mteb/CovidQA huggingface dataset:
The risk of 2019-nCoV exposure may cause significant psychosocial stress on healthcare workers [2] . The death of a retired ENT physician from a 2019-nCoV infection has added to fears in January 2020. Psychotherapists have also been invited to join medical teams to evaluate and deal with potential stress and depression for the safety of the healthcare workers.

Critical management 2019-nCoV management was largely supportive, including intubation, early prone positioning, neuromuscular blockade, and extracorporeal membrane oxygenation (ECMO) according to the recommendations updated by CNHC. Low-dose systematic corticosteroids, lopinavir/ritonavir, and atomization inhalation of interferon were encouraged. These critical managements have worked well so far, as our 2019-nCoV patients had zero mortality. On the contrary, the previously reported mortality of 2019-nCoV patients in Wuhan ranged from 11 to 15% [1, 9] .
Statistics-Based Predictions of Coronavirus Epidemic Spreading in Mainland China

https://doi.org/10.20535/ibb.2020.4.1.195074

SHA: 4ff89a71126d2932544a8337ba28787fde5f02a8

Authors: Nesteruk, Igor
Date: 2020
DOI: 10.20535/ibb.2020.4.1.195074
License: cc-by

Abstract: Information about the open-access article 'Statistics-Based Predictions of Coronavirus Epidemic Spreading in Mainland China' in DOAJ. DOAJ is an online directory that indexes and provides access to quality open access, peer-reviewed journals.
Text: Here, we consider the development of an epidemic outbreak caused by coronavirus COVID-19 (the previous name was 2019-nCoV) (see e.g., [1] [2] [3] ). Since long-term data are available only for mainland China, we will try to predict the number of coronavirus victims V (number of persons who caught the infection and got sick) only in this area. The first estimations of V(t) exponential growth versus time t, typical for the initial stages of every epidemic (see e.g., [4] ) have been done in [3] . For long-time predictions, more complicated mathematical models are necessary. For example, a susceptible-exposed-infectious-recovered (SEIR) model was used in [2] . Nevertheless, complicated models need more effort for unknown parameters identification. This procedure may be especially difficult if reliable data are limited.
In this study, we use the known SIR model for the dynamics of an epidemic [4] [5] [6] [7] [8] . For the parameter identification, we will use the exact solution of the SIR set of linear equations and statistical approach developed in [4] (tested also in [9] ). These methods were applied for investigation of the children disease, which occurred in Chernivtsi (Ukraine) in 1988-1989. We will estimate some of the epidemic characteristics and present the dependencies for victim numbers, infected and removed persons versus time.

We shall analyze the daily data for the number of confirmed cases in mainland China, which origins from the National Health Commission of the People's Republic of China [1] . A part of the official diagram (its version, presented on February 15, 2020) is shown in Fig. 1 . For calculations, we have used the data for the period of time from January 16 to February 9, 2020. The numbers shown after February 9 were used for verification of predictions.
On February 12, 2020, the National Health Commission of the People's Republic of China has added 12289 new cases (not previously included in official counts) as "clinically diagnosed cases". The cases, reported by this official organization before, have the name of "tested confirmed cases" [1] . To avoid confusiong, we will denote "tested confirmed cases" as Wj; j corresponds to the different time moments tj (see the Table) . Let us denote the "clinically diagnosed cases" as Qj. The sum of Wj and Qj is shown in the last column in Fig. 1 and in the Table. The Table shows that the precise time of the epidemic beginning t0 is unknown. Therefore, the optimization procedures have to determine the optimal value of this parameter as well as for other parameters of SIR model. The sum of "tested confirmed cases" and "clinically diagnosed cases" Wj + Qj  16  0  45  1  16  14380  Unknown  17  1  62  2  17  17205  Unknown  18  2  121  3  18  20440  Unknown  19  3  198  4  19  24324  Unknown  20
4  291  5  20  28018  Unknown  21  5  440  6  21  31161  Unknown  22  6  571  7  22  34568  Unknown  23  7  830  8  23  37198  Unknown  24  8  1287  9  24  40171  Unknown  25  9  1975  10  25  42638  Unknown  26  10  2744  11  26  44653  Unknown  27  11  4515  12  27  46472  58761  28  12  5974  13  28  48467  63851  29  13  7711  14  29  49970  66492  30  14  9692  ----31 15 11791 ----
The SIR model for an infectious disease can be written as follows [6, 7] :

,

The number of susceptible persons is S, infected (persons who are sick and spread the infection) -I, removed (persons who do not spread the infection anymore, this number is the sum of isolated, recovered and dead people) -R; the infection and immunization rates are  and  respectively. 

It follows from (1) and (2) that

Integration of (5) with the initial conditions (4) yields:

Function I has a maximum at S  and tends to zero at infinity, see [6, 7] . In comparison, the number of susceptible persons at infinity 0, S   and can be calculated with the use of (6) from a non-linear equation 

yields:

Thus, for every set of parameters N, ,  ,  0 t and a fixed value of V the integral (10) can be calculated and the corresponding moment of time can be determined from (9) . Then I can be calculated from (6) by putting S = N  V and function R from
Statistical approach for parameter identification. Linear regression As in paper [4] , we shall use the fact that the random function 1 ( , , ) F V N  has a linear distribution (see (9) ). Then we can apply the linear regression (see [10] ) for every pair of parameters N and  and calculate the corresponding values of 0 t and .  The optimal (the most reliable) values of N and  correspond to the maximum value of the correlation coefficient r (see [4, 9] ).

Since we did not know and still don't know the values of Qj before February 12, 2020, we supposed that Vj = Wj and have done the calculations with the use of data for the time period from January 16 to February 9, 2020. The optimal values of the parameters are:

The corresponding correlation coefficient is very high r = 0.997966487046645. The solution of (7) yields the value 45579.
The corresponding number of infected I, susceptible S and removed R persons versus time (starting from January 16, 2020) were calculated and shown in Fig. 2 . The blue line represents the number of victims V = I + R and is in good agreement with "tested confirmed cases" Wj, reported by the National Health Commission of the People's Republic of China [1] (blue markers).

Unfortunately, many cases have not been included in the official counts and have appeared in the official Table from [1] only on February 12 as "clinically diagnosed cases" Qj (see Fig. 1 ). Since the National Health Commission of the the People's Republic of China has proposed two different ways of registration of the same disease [1] , Vj must be the sum of Wj and Qj , i.e. Vj = Wj + Qj (provided that no new methods of registering the same disease would appear). Values Wj after February 9 are shown in Fig. 3 by "stars". "Crosses" represent the sum Wj + Qj .
Since the optimal curve was obtained only with the use of Wj and the difference between Wj and Vj is very big (e.g., it was 12 289 persons on February 12, 2020), the predictions shown in Fig. 2 and reported in [11] are no longer relevant. To have better predictions, it is necessary to have exact Qjdata for the period before February 12. Blue markers show the "tested confirmed cases" W j , reported by the National Health Commission of the People's Republic of China [1] . The "circles" correspond to the points used for calculations (it was supposed that V j = W j ); "stars" -to the points used only for verification Circles" show the "tested confirmed cases" W j for the period from January 16 to February 9, 2020, [2] . These points were used to calculate the prediction curve. "Stars" correspond to the "tested confirmed cases" W j for the period from February 10 to February 14, 2020, [1] . "Crosses" represent the sum W j + Q j from [1]
The simple mathematical model was used to predict the characteristics of the epidemic caused by coronavirus in mainland China. The numbers of infected, susceptible, and removed persons versus time were predicted and compared with the new data obtained after February 10, 2020, when the calculations were completed. Unfortunately, many cases have not been included in the official counts and have appeared on February 12 only. It makes the predictions reported on February 10, 2020, no longer relevant. Further research should focus on updating the predictions with the use of corrected data and more complicated mathematical models.
The Intranasal Application of Zanamivir and Carrageenan Is Synergistically Active against Influenza A Virus in the Murine Model

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459876/

SHA: f0b1fa4036434b57c8307d43c39a4193f7e8053a

Authors: Morokutti-Kurz, Martina; König-Schuster, Marielle; Koller, Christiane; Graf, Christine; Graf, Philipp; Kirchoff, Norman; Reutterer, Benjamin; Seifert, Jan-Marcus; Unger, Hermann; Grassauer, Andreas; Prieschl-Grassauer, Eva; Nakowitsch, Sabine
Date: 2015-06-08
DOI: 10.1371/journal.pone.0128794
License: cc-by
Abstract: BACKGROUND: Carrageenan is a clinically proven and marketed compound for the treatment of viral upper respiratory tract infections. As infections caused by influenza virus are often accompanied by infections with other respiratory viruses the combination of a specific anti-influenza compound with the broadly active antiviral polymer has huge potential for the treatment of respiratory infections. Thus, the combination of the specific anti-influenza drug Zanamivir together with carrageenan in a formulation suitable for intranasal application was evaluated in-vitro and in-vivo. PRINCIPAL FINDINGS: We show in-vitro that carrageenan and Zanamivir act synergistically against several influenza A virus strains (H1N1(09)pdm, H3N2, H5N1, H7N7). Moreover, we demonstrate in a lethal influenza model with a low pathogenic H7N7 virus (HA closely related to the avian influenza A(H7N9) virus) and a H1N1(09)pdm influenza virus in C57BL/6 mice that the combined use of both compounds
significantly increases survival of infected animals in comparison with both mono-therapies or placebo. Remarkably, this benefit is maintained even when the treatment starts up to 72 hours post infection. CONCLUSION: A nasal spray containing carrageenan and Zanamivir should therefore be tested for prevention and treatment of uncomplicated influenza in clinical trials.
Text: The periodic appearance of new influenza variants poses a worldwide pandemic threat. Since the emergence of the new A(H7N9) virus, more than 400 human cases were reported to the WHO with a mortality rate of more than 35%. Most patients with A(H7N9) infections had contact with poultry or visited live animal markets. However, some sporadic cases seemed to be a result of human to human transmissions [1, 2] . In contrast to pandemic viruses which fulminantly enter the human population and cause high mortality rates, seasonal influenza viruses generally cause uncomplicated and transient infections in humans, with virus replication localized to the upper respiratory tract [3, 4] . However, in its fully developed form influenza is an acute respiratory disease resulting in hospitalizations and deaths mainly among high-risk groups. Worldwide, annual epidemics result in about three to five million cases of severe illness, and about 250,000 to 500,000 deaths [5] . For this reason WHO [6]
and CDC [7] recommend antiviral treatment for any patient with suspected influenza who is at risk for influenza complications without previous laboratory confirmation.
It is known that influenza virus infections are often accompanied by other viral pathogens [8] . Depending on the detection method (qRT-PCR or immunofluorescence) different ratios of co-infections have been found. Analysis by qRT-PCR revealed that 54.5-83.3% of influenza A or B positive patients were found to have at least one concomitant respiratory viral infection [9] [10] [11] [12] . The detection frequency with immunofluorescence was found to be even higher (90-100%) [13, 14] . Potential concomitant viral pathogens of influenza virus infections include human rhinovirus (hRV), respiratory syncytial virus, adenovirus, human coronavirus, human metapneumovirus and parainfluenza virus [14, 15] .
As a result of the multiple infections, a specific anti-influenza mono-therapy treats the influenza virus infection only, but not the infection with the concomitant viral pathogen. Hence, the therapy often fails to sufficiently resolve symptoms. This is also reflected by the fact that neuraminidase inhibitors (NI) are highly efficacious in animal models investigating influenza mono-infections [16, 17] but show lower efficacy against influenza symptoms in clinical trials in adults with natural infections [18] . Therefore, there is a high medical need for a broadly acting antiviral therapy in combination with a specific anti-influenza therapy for treatment of patients suffering from upper respiratory tract symptoms. Ideally, the substances present in the combination complement each other by different modes of action, leading to a treatment that provides full protection against a broad range of different respiratory viruses as well as different influenza strains with a low probability to
induce escape mutations.
One approach for a broad antiviral therapy is the creation of a protective physical barrier in the nasal cavity using carrageenan. Carrageenan is a high molecular weight sulfated polymer derived from red seaweed (Rhodophyceae) that has been extensively used in food, cosmetic and pharmaceutical industry and is generally recognized as safe by the FDA (GRAS) (reviewed in [19] ). Three main forms of carrageenans are commercially used: kappa, iota and lambda. They differ from each other in the degree of sulfation, solubility and gelling properties [20] . The antiviral mechanism of carrageenan is based on the interference with viral attachment; as a consequence, viral entry is inhibited [21, 22] . Its antiviral activity is dependent on the type of polymer as well as the virus and the host cells [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] and has been reviewed in [33] [34] [35] . We published that iota-carrageenan is a potent inhibitor of hRV [36] and influenza A [37] replication and
demonstrated the antiviral efficacy of iota-carrageenan against common cold viruses by intranasal application in several randomized, double-blind, parallel group, placebo-controlled clinical trials [38] [39] [40] . The pooled analysis of two studies conducted in 153 children and 203 adults revealed that patients infected with any respiratory virus, who were intranasally treated with iota-carrageenan showed a 1.9 day faster recovery from common cold symptoms than placebo treated patients in the intention-to-treat population [41, 42] . The anti-influenza activity was shown by subgroup analysis of 49 influenza infected patients who benefited from a 3.3 days faster recovery from symptoms. The use of carrageenan nasal spray was associated with a significant reduction of the influenza viral load in nasal fluids and a significant increase in the number of virus free patients within the treatment period of 7 days. In good accordance Prieschl-Grassauer are co-founders of Marinomed
Biotechnologie GmbH. Marinomed Biotechnologie GmbH had a role in study design, data collection and analysis, decision to publish, preparation of the manuscript and is financing the processing charge of the manuscript. with the literature [9] [10] [11] [12] [13] [14] we observed that the majority of influenza virus infected patients suffered from a concomitant respiratory viral infection (66%) as determined by real-time PCR. Carrageenan containing nasal sprays are already marketed for the treatment of respiratory viral infections under different brand names in 18 countries.
At present the only available effective drugs for treatment and post exposure prevention of influenza are the NI (Oseltamivir and Zanamivir worldwide; Peramivir in Japan and South Korea). Since the large-scale use of M2 blockers for prophylaxis and treatment in humans [43] and farming [44] , the currently circulating influenza viruses already lack sensitivity to this drug group [45] .

We have already shown an additive therapeutic effect of a combination therapy with intranasally applied iota-carrageenan and orally administered Oseltamivir in lethally H1N1 A/PR/ 8/34 infected mice and a treatment start 48 hours post infection (hpi) [37] .
Due to these very promising results we further developed the concept of combining carrageenan with an NI therapy. In contrast to Oseltamivir, which needs to be activated by metabolic conversion, Zanamivir is directly applied as active drug and can also be administered intranasally [46] [47] [48] [49] [50] [51] [52] . The potential of an intranasal administration of Zanamivir was investigated by GlaxoSmithKline. In seven clinical challenge trials 66 volunteers were infected with influenza B/Yamagata/16/88 and 213 with influenza A/Texas/36/91 (H1N1). 156 of these participants got intranasally applied Zanamivir at different doses (daily dose levels from 6.4 mg to 96 mg) for prophylaxis or therapy [46, 47, 53, 54] . These challenge trials showed that treatment starting before and up to 36 hours post virus inoculation was associated with prevention of laboratory confirmed influenza and febrile illness as well as a reduction in viral titers, duration of shedding and symptoms. In total,
safety data from 1092 patients after intranasal application of Zanamivir were published and no evidence for Zanamivir induced adverse events or increased frequencies of local nasal intolerance in comparison to placebo groups was found [46, 49, 52] .
Taken together, the combination of a carrageenan nasal spray that provides broad antiviral activity against upper respiratory infections-including influenza-with Zanamivir, a specific anti-influenza drug, meets the existing medical need to treat multiple viral infections. In the present work we investigate the therapeutic effect of a combination of carrageenan and Zanamivir in-vitro and in an animal model.
Kappa-carrageenan and iota-carrageenan were purchased from FMC Biopolymers (Philadelphia, PA). The identity, purity (>95%) of carrageenan subtypes and the molecular weight (>100,000) was confirmed by NMR analysis as described elsewhere [55] and the presence of lambda-carrageenan was below the detection limit of 3%. The dry polymer powders were dissolved in aqua bidest (Fresenius Kabi, Austria) to a final concentration of 2.4 mg/ml iota-and 0.8 mg/ml kappa-carrageenan. This 2x stock solution was sterile filtered through a 0.22 μm filter (PAA, Switzerland) and stored at room temperature until use. For further testing the stock solution was diluted to a mixture containing 1.2 mg/ml iota-carrageenan and 0.4 mg/ml kappa-carrageenan (hereinafter referred to as "carrageenan").
Zanamivir was purchased as powder (Haosun Pharma, China) and the identity and purity was confirmed by NMR analysis. Zanamivir was either dissolved in carrageenan or placebo solutions, followed by sterile filtration through a 0.22 μm filter (Sarstedt, Germany). For in-vivo studies all Zanamivir containing solutions were freshly prepared.

Madin-Darby canine kidney (MDCK) cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA) and cultivated in a 37°C incubator (Sanyo, Japan; CO 2 : 5%, relative humidity: >95%). MDCK cells were grown in Dulbecco's minimal essential (DMEM) high glucose medium (PAA, Austria) supplemented with 10% fetal bovine serum (FBS; PAA, Austria; heat inactivated).
Influenza virus A/Hansa Hamburg/01/09 (H1N1(09)pdm) was kindly provided by Peter Staeheli Department of Virology, University of Freiburg, Germany and previously described in [56] ; A/Teal/Germany/Wv632/05 (H5N1) previously published in [57] (accession numbers CY061882-9) and A/Turkey/Germany/R11/01 (H7N7) (taxonomy ID 278191, accession number AEZ68716) were supplied by courtesy of Martin Beer, Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, Riems, Germany; A/Aichi/2/68 (H3N2) was purchased from the ATCC. All influenza viruses were propagated in MDCK cells at 37°C and 5% CO 2 in influenza medium [Opti-Pro serum free medium (Gibco, Austria) supplemented with 4 mM L-glutamine (PAA, Austria), 1% antibiotic-antimycotic mix (PAA, Austria) and 5 μg/ml trypsin (Sigma Aldrich, Austria)].
To determine the 50% inhibitory concentration (IC 50 ) and the combination effect of carrageenan and Zanamivir, a semi-liquid plaque assay was developed. Into 96 well tissue culture plates 1.7x10 4 MDCK cells/well were seeded and infected at 90% confluence (24-28 hours later). Serial dilutions of carrageenan and Zanamivir were prepared in assay medium (influenza medium without trypsin). For infection, viruses were diluted to an MOI of 0.003 (H1N1(09)pdm and H3N2 Aichi), 0.015 (H5N1) or 0.004 (H7N7), respectively, in assay medium and incubated at room temperature (RT) for 10 min with the serial dilutions of carrageenan and/or Zanamivir, respectively. For evaluation of the combination effect of carrageenan and Zanamivir, viruses were diluted in assay medium containing constant concentrations of either carrageenan or Zanamivir. The other substance was serially diluted and used for virus incubation. Cells were infected in 6 replicates/compound dilution, respectively, and incubated at RT
for 45 min before inoculum removal. Cells were further incubated with the respective concentration of the investigated substances present in the overlay [influenza medium with 2.25% Carboxymethylcellulose (CMC, Fluka, Austria)] for 30-42 hours at 37°C. Evolving plaques were evaluated after methanol/acetone cell fixation by immune staining with antibodies either directed against the influenza A nucleoprotein (AbD Serotec, Germany) (for H1N1(09)pdm, H5N1 and H7N7) or the hemagglutinin (AbD Serotec, Germany) (for H3N2). Analysis was done with a HRP labeled detection antibody (Thermo Scientific, Germany) using TMB (Biolegend, Germany) as substrate and a microplate reader at 450 nm. The reduction of detected signal represents a reduction in the number and size of plaques and indicates suppression of viral replication during infection and cultivation.
After the immunostaining cells were stained with 0.005% crystal violet solution to assess the condition of the cell layer and the toxicity of the compounds. IC 50 values and standard deviations were calculated for a sigmoidal dose response model using XLfit Excel add-in version 5.3.1.3.
All animal experiments were carried out according to the guidelines of the "European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes" and the Austrian law for animal experiments. All animal experiments were approved by the Veterinary University of Vienna institutional ethics committee and performed under the Austrian Federal Ministry of Science and Research experimental animal license numbers BMWF-68.205/0262-II/3b/2011 and BMWF-68.205/0142-II/3b2012. C57BL/6 mice were purchased from Janvier Labs, France and maintained under standard laboratory conditions in the animal facilities of the Veterinary University of Vienna. For euthanasia and anesthesia asphyxiation through CO 2 was used and all efforts were made to minimize suffering.