Weight: 9.90 Paper Topics: passed cords bougie used 46 technique does use bronchoscopic control bougie tracheal tube tt trachea tt withdrawn cuff vocal cuff fully inflated tt advanced using bougie guide cuff impacts vocal cords gas- table complications type numbervisible cut bougie tt pulled far bougie murphy eye tt failure advance blue rhino bleeding late complication case seldinger needle blocked bougie material patient hard collar case seldinger needle perforated tt cuff tt prevented tracheostomy cuff sealing case seldinger wire passed murphy eye tt dilation process caused tt advance trachea second passage
Weight: 5.89 Paper Topics: december world china 2019-ncov cluster pneumonia cases unknown cause emerged connections huanan south seafood market wuhan city hubei province china late 2019 january 7 2020 positive-sense single-stranded rna coronavirus cov identified causative agent world health organization who named novel coronavirus 2019-ncov january 10 january 30 total 9692 confirmed cases 213 deaths reported reported in comparison basic reproduction number r severe acute respiratory syndrome sars epidemic 491 2019-ncov epidemic estimated high 647 implies severity widespread dissemination caused 2019-ncov current health emergency researchers world engaged investigation genetic functional data compare coronaviruses design proper infection control strategy 2
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Effectiveness of some anti-HIV/AIDS drugs for 2019-nCoVLopinavir is an antiretroviral medication used to inhibit HIV/AIDS viral protease. It is often used as a fixed-dose combination with another protease inhibitor, ritonavir, sold under the name Kaletra or Aluvia. Ritonavir, sold under the trade name Norvir, is another antiretroviral medication. Its combination with Lopinavir is known as highly active antiretroviral therapy (HAART). Although there is no tractable clinical evidence, Kaletra or Aluvia has been proposed as a potential anticoronavirus drug for 2019-nCoV. The possibility of repurposing some HIV drugs for SARS-CoV treatment has also studied in the literature. 16 It is important to evaluate their binding affinities, which are obtained with two ligand-based methods (i.e., LS-BP and 2DFP) and two 3D models (3DALL and 3DMT). To carry out 3D model predictions, we dock them to the 2019-nCoV protease inhibition site. The resulting complexes are optimized with molecular dynamics and then evaluated by 3DALL and 3DMT. Table 1 shows the low sequence identity between HIV viral protease and 2019-nCoV protease, which might suggest the limited potential for repurposing Aluvia and Norvir for 2019-nCoV treatment. For Lopinavir, our LS-BP and 2DFP predicted the binding affinities of -5.66 kcal/mol and -5.54 kcal/mol, respectively. For Ritonavir, similar low binding affinities of -5.14 kcal/mol and -4.96 kcal/mol were predicted by our LS-BP and 2DFP, respectively. However, our 3D model 3DALL predicted better binding affinities, i.e., -7.78 kcal/mol and -8.44 kcal/mol for Lopinavir and Ritonavir, respectively. The other 3D model, 3DMT, also predicted moderately high binding affinities of -8.13 kcal/mol and -8.07 kcal/mol for Lopinavir and Ritonavir, respectively. Considering the fact that the small training set for LS-BP and 2DFP models is very small, the results predicted by 3D models are more reliable. Figures 20 and 21 indicate that these drugs have reasonable dock poses with 2019-nCoV protease. Therefore, HIV drugs Kaletra (or Aluvia) and Norvir might indeed have a moderate effect in the treatment of 2019-nCoV. However, Many new compounds generated by our GNC appear to have better druggable properties than these HIV inhibitors do. epidemic. Although we know quite a little about 2019-nCoV, it is fortunate that the sequence identity of the 2019-nCoV protease and that of severe acute respiratory syndrome virus (SARS-CoV) is as high as 96.1%. In this work, we show that the protease inhibitor binding sites of 2019-nCoV and SARS-CoV are almost identical, which provides a foundation for us to hypothesize that all potential anti-SARS-CoV chemotherapies are also effective anti-2019-CoV molecules. Additionally, we employed a recently developed generative network complex (GNC) to seek potential protease inhibitors for effective treatment of pneumonia caused by 2019-nCoV. Two datasets 13 . CC-BY-NC 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.01.30.927889 doi: bioRxiv preprint are utilized in this work. One is a SARS-CoV protease inhibitor dataset, which is constructed by collecting 115 SRAS-CoV inhibitors from open database ChEMBL. The other dataset is a binding affinity training set mainly containing the PDBbind refined set. Our GNC model predicts over 8000 potential anti-2019-nCoV drugs which are evaluated by a latent space binding predictor (LS-BP) and a 2D fingerprint predictor (2DFP). Promising drug candidates are further evaluated by two 3D deep learning models trained with all the training sets together, including the dataset for coronaviral protease (3DALL), and the 3D deep learning multitask model trained with the dataset for coronaviral protease as a separated task (3DMT). Furthermore, we choose 15 potential anti-2019-nCoV drugs to analyze partition coefficient (logP), solubility (logS), and synthetic accessibility score (SAscore) according to binding affinity ranking computed by the 3DALL model. The reasonable logP, logS, and SAscore show that our top 15 anti-2019-nCoV drug candidates are potentially effective for inhibiting 2019-nCoV. Finally, the effectiveness of some anti-HIV/AIDS drugs for treating 2019-nCoV is analyzed. Although HIV drugs Kaletra (or Aluvia) and Norvir might indeed have a moderate effect in the treatment of 2019-nCoV, the analysis of these anti-HIV/AIDS drugs together with our top 15 anti-2019-nCoV molecules shows that the new compounds generated by our GNC appear to have better druggable properties than these HIV inhibitors do.
Weight: 5.28 Paper Topics: symptomatic respiratory viral infections global public health concern common cause disease leading heavy economic burden increased number sick days borchardt rolston 2012 kim et al 2017 addition respiratory diseases common causes mortality developing countries ferkol schraufnagel 2014 among leading causes respiratory virus infection influenza a b viruses respiratory syncytial virus rsv amarelle et al 2017 heylen et al 2017 yip et al 2018 cases observed infants children elderly immunocompromised high risk getting infected develop severe disease jorquera tripp 2017 while influenza viruses rsv circulate seasonally beginning fall early spring increased numbers avian influenza h7n9 china including highly pathogenic
Weight: 4.01 Paper Topics: alphacoronavirus situation family cause world coronaviruses covs belonging family coronaviridae positive-sense enveloped rna viruses infections birds mammals humans 1 2 3 includes genera betacoronavirus deltacoronavirus gammacoronavirus 4 infamous infectious coronaviruses genus betacoronavirus severe acute respiratory syndrome coronavirus sars-cov 5 middle east respiratory syndrome coronavirus mers-cov 6 infected 10000 people past decades unfortunately incidence accompanied high mortality rates 96% sars-cov 344% mers-cov indicating urgent need effective treatment beginning outbreak prevent spread 7 8 however achieved current drug development application system taking years newly developed drugs come marketunexpectedly world facing previous outbreak recent epidemic atypical pneumonia caused novel
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Abstractdesigned to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of 2019-nCoV with an inhibitory potency with Kd < 1000 nM. In addition, we also found that several antiviral agents, such as Kaletra, could be used for the treatment of 2019-nCoV, although there is no real-world evidence supporting the prediction. Overall, we suggest that the list of antiviral drugs identified by the MT-DTI model should be considered, when establishing effective treatment strategies for 2019-nCoV.
Weight: 3.96 Paper Topics: mers-cov 27 2012 report infection middle east respiratory syndrome coronavirus mers-cov published world health organization notified 2123 laboratory-confirmed infections mers-cov countries 740 reported deaths case fatality 35% 1 specific therapy proven efficacy available potential treatment tested randomized clinical trial rct evaluation 2 3 4 based results vitro animal studies infection guanosine analog ribavirin combination interferon alpha ifn-α used treat patients mers 5 6 7 8 however concentration ribavirin required inhibit mers-cov vitro exceeds peak levels blood therapeutic doses humans 9 10 11 furthermore retrospective studies ifn-α2a ifn-α2b ifn-β1a combination ribavirin shown clear benefit patients mers 6
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BackgroundBased on in vitro data, the combination of lopinavir and ritonavir has been considered as a candidate therapy for MERS. Lopinavir and ritonavir are antiretroviral protease inhibitors used in combination for the treatment of human immunodeficiency virus (HIV) infection and have limited side effects  . The combination of lopinavir/ritonavir (Kaletra®, Abbott Laboratories, Chicago, IL, USA) has also been used for the treatment of SARS. In one study, the combination of lopinavir/ritonavir used in 41 patients with SARS was associated with significantly fewer adverse clinical outcomes (acute respiratory distress syndrome or death) 21 days after the onset of symptoms compare to ribavirin alone used in 111 historical controls (2.4% versus 28.8%, p = 0.001)  . However, the historical nature of the control comparison does not allow for a valid estimate of efficacy. In a high-throughput screening for antiviral compounds, lopinavir inhibited the replication of MERS-CoV at levels below those that occur in the circulation after a single oral dose of lopinavir/ritonavir (400 mg lopinavir with 100 mg ritonavir), suggesting that the drug can achieve therapeutic levels in vivo [16, 22] . The effects of lopinavir/ritonavir, IFN-β1b and mycophenolate mofetil (MMF), all of which have shown viral inhibitory effects in vitro, have been tested in common marmosets with severe MERS-CoV infection  . The animals treated with lopinavir/ritonavir or IFN-β1b had improved clinical, radiological, pathological and viral-load outcomes compared with untreated animals. By contrast, treatment with MMF resulted in severe or fatal disease, with higher mean viral loads than in untreated animals. Untreated animals and MMF-treated animals had a mortality of 67% by 36 h compared to 0-33% among animals treated with lopinavir/ritonavir or IFN-β1b  .
Weight: 3.81 Paper Topics: rising sars-cov-2 mortality world respiratory december 2019 coronavirus disease 2019 covid-19 caused severe acute syndrome coronavirus sars-cov-2 occurred wuhan china quickly global concern health organization declared sixth public health emergency international concern pheic 30 january 2020 time 14:50 february 8 2020 34638 covid-19 cases confirmed china 723 patients died it resulting 22% sars-cov-2 novel species non-segmented positive-sense rna virus spread distribute humans mammals 1 previous studies discovered sars-cov-2 belongs distinct clade β-coronavirus associated human severe acute respiratory syndrome sars middle east respiratory syndrome mers 2 shi zl et al shares 795% sequence identity sars-related coronavirus 96% identical
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IntroductionThe trial fifth edition of diagnosis and treatment guideline of COVID-19 issued by National Health Commission of the People's Republic of China (http://www.nhc.gov.cn/) recommends to use Kaletra for treatment. Kaletra, an anti-HIV drug which is composed of two protease inhibitors, ritonavir (CAS#: 155213-67-5) and lopinavir (CAS#: 192725-17-0), might have therapeutic effect on coronavirus diseases like SARS and MERS     . However, whether it can inhibit SARS-CoV-2 or treat COVID-19 lacks clinical evidences and randomized clinical trials, and the safety of its use in COVID-19 patients is unclear. Otherwise, Lanjuan Li, infectious disease scientist, academician of Chinese Academy of Engineering, recommended darunavir (CAS#: 206361-99-1), also an HIV protease inhibitor, as a treatment for COVID-19. Although the inhibitory effect of darunavir on SARS-CoV-2 has been verified in vitro, its therapeutic effect on COVID-19 is still unknown. At the same time, the mechanism of how these drugs inhibit SARS-CoV-2 is also unknown.
Weight: 2.49 Paper Topics: originating coronavirus mid-december 2019 early february 2020 2019 novel coronavirus 2019-ncov wuhan hubei province china infected 25000 laboratory-confirmed cases 28 countries 500 deaths a case-fatality rate 2% 90% cases deaths china 1 based initial reported surge cases wuhan majority males median age 55 years linked huanan seafood wholesale market 2 reported cases similar symptoms onset illness fever cough myalgia fatigue cases developed pneumonia severe fatal respiratory diseases acute respiratory distress syndrome 3 the 2019 novel coronavirus 2019-ncov betacoronavirus forms clade subgenus sarbecovirus orthocoronavirinae subfamily 4 severe acute respiratory syndrome sars-cov middle east respiratory syndrome coronavirus mers-cov betacoronaviruses
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TherapeuticsMany interferons from the three classes have been tested for their antiviral activities against SARS-CoV both in vitro and in animal models. Interferon β has consistently been shown to be the most active, followed by interferon α. The use of corticosteroids with interferon alfacon-1 (synthetic interferon α) appeared to have improved oxygenation and faster resolution of chest radiograph abnormalities in observational studies with untreated controls. Interferon has been used in multiple observational studies to treat SARS-CoV and MERS-CoV patients [116, 117] . Interferons, with or without ribavirin, and lopinavir/ritonavir are most likely to be beneficial and are being trialed in China for 2019-nCoV. This drug treatment appears to be the most advanced. Timing of treatment is likely an important factor in effectiveness. A combination of ribavirin and lopinavir/ritonavir was used as a post-exposure prophylaxis in health care workers and may have reduced the risk of infection. Ribavirin alone is unlikely to have substantial antiviral activities at clinically used dosages. Hence, ribavirin with or without corticosteroids and with lopinavir and ritonavir are among the combinations employed. This was the most common agent reported in the available literature. Its efficacy has been assessed in observational studies, retrospective case series, retrospective cohort study, a prospective observational study, a prospective cohort study and randomized controlled trial ranging from seven to 229 participants  . Lopinavir/ritonavir (Kaletra) was the earliest protease inhibitor combination introduced for the treatment of SARS-CoV. Its efficacy was documented in several studies, causing notably lower incidence of adverse outcomes than with ribavirin alone. Combined usage with ribavirin was also associated with lower incidence of acute respiratory distress syndrome, nosocomial infection and death, amongst other favorable outcomes. Recent in vitro studies have shown another HIV protease inhibitor, nelfinavir, to have antiviral capacity against SARS-CoV, although it has yet to show favorable outcomes in animal studies  . Remdesivir (Gilead Sciences, GS-5734) nucleoside analogue in vitro and in vivo data support GS-5734 development as a potential pan-coronavirus antiviral based on results against several coronaviruses (CoVs), including highly pathogenic CoVs and potentially emergent BatCoVs. The use of remdesivir may be a good candidate as an investigational treatment.
Weight: 1.32 Paper Topics: in-hospital performed 9 cardiovascular reports clinic experiences increases clinicians conscious cardiovascular comorbidities manifestations covid-19 showed patients covid-19 hypertension coronary artery disease worse outcomes 8 cardiovascular manifestations cvms initial presentation appear course covid-19 liu et al analyzed 12% patients 11 wang et al reported single-center case series involving 138 patients covid-19 complications rare arrhythmia acute cardiac injury accounted 167% 72% respectively level hypersensitive troponin admission significantly higher admitted intensive care unit icu 12 further comparative study applied explain concomitant cvms effect in-hospital outcomes covid-19 casesas retrospective study data analysis anonymously requirement informed consent waived ethics committees central
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Treatment Situation and In-hospital OutcomesThere were 40 cases (97.6%) received at least one kind of antiviral drugs empirically including oseltamivir, ribavirin, arbidol or lopinavir/ritonavir (Kaletra), which were accessible clinically in China. Antibiotics or anti-fungus drugs were applied in 95.1% cases regarding to confirmed secondary infection or preventing secondary infection in relatively severe cases. Corticosteroid was used in 78.0% cases to control immune overreaction. Human albumin was applied when serum albumin . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Weight: 0.99 Paper Topics: 1 focus coronavirus 2003 outbreak severe acute respiratory syndrome sars caused sars-associated involved 26 countries 8098 patients resulted 774 deaths thereafter sars re-emerged sporadically laboratory community settings clinical spectrum varies minimal respiratory symptoms severe respiratory failure previously contributed overview contemporary treatment sars 2 topic reviewed 3 article aim management subgroup critically ill sars patients significant respiratory failurecritically ill sars patients frequently demonstrate following clinical features: persistent pyrexia occasionally admission recurring initial period defervescence tachycardia infrequently bradycardia tachypnoea significant oxygen desaturation onethird sars patients required high flow oxygen therapy 4 20-30% required intensive care unit icu admission
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Antiviral therapyLopinavir-ritonavir co-formulation (Kaletra ® , Abbott Laboratories, USA) is a protease inhibitor for the treatment of human immunodeficiency virus (HIV) infection. It can inhibit the coronaviral proteases, thus blocking the processing of viral replicase polyprotein and preventing the replication of viral RNA. Ritonavir inhibits lopinavir metabolism thus increasing its serum concentration, but it has no activity against SARS-CoV. In a retrospective analysis in Hong Kong  , 31 patients who had received Kaletra as rescue therapy together with high dose corticosteroids had no difference in rates of oxygen desaturation, intubation and mortality compared with a matched cohort. However, when given as initial treatment in combination with ribavirin in another subgroup of 44 patients, there were significant reductions in the need for rescue pulsed corticosteroid therapy, intubation rate and overall mortality. In addition to the prevalence of diarrhoea among these patients which may render oral drugs more appropriate and useful, synergism between kaletra and ribavirin might have contributed to the benefits since either drug alone has only weak anti-viral activities. Another Hong Kong study of 41 SARS patients treated with a combination of lopinavir/ritonavir and ribavirin compared with 111 patients (historical controls) treated with ribavirin only showed that adverse clinical outcomes (ARDS or death) were significantly lower in the treatment group than in the historical controls at day 21 after symptom onset. Further randomised placebo controlled trials are required  .
Weight: 0.99 Paper Topics: health concern" edition clinical pneumonia caused novel coronavirus discovered wuhan hubei china epidemic broke out defined world health organization "an international public emergency public 1 2 recently researches lancet reported epidemiological clinical symptoms laboratory data imaging features treatment methods clinical outcomes non-pregnant adults pregnant women infected 2019-ncov 3 4 however characteristics children disclosed differences treatment methods determined retrospectively analyzed clinical data 28 children covid-19 tested positive 2019-ncov use rt-pcr sampleswe reviewed 26 cases children>1 year old <14 years old people's hospital shenzhen january 16 february 8 2020 diagnosis ofprogram6th issued national health health committee china 5 the