Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity—but also aided in the control—of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6–8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples—in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19. Detailed virological analysis of nine cases of coronavirus disease 2019 (COVID-19) provides proof of active replication of the SARS-CoV-2 virus in tissues of the upper respiratory tract.

Virological assessment of hospitalized patients with COVID-2019.

A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world1–3. Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1–3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies. High-resolution crystal structures of the receptor-binding domain of the spike protein of SARS-CoV-2 and SARS-CoV in complex with ACE2 provide insights into the binding mode of these coronaviruses and highlight essential ACE2-interacting residues.

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Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.

https://cronfa.swan.ac.uk/Record/cronfa54196/Download/54196__17493__47815979be224dde9a7b3f9b037ce7ec.pdf

Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science.

Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

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Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

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A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Bifid nose is a rare congenital anomaly. Because of its low incidence, few cases of surgical treatment have been reported. We propose a surgical method using an open W-shaped incision as a treatment option for severe bifid nose. Based on our 10-year experience, we describe the technique and discuss outcomes, patient selection, and complications.From May 2009 to December 2020, 32 patients with bifid nose underwent surgical correction of the nasal deformity characterized by dorsal hypertelorism, midline cleft of nasal bone and cartilage, and shortened nose using an open W-shaped surgical incision. Nasal subunit morphology before and after surgery was measured by three-dimensional simulation technology. Indications, outcomes, and complications including possible underlying reasons were analyzed. Patient satisfaction was evaluated using a self-assessment survey.Correction of the bifid nasal deformity was successfully achieved using an open W-shaped surgical incision with increased nasal length and improved nasal appearance. Patients were followed-up for a period of 10 months on average, ranging from 6 months to 10 years. Follow-up examinations demonstrated stable results. The overall complication rate was 1.9%. Complications included temporary scar, ventilation disorder, and mild infection of the nasal skin. The majority of patients (98.1%) rated their outcome as improved and much improved (Table 1).The open W-shaped incision technique is an effective therapeutic approach for the correction of severe bifid nose. This is a simple and safe method for the treatment of bifid noses with a high patient acceptance and stable postoperative results. 

Correction of severe bifid nose deformity using an open W-shaped incision.

Bifid nose generally appears short columellar and lacks the nasal tip. Here, we describe a surgical correction technique for correcting the short columellar and nasal tip of biﬁd nose using a local flap to discuss outcomes, patient selection, and complications based on 11 years of experience. Thirty-two patients with mild wide biﬁd nose and shortened columella were included in this retrospective study. All patients underwent nasal rhinoplasty using a propeller flap based on the nasal columella artery. Nasal columella length, horizontal distance of tip-defining point, and angle of facial convexity were evaluated based on three-dimensional simulation technology. Complications including possible underlying reasons were analyzed. Patient satisfaction was evaluated using a self-assessment survey. Nasal esthetics and function were considerably improved. Follow-up examinations during a period of 9 months on average demonstrated stable results. The columella length was 9.7 ± 4.6 mm preoperatively and 19.9 ± 3.2 mm postoperatively (P < 0.05). The horizontal distance of tip-defining point (mm) decreased to 18.9 ± 5.5 mm postoperatively from a preoperative 23.3 ± 5.4 mm (P < 0.05). There were no severe postoperative complications. Complications were scar, temporary hematoma, and mild infection of nasal skin. The majority of patients (97%) rated their outcome as improved and much improved. Surgical correction using a nasal columella artery propeller flap is an effective therapeutic approach for patients with mild bifid nose. The use of a local flap along with minimal donor-site morbidity and reliable outcomes contributes to the high patient acceptance. Meticulous surgical technique and careful patient selection are prerequisites for successful results. 

Tanja Herrler

Papers

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Correction of severe bifid nose deformity using an open W-shaped incision.

Reconstruction of the shortened columella in mild bifid nose using a propeller flap based on the nasal columella artery.