated with poor 2-year OS for PTCL/NOS (46.7% x 21.4%, p=0.04) and for ALK-negative ALCL (85.7% x 54.5%, p=0.04). Conclusion: Despite the relative small and heterogeneous group of patients with nPTCLs, GATA3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL/NOS and ALK-negative ALCL. Moreover it may also discriminate different subtypes of nPTCLs. Further studies with larger series of patients should confirm our findings.
Tue, 28 April 2020
ARTICLE | doi:10.20944/preprints201907.0142.v2
Subject: Medicine & Pharmacology, Ophthalmology Keywords: glaucoma; tissue engineering; trabecular meshwork; outflow facility
Online: 28 April 2020 (10:42:13 CEST)
Glaucoma is a blinding disease largely caused by increased resistance to drainage of fluid from the eye’s anterior chamber, resulting in elevated intraocular pressure (IOP). A major site of fluid outflow regulation and pathology is the trabecular meshwork (TM) at the entrance of the eye’s drainage system. We aimed to characterize the structural and functional properties of a newly developed tissue-engineered anterior segment eye culture model. We hypothesized that repopulation of a decellularized TM with non-native TM cells could restore aspects of normal TM. The decellularization protocol removed all cells and debris while preserving the ECM. Seeded cells localized to the TM region and progressively infiltrated the meshwork ECM. Cells reached a distribution comparable to control TM after four days of perfusion culture. After a perfusion rate increase challenge, tissue-engineered cultures reestablished normal IOPs (reseeded = 13.7±0.4 mmHg, decellularized = 35.2±2.2 mmHg, p < 0.0001). eGFP expressing CrFK control cells caused a high and unstable IOP (27.0±6.2 mmHg). In conclusion, we describe a readily available, storable, and biocompatible scaffold for anterior segment perfusion culture of non-native cells. Tissue-engineered organs demonstrated similarities to native tissues and may reduce the need for scarce donor globes in outflow research.
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.
Mon, 27 April 2020
ARTICLE | doi:10.20944/preprints202004.0473.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; Egypt; prediction exponential growth rate; hospital preparedness
Online: 27 April 2020 (03:27:47 CEST)
BackgroundThe novel virus COVID-19, also known as SARS-CoV‑2, is currently rapidly spreading around the globe and pushing healthcare systems to the limits of their capacity. One of the functions of predictive models is to timely act for epidemic preparedness including hospital preparedness. In Egypt, like many other countries in the world, the epidemic situation and forecasting have not yet sufficiently studied. ObjectiveThe study was carried out to develop a short-term forecast scenario for the COVID-19 epidemic situation in Egypt and predict the hospital needs to accommodate the growing number of cases.MethodsSecondary data from the COVID-2019 daily reports and the report issued 8th of April by the Egyptian Ministry of Health and Population were used. Due to the daily changing level of knowledge and data, the article reflects the status up to 18 April 2020. The prediction was based on the exponential growth rate model. For the depiction of the situation, the full length of the epidemic timeline was analyzed (from February 14th till April 18th). The growth rates and their rates of decline during the period from the 22nd of March till the 18th of April were calculated and extrapolated in the coming 7 weeks. The predicted hospital needs were assessed against the announced allocated resources.ResultsThe epidemic curve in Egypt is on the ascending arm as of April, 18. The active cases showed exponential growth from the start of the epidemic till April, 18. At the end of this period time, the recovery rate was 23.12% and the case fatality rate (CFR) was7.39. The case fatality rate median level during the last four weeks was 6.64. The active cases are expected to reach more than 20,000 by late May then starts to decline. The allocated regular hospital beds are predicted to show shortage by the time of the release of the paper. The intensive care units (ICU) beds and ventilators are predicted to show insufficiency on May 6.Conclusions: The COVID-19 epidemic in Egypt is expected to continue on the rise for the next few weeks and expected to start to decline late in May, 2020. Our estimates should be useful in preparedness planning. Serious actions should be taken to provide ICU beds and ventilators enough for the predicted number of cases that would need them, not later than the end of April. Mitigation actions have to continue for the coming 6 weeks or until the epidemic situation is more clearly seen.
REVIEW | doi:10.20944/preprints202004.0470.v1
Subject: Medicine & Pharmacology, Other Keywords: non-pharmacological interventions; COVID 19; health policy; mortality; economic; intensive care unit
Online: 27 April 2020 (02:43:02 CEST)
Non-pharmacological interventions in the fight against COVID 19 include: a) suppression, which facilitates its extinction; and b) mitigation, which reduces its speed of spread. Left unmitigated, the intensive care unit bed capacity (ICU) is exceeded over its maximum supply, resulting in increased deaths. Suppression has shown in simulation models the potential for decreasing ICU occupation below its surge limit, effectively decreasing mortality. However, for avoiding a rebound in transmission, suppression must be maintained intermittently until a vaccine is available (which may take up to 2 years). The objective of this paper was to describe the mortality patterns observed in Spain, Italy and South Korea for discussing a hypothetical combined public health policy and socioeconomic model that could potentially reduce mortality while reducing the economic impact of this pandemic in Spain. The plan is based on a progressive-voluntary reinstatement to work of the population exposed to the lowest risks (healthy non-immune family units <50 y/o and immune population) and it depends on having sufficiently available ICU beds for providing adequate support. This model, if proven correct for Spain, could eventually be followed by other countries facing a similar impact of the present pandemic.
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.
ARTICLE | doi:10.20944/preprints202004.0459.v1
Subject: Medicine & Pharmacology, Other Keywords: emergency department; crowding; return visit; admission; patient satisfaction; quality of healthcare
Online: 25 April 2020 (10:45:25 CEST)
This study was conducted to determine whether overcrowding in the emergency department (ED) affects the occurrence of a return visit (RV) within 72 hours. The crowding indicator of index visit was the average number of total patients, patients under observation, and boarding patients during the first 1 and 4 hours from ED arrival time and the last 1 hour before ED departure. Logistic regression analysis was conducted to determine whether each indicator affects the occurrence of RV and post-RV admission. Of the 87,360 discharged patients, 3,743 (4.3%) returned to the ED within 72 hours. Of the crowding indicators pertaining to total patients, the last 1 hour significantly affected decrease in RV (p=0.0046). Boarding patients were found to increase RV occurrence during the first 1 hour (p=0.0146) and 4 hours (p=0.0326). Crowding indicators that increased the likelihood of admission post-RV were total number of patients during the first 1 hour (p=0.0166) and 4 hours (p=0.0335) and evaluationg patients during the first 1 hour (p=0.0059). Overcrowding in the ED increased the incidence of RV and likelihood of post-RV admission. However, overcrowding at the time of ED departure was related to reduced RV.
ARTICLE | doi:10.20944/preprints202004.0457.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-19; vitamin K; vitamin K antagonists; SARS-CoV-2; matrix Gla protein; desmosine; protein C; protein S
Online: 25 April 2020 (03:13:45 CEST)
Introduction: Coronavirus 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2. The majority of patients have at most mild symptoms, however, a significant proportion develops respiratory failure. COVID-19 may also progress beyond the lungs. Coagulopathy and thromboembolism are prevalent in severe COVID-19 and relate to decreased survival. Coagulation is an intricate balance between clot promoting and dissolving processes in which vitamin K plays a well-known role. We hypothesized that vitamin K status is reduced in patients with severe COVID-19. Methods: Vitamin K status was assessed by measuring desphospho-uncarboxylated matrix Gla protein (dp-ucMGP; inversely related to vitamin K status) and the rate of elastin degradation by measuring desmosine. We included 123 patients who were admitted with COVID-19 and 184 controls. Results: Dp-ucMGP levels were significantly elevated in COVID-19 patients (1,673Å}1,584 pmol/L) compared to controls (536±291 pmol/L; p<0.0005). Dp-ucMGP levels were significantly higher in COVID-19 patients with unfavorable outcome compared to those with less severe disease. Furthermore, dp-ucMGP and desmosine levels were significantly associated (r=0.65; p<0.0005). Conclusions: Vitamin K status was reduced in patients with COVID-19 and related to poor prognosis. Also, low vitamin K status seems to be associated with accelerated elastin degradation. An intervention trial is now needed to assess whether vitamin K administration improves outcome in patients with COVID-19.
ARTICLE | doi:10.20944/preprints202004.0454.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: casein hydrolysate; Val-Pro-Pro; Ile-Pro-Pro; brachial ankle pulse wave velocity; advanced glycation end products; facial pigmentation
Online: 25 April 2020 (02:42:35 CEST)
Casein hydrolysate improves arterial stiffness, as estimated by brachial ankle pulse wave velocity (baPWV), in untreated hypertensive subjects. Facial pigmentation is a useful biomarker for arterial stiffness. This trial evaluated whether casein hydrolysate improves facial pigmentation in association with changes in arterial stiffness. A randomized, double-blind, placebo-controlled trial was conducted in 80 non-hypertensive Japanese participants randomly assigned to receive either active tablets containing casein hydrolysate or placebo for 48 weeks. Facial pigmentation and baPWV were measured at baseline and at the end of the intervention. Other biochemical atherosclerosis-related parameters were also measured, including advanced glycation end products (AGEs). Changes in facial pigmentation showed a significant difference between the groups. Change in baPWV was significantly better in the active than in the placebo group. In contrast, no significant association was seen between changes in facial pigmentation and those in baPWV. Among other atherosclerosis-related factors, changes in advanced glycation products (AGEs) were significantly decreased in the active compared to the placebo group. Further, changes in facial pigmentation were positively correlated with those in AGEs. Changes in AGEs were independently associated with changes in facial pigmentation. Casein hydrolysate improves facial pigmentation in non-hypertensive participants. Casein hydrolysate may have beneficial effects on glycation stress.
REVIEW | doi:10.20944/preprints202004.0453.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: neurology; clinical features; coronavirus; stroke; encephalitis; headache; delirium
Online: 25 April 2020 (02:36:21 CEST)
The Coronavirus disease due to SARS-CoV-2 emerged in Wuhan city, China in December 2019 and rapidly spread more than 200 countries as a global health pandemic. There are more 3 million confirmed cases and around 207,000 fatalities. The primary manifestation is respiratory and cardiac but neurological manifestations are being reported in the literature as case reports and case series. The most common reported symptoms to include headache and dizziness followed by encephalopathy and delirium. Among the complications noted are Cerebrovascular accident, Guillian barre syndrome, acute transverse myelitis, and acute encephalitis. The most common peripheral manifestation was hyposmia. It is further noted that sometimes the neurological manifestations can precede the typical features like fever and cough and later on typical manifestations develop in these patients. Hence a high index of suspicion is required for timely diagnosis and isolation of cases to prevent the spread in neurology wards. We present a narrative review of the neurological manifestations and complications of COVID-19. Our aim is to update the neurologists and physicians working with suspected cases of COVID-19 about the possible neurological presentations and the probable neurological complications resulting from this novel virus infection.
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.
Fri, 24 April 2020
CASE REPORT | doi:10.20944/preprints202004.0446.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Central Disequilibrium; CNS; covid-19 coronavirus; SARS-CoV-2
Online: 24 April 2020 (14:07:43 CEST)
We describe a 90-year-old male presenting with disequilibrium, loss of balance and difficulty walking for three days prior to initial presentation. Interestingly, he denied cough, fever or dyspnea prior to arrival. Over the course of 48 hours, the patient developed acute respiratory distress syndrome (ARDS) requiring intubation, diagnosed with COVID-19 infection and was treated in the intensive care unit where he died. Since the initial cases in Wuhan China in Dec 2019, the medical and epidemiological communities have learned much about the presenting features, symptomatology, epidemiology, transmission and common physical, laboratory and radiological findings of this disease. Although common symptoms are already established, it is very important to learn and record atypical symptoms or presentations of this highly contagious disease. By doing so, we will be able to recognize earlier atypical symptoms and prevent the environmental exposure to Health care workers and future patients as well. We report that Central disequilibrium may be such as initial presenting sign and symptom of impending respiratory failure from SARS-CoV-2 virus. These atypical findings such as presyncope may precede common respiratory complications of SARS-CoV-2.
COMMUNICATION | doi:10.20944/preprints202004.0445.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COVID-19; Coronavirus; Respiratory Distress; Tobacco Smoking; Correlation Statistics; Conditional Probability; Regression; China; U.S.A.
Online: 24 April 2020 (14:03:31 CEST)
The novel COVID-19 disease is a contagious acute respiratory infectious disease whose causative agent has been demonstrated to be a new virus of the coronavirus family, SARS-CoV-2. Multiple studies have already reported that risk factors for severe disease include older age and the presence of at least one of several underlying health conditions. However, a recent physiopathological report and the French COVID-19 scientifific council have postulated a protective effect of tobacco smoking. We have been able to demonstrate the statistical signifificance in this regard of recent series from both China and in the US, reporting smoking status as well as disease severity (p-values of 2.27 × 10 3 and 11.7 × 10 15, respectively). Subsequently and using a Bayesian approach we have established that disease severity is positively associated with smoking status. Finally, we refute claims linking general population smoking status (N in O(108) or O(109)) to much smaller disease course series (N in O(103)). The latter point in particular is presented to stimulate academic discussion, and must be further investigated by well-designed studies.
ARTICLE | doi:10.20944/preprints202004.0442.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: nutrition status; muscle strength; diabetes; handgrip; insulin resistance; functional tests
Online: 24 April 2020 (13:52:32 CEST)
Background and Aims: We aimed to investigate cross-sectional relationships of relative handgrip strength (RHGS) with presence of diabetes and hypertension in a community setting. Methods and Results: Between 2016 and 2018, we enrolled 601 consecutive women with an average age of 70.7 ± 6.9 years (mean ± SD). Nutritional status was evaluated by the Mini Nutritional Assessment (MNA) score. Muscular strength and level of fitness were assessed by handgrip strength (HGS) and other standardized physical functional tests. The majority of participants were overweight or obese (80% with BMI > 25). Prevalence of diabetes and hypertension was 13 and 60%, respectively. Participants in the lowest quartile of HGS adjusted for BMI (RHGS) had significantly higher prevalence of diabetes and hypertension compared with those in the lower quartile (20.7 vs. 5.3% and 49.3 vs. 39.3%, respectively, p < 0.01 for both), whereas differences in nutritional status were not observed. Likelihood of having diabetes was significantly reduced in women with higher RHGS values (OR 0.77; 0.59–0.86 CI95%; p=0.002), independently of age, abdominal adiposity and presence of hypertension. RHGS was positively correlated with most of the physical functional tests performed. Conclusion: RHGS is an easy-to-obtain and inexpensive measure of muscular strength, independently associated with presence of diabetes in overweight elderly women. Prospective studies are required to assess its predictive value in individuals at risk of new onset or progression of diabetes.
Subject: Medicine & Pharmacology, Allergology Keywords: antibodies; COVID-19; glycans; immunoglobulin M; SARS-CoV-2; pneumonia; prediction; protection
Online: 24 April 2020 (10:25:27 CEST)
The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic infection, to pneumonia, and to complications eventually fatal. We propose here the first model, explaining how the outcome of first, crucial 10-15 days after infection, hangs on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, MBL). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm) leading to complications often requiring intensive therapy and being, in some patients, fatal. Strenuous exercise and high flow air in the incubation days and early stages of COVID-19, facilitates direct penetration of the virus to the lower airways and the alveoli, without impacting on the airway’s mucosae covered by neutralizing antibodies. This allows the virus to bypass the efficient immune barrier of the upper airways mucosa in young and healthy athletes. In conclusion, whether the virus or the adaptative immune response reach the lungs first, is a crucial factor deciding the fate of the patient. This “quantitative and time-sequence dependent” model has several implications for prevention, diagnosis, and therapy of COVID-19.
CONCEPT PAPER | doi:10.20944/preprints202004.0432.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: SARS CoV-2; COVID-19; Nitazoxanide; Azithromycin; Interferons
Online: 24 April 2020 (09:24:23 CEST)
Azithromycin has been shown to have a clinical efficacy against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2); ivermectin has also demonstrated a remarkable experimental efficacy with a potential to be used for Coronavirus disease 2019 (COVID-19). Further, BCG vaccination is being considered for clinical trials aiming to test its potential for lowering COVID-19 morbidity and mortality. This article illustrates some structural and functional relationships that may gather these drugs and the author, basing on a combined pathophysiological and pharmacological approach, recommends the FDA-approved antidiarrhea drug; nitazoxanide, which has been previously suggested but unfortunately ignored, to be tested in combination with azithromycin for their potential activity against SARS CoV-2 soonest. The author recommends testing their combined administration as early during the clinical course of COVID-19 as possible. Further, basing on the same represented concept, the author recommends more trials for interferons to be tested against SARS CoV-2 especially in severe and critical cases.
ARTICLE | doi:10.20944/preprints202004.0227.v2
Subject: Medicine & Pharmacology, Cardiology Keywords: global myocardial injury; BMSCs; active cardiac support device (ASD); stem cell treatment; epicardial delivery
Online: 24 April 2020 (04:34:11 CEST)
Bone marrow-derived mesenchymal stem cells (BMSCs) have been considered a promising therapeutic approach to cardiovascular disease. This study intends to compare the effect of BMSCs through a standard active cardiac support device (ASD) and intravenous injection on global myocardial injury induced by isoproterenol. BMSCs were cultured in vitro, and the transplanted cells were labeled with a fluorescent dye CM-Dil. Isoproterenol (ISO) was injected into the rats; two weeks later, the labeled cells were transplanted into ISO-induced heart injury rats through the tail vein and ASD device for five days. The rats were sacrificed on the first day, the third day, and the fifth day after transplantation to observe the distribution of cells in the myocardium by fluorescence microscopy. The hemodynamic indexes of the left ventricle were measured before sacrificing. H&E staining and Masson’s trichrome staining were used to evaluate the cardiac histopathology. In the ASD groups, after three days of transplantation, there were a large number of BMSCs on the epicardial surface, and after five days of transplantation, BMSCs were widely distributed in the ventricular muscle. But in the intravenous injection group, there were no labeled-BMSCs distributed. In the ASD+BMSCs-three days treated group and ASD+BMSCs -five days-treated group, left ventricular systolic pressure (LVSP), maximum rate of left ventricular pressure rise (+dP/dt), maximum rate of left ventricular pressure decline (-dP/dt) increased compared with model group and intravenous injection group (P<0.05). By giving BMSCs through ASD device, cells can rapidly and widely are distributed in the myocardium and significantly improve heart function.
ARTICLE | doi:10.20944/preprints202004.0301.v2
Subject: Medicine & Pharmacology, Urology Keywords: Qianlie Tongli decoction; chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); anti-inflammation; therapeutic effects; immunization
Online: 24 April 2020 (04:30:56 CEST)
Objectives: This study was undertaken to reveal therapeutic effects and the preliminary mechanism of Chinese medicine formula Qianlie Tongli decoction (QTD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Methods: A total of 50 male C57BL/6 mice were randomly divided into five groups. All groups except the control group were injected subcutaneously T2 peptide emulsion, which induced the CP/CPPS model. After the induction of CP/CPPS, the model group was given 0.9% NaCl by oral gavage while low-dose, medium-dose, and high-dose groups were treated with Chinese medicine formula. Micturition habits and pain behavior of mice were analyzed for each group. Hematoxylin and eosin staining were used to investigate prostate inflammation. The serum level of tumor necrosis factor-α (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA) kit. Key findings: Chinese medicine formula significantly reduced the number of urine spots and improved pain response frequency in the medium-dose and high-dose group. The high-dose group showed reduced considerably inflammatory lesion and inflammatory cell infiltration than the low-dose and medium-dose groups. Serum levels of TNF-α in the high-dose group were significantly reduced compared with the model group. Conclusions: The results demonstrated the therapeutic effects of Qianlie Tongli decoction in CP/CPPS mice by analyzing clinically relevant symptoms (urinary tract system, pelvic pain, and prostate inflammation), and preliminary explored the inflammatory-related treatment mechanisms by measuring TNF-α.
ARTICLE | doi:10.20944/preprints202004.0423.v1
Subject: Medicine & Pharmacology, Ophthalmology Keywords: mix-and-match; extended-depth-of-focus intraocular lens; diffractive multifocal intraocular lens; stereopsis
Online: 24 April 2020 (03:30:03 CEST)
Purpose: To evaluate clinical outcomes after bilateral mix-and-match cataract surgery using extended depth of focus (EDOF) and diffractive multifocal (DMF) intraocular lenses (IOLs). Methods: Thirty-seven patients received Tecnis Symfony EDOF IOL (ZXR00) implantation in the dominant eye, and Tecnis +3.25 DMF IOL (ZLB00) in the non-dominant eye. Patients were followed for 3 months, and uncorrected and corrected distance visual acuity (UDVA, CDVA) , uncorrected intermediate and near visual acuity (UIVA, UNVA), contrast sensitivity, defocus curves, stereopsis, and patient satisfaction were assessed. Results: At 3 months, mean logMAR UDVA was 0.07 ± 0.09 in EDOF IOL eyes, 0.12 ± 0.11 in DMF IOL eyes, and 0.02 ± 0.05 in both eyes. UIVA was 0.11 ± 0.11 in EDOF IOL eyes, 0.16 ± 0.12 in DMF IOL eyes, and 0.04 ± 0.07 in both eyes. UNVA was 0.25 ± 0.15 in EDOF IOL eyes, 0.22 ± 0.16 in DMF IOL eyes, and 0.13 ± 0.13 in both eyes. Thirty patients(81.1%) were more than satisfied with near vision, and 8 patients(21.6%) complained of severe glare and halo. Spectacle independence for near vision was achieved in 34 patients(91.9%), and 31 patients(83.8%) had better than a 50 second arc of stereopsis. Conclusion: Mix-and-match cataract surgery with EDOF and DMF IOL implantation provided good visual outcomes through all distances. Also excellent patient satisfaction was achieved with high level of spectacle independence and minimal photic phenomena.
Thu, 23 April 2020
ARTICLE | doi:10.20944/preprints202004.0418.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Diagnosis; Health sensing system; Nocturnal perspiration; Parameter; Pathology; Predictor; Q-strip; Subjective measurement; Sweat pattern; Symptoms; Prodromal; biomarker
Online: 23 April 2020 (15:26:39 CEST)
One third of a person’s life is spent on sleep, therefore the quality and habit of sleep affects health. A single case study indicated that perspiration could serve as a prognostic marker. Diagnosing nocturnal perspiration is common clinical practice, since this serves as a major symptom in many pathologies. Till this day no specific evidence-based approach for diagnosing nocturnal perspiration exists. By introducing the Q-strip, a device which quantitatively measures nocturnal perspiration, this could be acquired. The Q-strip could serve a purpose in diagnosing nocturnal perspiration more efficient without being intrusive. In addition to its health sensing potentials, the Q-strip makes it possible to visualise perspiration patterns. This introduces the possibility to examine the quality of sleep. Future research is recommended to investigate this.
REVIEW | doi:10.20944/preprints202004.0417.v1
Subject: Medicine & Pharmacology, Nursing & Health Studies Keywords: Coronavirus; COVID-19; SARS-Cov-2; infection; physiotherapy; rehabilitation.
Online: 23 April 2020 (15:22:55 CEST)
This document outlines best practice recommendations for acute care physiotherapy for patients with COVID-19 infections developed for practice in Qatar but adaptable with any settings. This recommendation is the result of a combination of systematic evidence search, subsequent critical evaluation of retrieved evidence and consensus process. The agreed recommendations were integrated into a physiotherapy clinical reasoning algorithm. It includes recommendations on Physiotherapy referral, screening, management categories and best practice recommendations. It is intended for use by physiotherapists and other relevant stakeholders in the acute care setting caring for adult patients with suspected and/or confirmed COVID-19.
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).
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS; Covid-19; Vitamins; Therapy
Online: 23 April 2020 (05:44:52 CEST)
In December 2019 a novel human-infecting coronavirus, named SARS-CoV-2 has been recognized to cause a pneumonia epidemic outbreak with different degree of severity in Wuhan, Hubei Province in China. Since then this epidemic spread worldwide an in the last week Europe and Italy also have been involved. Effective preventive and therapeutic strategies are absolutely required to block this serious public health concern. Unfortunately, SARS-CoV-2 has been isolated only recently, therefore a few studies concerning its immunopathogenesis and tretament are available. Therefore, on the basis of the assumption that the SARS-CoV-2 is genetically related to SARS-CoV (about 82% of genome homology) and that its characteristics, like the modality of transmission, the route of infection, the organ localization, the type of the immune response it may stimulate, the morbidity and the mortality rates are still poor-known, a literature search was performed to identify the reports assessing these elements in patients with SARS-CoV-induced infection. Therefore, we have analysed: 1) the structure of SARS CoV-2 and SARS CoV; 2) the clinical signs and symptoms and pathogenic mechanisms observed during the development of acute respiratory syndrome and the Cytokine Release Syndrome; 3) the modification of the cell microRNome and of the immune response in patients with SARS infection; 4) the possible role of some liposoluble compounds (such as vitamin A, D and E) in modulating directly or indirectly the replication ability of SARS-CoV-2 and host immune response.
ARTICLE | doi:10.20944/preprints202004.0404.v1
Subject: Medicine & Pharmacology, Pediatrics Keywords: milk; human; microbiota; microbiome; extracellular vesicle; breastfeeding
Online: 23 April 2020 (05:11:19 CEST)
The microbiota of human breast milk (HBM) contributes to infant gut colonization; however, whether bacterial extracellular vesicles (EVs) are present in HBM or might contribute to this process remains unknown. In the present study, we characterized the HBM microbiota of healthy Korean mothers and measured the key bacteria likely affecting infant gut colonization by analyzing both the microbiota and bacterial EVs. A total of 22 HBM samples were collected from lactating mothers. The DNA of bacteria and bacteria-derived EVs was extracted from each sample. Gene analysis was performed using Illumina MiSeq. Firmicutes accounted for the largest portion among the phyla, followed by Proteobacteria, Bacteroides, and Actinobacteria in both bacteria and bacterial EV samples. At the genus level, Streptococcus (25.1%) and Staphylococcus (10.7%) were predominant in bacterial samples, whereas Bacteroides (9.1%), Acinetobacter (6.9%), and Lactobacillaceae(f) (5.5%) were prevalent in bacterial EV samples. Several genera including Bifidobacterium were significantly positively correlated between the two samples. Our findings reveal the diverse bacterial communities in HBM of healthy lactating mothers and suggest the presence of key bacteria with metabolic activity in HBM and that EVs derived from these bacteria may contribute to the vertical transfer of gut microbiota from mother to infant.
REVIEW | doi:10.20944/preprints202004.0400.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: angiogenesis; cancer; VEGF; anticancer; vessel co-option; resistance to anti-angiogenesis treatment; cancer hallmark
Online: 23 April 2020 (04:09:02 CEST)
Angiogenesis is a term that describes the formation of new blood and lymphatic vessels from a pre-existing vasculature. This allows tumour cells to acquire sustenance in the form of nutrients and oxygen and the ability to evacuate metabolic waste. As one of the hallmarks of cancer, angiogenesis has been studied extensively in animal and human models to enable better understanding of cancer biology and the development of new anti-cancer treatments. Angiogenesis plays a crucial role in the process of tumour genesis, because solid tumour need a blood supply if they are to grow beyond a few millimeters in size. On the other hand, there is growing evidence that some solid tumour exploit existing normal blood supply and do not require a new vessel formation to grow and to undergo metastasis. This review of the literature will present the current understanding of this intricate process and the latest advances in the use of angiogenesis-targeting therapies in the fight against cancer.
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.
REVIEW | doi:10.20944/preprints202004.0395.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: coronavirus disease 2019; chloroquine; drug repurposing; HIV; Africa
Online: 22 April 2020 (08:33:34 CEST)
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, has been declared by the World Health Organization (WHO) as a pandemic. Unfortunately, finding a vaccine or developing drugs from the scratch is a time-consuming luxury given the widespread and high fatality rates of the virus. In the short term, repurposing of drugs already in use seem to be the most rational step to quickly and effectively curb the virus. Several antiviral agents had been proposed as possible remedies, but the 4-aminoquinolines, Chloroquine (CHQ) and hydroxychloroquine (HCHQ) appear to be generating more interest. They are generic, cheaply available and have proven efficacy against malaria parasites in Africa. The human immunodeficiency virus (HIV), on the other hand, targets the immune system thereby reducing the patient’s ability to fight infections. Sadly, 68% of the global HIV burden occur in Africa. It is therefore anticipated that incidence of severe forms of COVID-19 could occur in Africa because of associated endemic conditions that compromise the immune system. With CHQ and HCHQ being considered for clinical use against COVID-19, there is a need to highlight their potential merits and confounding variables in the subgroup of patients with or without HIV.
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.
REVIEW | doi:10.20944/preprints202004.0376.v1
Subject: Medicine & Pharmacology, Clinical Neurology Keywords: urinary tract infection; multiple sclerosis; hospitalization and mortality rate
Online: 21 April 2020 (06:03:22 CEST)
Introduction: Multiple sclerosis (MS) is a demyelinating, chronic, inflammatory and autoimmune disease of the central nervous system (CNS) with axonal degeneration, presenting a progressive and variable course. MS patients usually have complications, such as bladder dysfunction, presence of urinary symptoms and Urinary Tract infection (UTI), which is one of the three most common non-neurological complications in MS patients. Objective: Analyze the most diverse aspects of UTI in MS patients, focusing on risk factors, prevalence, hospitalization and mortality rates of UTIs in this group. Methods: A non-systematic review of articles published on PubMed in the last 10 years with the search terms "Urinary Tract Infection" AND "Multiple Sclerosis". Discussion: MS patients have a high UTI prevalence, mainly due to the occurrence of urinary disorders in these patients. The most common symptoms of UTI in MS patients are urinary urgency, polyuria, nocturia, urinary retention, and incontinence. Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the most found organisms and treatment is based on antibiotic therapy. Moreover, UTIs can precipitate outbreaks, worsen the disease, causing more damage and a severe neurological condition deterioration. Therefore, UTIs in this group are associated with a high hospitalizations rate and a high mortality rate. Conclusion: UTI represents a great risk and concern in MS patients. The high prevalence, hospitalization rate and mortality rate of UTI in MS is worrying, such as the cause-consequence relationship between UTIs and the use of corticosteroids in outbreaks. Therefore, it is important to be aware of a UTI in this group to make early diagnoses, adequate management, and new infections prevention. Thus, further studies are needed to thoroughly analyze each nuance of this important comorbidity for MS patients.
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.
REVIEW | doi:10.20944/preprints202004.0373.v1
Subject: Medicine & Pharmacology, Other Keywords: Romania; COVID-19; coronavirus; pandemic; epidemic; public health; healthcare; policy; diaspora; sociocultural;
Online: 21 April 2020 (04:47:30 CEST)
In the context of the COVID-19 pandemic, countries around the world varied in the strength and timeliness of their responses. In Romania, specific challenges were faced with regards to managing the spread and limiting the impact of the disease, ranging from healthcare infrastructure to demographic and sociocultural aspects. As the country has a sizeable diaspora, major difficulties were faced when large numbers of individuals from highly affected areas returned to Romania. However, the fast implementation of control measures successfully averted a surge in the number of COVID-19 cases. This delayed the overburdening of an already challenged healthcare system during the initial phases of the epidemic. Furthermore, early control was facilitated by the exploitation of communication channels that penetrated all layers of society, from ordinary citizens to governmental authorities and high-ranking religious figures. The management of the COVID-19 crisis in Romania illustrates the importance of a fast initial response which takes into account the role played by sociocultural aspects in the context of an epidemic. As the challenges faced by Romania are not unique, these results could inform future public health strategies worldwide.
Mon, 20 April 2020
REVIEW | doi:10.20944/preprints202004.0367.v1
Subject: Medicine & Pharmacology, Allergology Keywords: COVID-19; drugs; 2019-nCoV; clinical trials; SARS-CoV-2
Online: 20 April 2020 (15:53:56 CEST)
The emergence of new type of viral pneumonia cases in China, on December 31, 2019; identified as the cause of human coronavirus, labeled as "COVID-19," took a heavy toll of death and reported cases of infected people all over the world, with the potential to spread widely and rapidly, achieved worldwide prominence but arose without the procurement guidance. There is an immediate need for active intervention and fast drug discovery against the 2019-nCoV outbreak. Herein, the study provides numerous candidates of drugs (either alone or integrated with another drugs) which could prove to be effective against 2019-nCoV, are under different stages of clinical trials. This review will offer rapid identification of a number of repurposable drugs and potential drug combinations targeting 2019-nCoV and preferentially allow the international research community to evaluate the findings, to validate the efficacy of the proposed drugs in prospective trials and to lead potential clinical practices.
REVIEW | doi:10.20944/preprints202004.0365.v1
Subject: Medicine & Pharmacology, Obstetrics & Gynaecology Keywords: semen quality; male infertility; nutritional model; diet
Online: 20 April 2020 (14:54:04 CEST)
Abnormalities in male fertility constitute about 50% of all infertility causes. According to some data, the quality of human semen has deteriorated by 50-60 % over the last 40 years. A high-fat diet and obesity, the development of which is encouraged by the western lifestyle, affects the structure of spermatozoa, but also the development of the offspring and their health in later stages of life. In obese individuals, disorders on the hypothalamic-pituitary-gonadal axis are observed, as well as elevated oestrogen levels with simultaneous decrease of testosterone, LH and FSH hormone levels. Healthy dietary models clearly correlate with better sperm quality and a smaller risk of abnormalities in parameters, such as sperm count, sperm concentration and motility, as well as lower sperm DNA fragmentation. Apart from mineral components such as zinc and selenium, the role of omega-3 fatty acids and antioxidant vitamins should be emphasized, since their action will be based primarily on the minimization of oxidative stress and inflammation process. Additionally, the incorporation of carnitine supplements and coenzyme Q10 in therapeutic intervention seems also promising. Therefore, it is advisable to have a varied and balanced diet based on vegetables and fruit, fish and seafood, nuts, seeds, whole-grain products, poultry and low-fat dairy products.
HYPOTHESIS | doi:10.20944/preprints202004.0360.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: SARS-CoV-2; acute respiratory distress syndrome; hypoxic pulmonary vasoconstriction; alveolar edema; early low-flow oxygen
Online: 20 April 2020 (08:30:29 CEST)
Acute respiratory distress syndrome (ARDS) and the serious complications are the most frequent causes of death of SARS-CoV-2 infection. We bring out a hypothesis that early low-flow oxygen inhalation would maintain the hypoxic pulmonary vasoconstriction (an essential protection mechanism of the lung that optimize gas exchange) and accelerate the re-absorption of pulmonary edema fluid. The optimal time for oxygen therapy was analyzed and four comments are proposed: (1) Finger SpO2 should be measured at home simultaneously with the first-time nucleic acid test. (2) If the patient's SpO2 was lower than the reference value by 2% or more, it is suggested to be hospitalized immediately for standard low-flow oxygen inhalation. (3) If it was not possible to be admitted to hospital immediately, the patient is recommended to take oxygen in the home. (4) The Patients with low SpO2 are advised to use prone position as much as possible.
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/preprints202004.0357.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: coronavirus; COVID-19; SARS-CoV2; dentistry; oral health; transmission
Online: 20 April 2020 (02:14:36 CEST)
On March 11th 2020, the World Health Organization (WHO) declared the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV2) as a pandemic. Until an effective treatment or a vaccine is developed, the current recommendations are to contain the disease, and control its transmission. It is now clear that the primary mode of SARS-CoV2 transmission is aerosol/droplet spread, and by contacting virus contaminated surfaces acting as fomites (inanimate vectors). Furthermore, recent data indicate that the live virus particles are present in saliva, and, more alarmingly, asymptomatic individuals may transmit the infection. By virtue of the nature of the practice of dentistry where intrinsically, a high volume of aerosols are produced, as well as the close proximity of dentists and patients during treatment, dentists and allied dental staff are considered the highest risk health professional group for acquiring SARS-CoV2 during patient management. Therefore, several organizations and specialty associations have proposed guidelines and recommendations for limiting the transmission of SARS-COV2 from carriers to dentists and vice versa. This paper aims to provide a review of these guidelines, and concludes with a brief look at how the practice of dentistry may be impacted by COVID-19, in the post-pandemic era.
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
ARTICLE | doi:10.20944/preprints202004.0308.v2
Subject: Medicine & Pharmacology, Other Keywords: Covid-19; mortality rate; cancer; cardiovascular disease; non-communicable respiratory disease; SARS-Cov-2
Online: 19 April 2020 (15:09:10 CEST)
Covid-19 has given a halt to all the activities in the world. Europe was most affected followed by the United States of America. In this study we have assessed the severity of Covid-19 by analyzing the mortality rate in Covid-19 and other diseases. The Covid-19 data and “death rate” data caused by other diseases (cardiovascular diseases, cancer, non-communicable respiratory diseases, respiratory infectious diseases, diabetes mellitus, and kidney diseases) were downloaded from the world health organization (WHO) website. A normalized period based method was used to see the mortality rate of Covid-19 in comparison to other diseases. The deaths occurred by cardiovascular diseases, cancer, and respiratory diseases were more in number than the Covid-19 caused deaths in the 45 days period where most of the Covid-19 deaths had taken place. The mortality rate of Covid-19 was highest in France followed by Belgium and the lowest in Russia while the share of Covid-19 caused deaths in total deaths by all causes was the highest in Belgium followed by Spain and the lowest in Japan. The severity of Covid-19 in the USA was moderate. The severity of Covid-19 in Asian countries was found to be moderate to low. The severity of Covid-19 was diverse in the world. Europe showed the highest diversity in the mortality rate of Covid-19. Cardiovascular diseases, cancer, and non-communicable diseases were still more lethal and caused more deaths than Covid-19.
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.
REVIEW | doi:10.20944/preprints202004.0346.v1
Online: 19 April 2020 (13:15:27 CEST)
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging infectious disease with currently a pandemic state. Cardiac function can be involved, affecting prognosis, in addition with lung feature severity, particularly in patients with comorbidities. Since the renin angiotensin aldosterone (RAA) system may interact with SARS-Cov-2, researches are still ongoing to assess the prognostic value of RAA blockers in cardiology.
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.
SHORT NOTE | doi:10.20944/preprints202004.0339.v1
Online: 19 April 2020 (08:22:24 CEST)
The emergence of SARS-CoV-2 is a challenge in the actual medical scenario. Besides the classical lung and respiratory disease, patients infected with the virus can present with cardiac injury, and pathogenic mechanisms point to a direct infection of the heart.
ARTICLE | doi:10.20944/preprints202004.0165.v2
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: Covid-19; Blastn; toxins protein; ACh; aChE; BuChE; CBP; Zero Point; bungaro-toxins, phospholipase A2; similar prothrombin activator protein
Online: 19 April 2020 (06:51:53 CEST)
Acetylcholine (ACh) is the best one characterized neurotransmitter. Its central roles in the cholinergic areas and central nervous system (CNS) and peripheral (PNS) synapses are well known. It was the first molecule identified as a neurotransmitter and appears to be phylogenetically the oldest one signaling molecules. ACh was detected in bacteria, protozoa, fungi, algae and primitive plants, indicating that the cholinergic system was widely distributed in living organisms before its appearance in the nervous system. The autonomous nervous system (ANS) is an integral part animal kingdom history. It determines fight-escape reactions as well as outlining the vital and cognitive functions bio-organization rhythms. The virus (Covid-19) extraneous effects acting on it could help to better understand its functions. The Blast results show some factors like protein that can be implicated such as bungaro-toxins, phospholipase A2 and the similar prothrombin activator protein. A positive correlation with different toxins is obtained and the Covid-19 double pathogenic mechanism theory is proposed. The process allows us to outline the possibility about toxic-like factors presence.
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/preprints202004.0330.v1
Subject: Medicine & Pharmacology, Other Keywords: SARS-CoV-2 (CoV-2); COVID-19; coronavirus; pandemic; respiratory distress; brainstem; respiratory center
Online: 19 April 2020 (05:37:30 CEST)
Covid-19 pandemic has captivated scientists to investigate if this new disease can affect the central nervous system (CNS). The most challenging symptoms of Covid-19 are related to respiratory distress, and most patients admitted in intensive care units cannot breathe by their own. Therefore, a crucial question is if respiratory distress can be partially explained by the CNS affection. SARS-Cov-2 is a beta-coronavirus that shares high similarities with SARS-CoV. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Those coronaviruses have been able to invade the brainstem via a synapse‐connected route to the medullary respiratory center, where the infected regions included the nucleus of the solitary tract and nucleus ambiguous. The vagal afferent nerves from receptors in the lung communicate with the medulla and pons respiratory control centers to coordinate inspiration and expiration. This suggests that neuroinvasion of SARS‐CoV‐2 might play a role in the acute respiratory failure of Covid-19. Therefore, acute respiratory distress in Covid-19 can be partially explained by brainstem dysfunction, suggesting the needs of more specific and aggressive treatments with the direct participation of neurologists and neurointensivists.
ARTICLE | doi:10.20944/preprints202004.0328.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; coronavirus; enhanced surveillance; real-time forecasts; phenomenological models; sub-exponential growth; Kadiogo; Burkina Faso
Online: 19 April 2020 (05:23:40 CEST)
On 9 March 2020, two cases of COVID-19 were reported in Burkina Faso. As of 10 April 2020, a total number of 484 cases (404 cases in the Kadiogo province) were reported nationwide. Real-time forecasts of COVID-19 are important to inform decision-making in the country. Here, we propose an approach that tests the performance of four models (Exponential Growth model, the Generalized Growth model (GGM), the Generalized Logistic Growth, and Richards Growth model) to select the model that best fit data and to generate short-term forecasting (5-, 10-, and 15-day forecasts from 11 to 25 April 2020) in Kadiogo, the epicenter of the outbreak. Using daily number of confirmed COVID-19 cases, the results suggests that GGM performed the best out of the 4 models. Overall, our GGM predictions suggested an average total number of cumulative cases of 514 (95% CI, 464–559), 629 (95% CI, 559–691), and 750 (95% CI, 661–840) between 11 to 15 April, 16 to 20 April, and 20 to 25 April 2020, respectively. COVID-19 in this province was best approximated by sub exponential growth rather than exponential or logistic growth. Current data suggest that COVID-19 cases would continue to increase over the next 15-days.
REVIEW | doi:10.20944/preprints202004.0325.v1