Selecting a stable solid form of remdesivir using microcrystal electron diffraction and crystal structure prediction† † Electronic supplementary information (ESI) available. CCDC 2061565, 2061566, 2061567 and 2061568. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ra03100g

Therapeutic options in response to the coronavirus disease 2019 (COVID-19) outbreak are urgently needed. In this communication, we demonstrate how to support selection of a stable solid form of an antiviral drug remdesivir in quick time using the microcrystal electron diffraction (MicroED) technique and a cloud-based and artificial intelligence implemented crystal structure prediction platform. We present the MicroED structures of remdesivir forms II and IV and conclude that form II is more stable than form IV at ambient temperature in agreement with experimental observations. The combined experimental and theoretical study can serve as a template for formulation scientists in the pharmaceutical industry. Combining microcrystal electron diffraction (MicroED) and a cloud-based and artificial intelligence implemented crystal structure prediction (CSP) platform to support selection of a stable solid form of remdesivir in quick time.

Optimize Data-Driven Multi-Agent Simulation for COVID-19 Transmission (preprint)

Background: Multi-Agent Simulation is an essential technique for exploring complex systems. In researches of contagious diseases, it is widely exploited to analyze their spread mechanisms, especially for preventing COVID-19. Nowadays, transmission dynamics and interventions of COVID-19 have been elaborately established by this method, but its computation performance is seldomly concerned. As it usually suffers from inadequate CPU utilization and pour data locality, optimizing the performance is challenging. Results: This paper explores approaches to optimize multi-agent simulation for COVID-19 disease. The focus of this work is on the algorithm and data structure designs for improving performance, as well as its parallelisation strategies. We propose two successive methods to optimize the computation. We construct a case-focused iteration algorithm to improve data locality, and create a thread-safe data-mapping paradigm called hierachical hash table to accelerate hash operations. Conclusions: Our performance results demonstrate capabilities of these methods exhibiting significant improvements of system performance. The case-focused method degrades $\sim 90 \%$ cache references and achieves $\times 4.3$ speedup. Hierachical hash table can further boost computation speed by 47\%. And parallel implementation with 20 threads on CPU achieves $\times 81$ speedup consequently.

Organizing Pneumonia of COVID-19: Time-dependent Evolution and Outcome in CT Findings (preprint)

Objective: As a pandemic, a most-common pattern resembled organizing pneumonia (OP) has been identified by CT findings in novel coronavirus disease (COVID-19). We aimed to delineate the evolution of CT findings and outcome in OP of COVID-19. Materials and Methods: 106 COVID-19 patients with OP based on CT findings were retrospectively included and categorized into non-severe (mild/common) and severe (severe/critical) groups. CT features including lobar distribution, presence of ground glass opacities (GGO), consolidation, linear opacities and total severity CT score were evaluated at three time intervals from symptom-onset to CT scan (day 0-7, day 8-14, day>14). Discharge or adverse outcome (admission to ICU or death), and pulmonary sequelae (complete absorption or lesion residuals) on CT after discharge were analyzed based on the CT features at different time interval. Results: 79(74.5%) patients were non-severe and 103(97.2%) were discharged at median day 25 (range, day 8-50) after symptom-onset. Of 67 patients with revisit CT at 2-4 weeks after discharge, 20(29.9%) had complete absorption of lesions at median day 38 (range, day 30-53) after symptom-onset. Significant differences between complete absorption and residuals groups were found in percentages of consolidation (1.5% vs. 13.8%, P=0.010), number of involved lobe >3 (40.0% vs. 72.5%, P=0.030), CT score >4 (20.0% vs. 65.0%, P=0.010) at day 8-14. Conclusions: Most OP cases had good prognosis. Approximately one-third of cases had complete absorption of lesions during 1-2 months after symptom-onset while those with increased frequency of consolidation, number of involved lobe>3, and CT score >4 at week 2 after symptom-onset may indicate lesion residuals on CT.

Differences of clinical and imaging findings in multiple generations of secondary COVID-19 infection in Xi'an, China (preprint)

PURPOSE: In the global presence of secondary infections with the coronavirus disease 2019 (COVID-19), little is known about the transmission characteristics of COVID-19 outside Wuhan, China. We evaluated differences in clinic and radiologic findings of multiple generations of COVID-19 infection in Xi'an (Shaanxi, China) to provide more clues for the correct estimate of the disease. METHODS: All COVID-19 infected patients reported in Xi'an up to 10 February 2020 were included for this analysis. Among these cases, clinical and chest CT data of 62 cases were obtained from three hospital in Xi'an. With this information, patients were grouped on basis of exposure history and transmission chains as first-generation, second-generation and third-generation patients. We described clinical characteristics and evaluated CT score/patterns in these COVID-19 cases. RESULTS: There was a clear age differences in multiple generations with COVID-19 infection. Above two thirds of the second-generation (75.0%) and third-generation patients (77.8%) were aged [≥]45 years while 40.0% of first-generation cases at this age (p=0.001). More than half of second-generation patients (52.8%) and third-generation patients (55.6%) have comorbidities and is predominantly hypertensive (22.8% of second-generation vs. 27.8% of third-generation infections). The main exposure of second- and third-generation patients in Xi'an is family exposure (35.2%). For evaluation of CT findings of pulmonary involvement, the total CT score were 4.22{+/-}3.00 in first-generation group, 4.35{+/-}3.03 in second-generation group and 7.62{+/-}3.56 in third-generation group (p<0.001). In all of three generations, the predominant pattern of abnormality observed was organizing pneumonia (65.5% in first-generation group, 61.5% in second-generation group and 71.4% in third-generation group). The average courses of the disease in third-generation infections has obviously extension (22.93{+/-}7.22 days of first-generation, 21.53{+/-}8.31 days of second-generation vs. 31.00{+/-}8.12 days of third-generation group, p=0.004). There were no significant differences of the pulmonary sequelae among three generation patients. CONCLUSION: There is more serious pulmonary infection of COVID-19 pneumonia in second- and third-generation patients, which might be attribute to the elder age and comorbidity of these patients.

A pattern categorization of CT findings to predict outcome of COVID-19 pneumonia (preprint)

AbstractsO_ST_ABSPurposeC_ST_ABSAs global healthcare system is overwhelmed by novel coronavirus disease (COVID-19), early identification of risks of adverse outcomes becomes the key to optimize management and improve survival. This study aimed to provide a CT-based pattern categorization to predict outcome of COVID-19 pneumonia. Methods165 patients with COVID-19 (91 men, 4-89 years) underwent chest CT were retrospectively enrolled. CT findings were categorized as Pattern0 (negative), Pattern1 (bronchopneumonia), Pattern2 (organizing pneumonia), Pattern3 (progressive organizing pneumonia) and Pattern4 (diffuse alveolar damage). Clinical findings were compared across different categories. Time-dependent progression of CT patterns and correlations with clinical outcomes, i.e. discharge or adverse outcome (admission to ICU, requiring mechanical ventilation, or death), with pulmonary sequelae (complete absorption or residuals) on CT after discharge were analyzed. ResultsOf 94 patients with outcome, 81(86.2%) were discharged, 3(3.2%) were admitted to ICU, 4(4.3%) required mechanical ventilation, 6(6.4%) died. 31(38.3%) had complete absorption at median day 37 after symptom-onset. Significant differences between pattern-categories were found in age, disease-severity, comorbidity and laboratory results (all P<0.05). Remarkable evolution was observed in Pattern0-2 and Pattern3-4 within 3 and 2 weeks after symptom-onset, respectively; most of patterns remained thereafter. After controlling for age, CT pattern significantly correlated with adverse outcomes (Pattern4 vs. Pattern0-3 [reference]; hazard-ratio[95%CI], 18.90[1.91-186.60], P=0.012). CT pattern (Pattern3-4 vs. Pattern0-2 [reference]; 0.26[0.08-0.88], P=0.030) and C-reactive protein (>10 vs. [≤]10mg/L [reference]; 0.31[0.13-0.72], P=0.006) were risk-factors associated with pulmonary residuals. ConclusionCT pattern categorization allied with clinical characteristics within 2 weeks after symptom-onset would facilitate early prognostic stratification in COVID-19 pneumonia.

The Reversed Halo Sign in COVID-19 Pneumonia (preprint)

ObjectivesTo evaluate the frequency and time course of RHS on CT in patient with COVID-19 pneumonia.Materials and methodsA total of 147 patients with COVID-19 pneumonia were divided into mild, moderate, severe and critical categories. The number, location, shape, wall appearance of RHS on CT were analyzed. Other parenchymal abnormalities include GGO, consolidation and linear opacity were also recorded.ResultsRHS was observed in 37 (25.2%) of 147 patients and it was more common in patients with moderate disease than severe or critical disease (31.3% vs. 13.0%, P = 0.019). Time from symptom onset to appearance of RHS was 9 ± 5 days in moderate patients and 14 ± 8 days in severe/critical patients. A total of 64 RHS lesions were identified and the majority of lesions were located in peripheral aspect of lungs (55, 85.9%) and lower lobes (52, 81.2%). All lesions with RHS were round or oval-shaped. The rim of RHS were smooth in 54 (84.4%) and irregular in 10 (15.6%). Follow-up CT scans of 27 patients (50 lesions) showed 43(86%) lesions gradually resolved or developed into GGO and linear opacities and 7(14%) lesions remained unchanged appearance.ConclusionsRHS occurred sooner after symptom onset and with higher frequency in patients with moderate compared to those with severe or critical disease. RHS may represent a favorable prognostic sign in COVID-19 pneumonia.Key Points• 37 (25.2%) of 147 patients with COVID-19 pneumonia had RHS on at least one CT• RHS was more prevalent in patients with moderate disease than those with severe or critical disease• RHSs (78.4%) mostly occurred within 2 weeks after symptom onset

Evolution of CT Findings in Patients with COVID-19 Pneumonia (preprint)

Objectives To delineate the evolution of CT findings in patients with mild COVID-19 pneumonia outside of Wuhan.Methods CT images and medical records of 88 patients with confirmed mild COVID-19 pneumonia outside of Wuhan, a baseline and at least one follow-up CT were retrospectively reviewed. CT features including lobar distribution and presence of ground glass opacities (GGO), consolidation, and linear opacities, were analyzed on per patient basis during each of five time intervals spanning the three weeks after disease onset. Total severity scores were calculated.Results 85.2 % of patients had travel history to Wuhan or known contact with infected individuals. The most common symptoms were fever (84.1%) and cough (56.8%). The baseline CT was obtained on average 5 days from symptom onset. Four patients (4.5%) had negative initial CT. Significant differences were found among the time intervals in the proportion of pulmonary lesions that are 1) pure GGO, 2) mixed attenuation, 3) mixed attenuation with linear opacities, 4) consolidation with linear opacities, and 5) pure consolidation. The majority of patients had involvement of ≥ 3 lobes. Bilateral involvement was more prevalent than unilateral involvement. The proportions of patients observed to have pure GGO or GGO and consolidation decreased over time while proportion of patients with GGO and linear opacities increased. Total severity score showed an increasing trend in the first two weeks. Conclusions While bilateral GGO are predominant features, CT findings changed during different time intervals in the three weeks after symptom onset in patients with COVID-19.