OrthoACCESS: Implementing a Sub-Internship Curriculum for MS4s Applying to Orthopaedic Surgery.

OBJECTIVE: Medical students pursuing orthopedic surgery residency build foundational knowledge during clinical rotations. Most clinical rotations, home and away, were paused during the COVID-19 pandemic. Given the lack of structured fourth-year medical student (MS4) education for basic orthopedics, educators developed the Ortho Acting-Intern Coordinated Clinical Education and Surgical Skills (OrthoACCESS) curriculum in 2019. This study demonstrates the accessibility and usability of a MS4 virtual orthopedic curriculum and examines the curriculum's role in increasing learner familiarity with basic orthopedic topics in 2020. DESIGN: OrthoACCESS faculty presented weekly lectures from July to October 2020 using Zoom Webinar. Website content included recorded webinars, external resources, and skills videos. Registrants were anonymously surveyed after each webinar characterizing the knowledge and utility of individual lectures. After the webinar series, registrants were emailed an anonymous post-curriculum survey characterizing their experience using the OrthoACCESS curriculum. RESULTS: OrthoACCESS had 1062 registrants, with 59% (624/1,062) MS4s. 4528 users accessed the OrthoACCESS website from 66 countries. The 15 lectures were viewed 3743 times, 1553 live views and 2190 asynchronous views. 444 postwebinar surveys were completed. Weekly response rates ranged from 18% to 45%. Respondents felt more knowledgeable and more able to apply their knowledge after viewing each lecture (p < 0.001), and found the webinars to be well-organized, well-paced, enthusiastically taught, and level-appropriate. 122/976 (13%) students and 45/291 (15%) faculty completed the postcurriculum survey. Faculty reported that OrthoACCESS was "quite useful" (4 [3-5]) for providing knowledge for an incoming orthopaedic intern. Faculty and students would recommend OrthoACCESS to future learners (5 [4-5]). CONCLUSIONS: OrthoACCESS delivered foundational musculoskeletal instruction during a period of increased need. In its initial iteration, this virtual curriculum demonstrated high utilization in the United States and internationally and improved participants' self-reported topical knowledge and ability to apply it clinically.

Optimization and Operations Research in Mitigation of a Pandemic

The pandemic of COVID-19 initiated in 2019 and spread all over the world in 2020 has caused significant damages to the human society, making troubles to all aspects of our daily life. Facing the serious outbreak of the virus, we consider possible solutions from the perspectives of both governments and enterprises. Particularly, this paper discusses several applications of supply chain management, public resource allocation, and pandemic prevention using optimization and machine learning methods. Some useful insights in mitigating the pandemic and economy reopening are provided at the end of this paper. These insights might help governments to reduce the severity of the current pandemic and prevent the next round of outbreak. They may also improve companies’ reactions to the increasing uncertainties appearing in the business operations. Although the coronavirus imposes challenges to the entire society at the moment, we are confident to develop new techniques to prevent and eradicate the disease.

The low-entropy hydration shell at the binding site of spike RBD determines the contagiousness of SARS-CoV-2 variants (preprint)

The infectivity of SARS-CoV-2 depends on the binding affinity of the receptor-binding domain (RBD) of the spike protein with the angiotensin converting enzyme 2 (ACE2) receptor. The calculated RBD-ACE2 binding energies indicate that the difference in transmission efficiency of SARS-CoV-2 variants cannot be fully explained by electrostatic interactions, hydrogen-bond interactions, van der Waals interactions, internal energy, and nonpolar solvation energies. Here, we demonstrate that low-entropy regions of hydration shells around proteins drive hydrophobic attraction between shape-matched low-entropy regions of the hydration shells, which essentially coordinates protein-protein binding in rotational-configurational space of mutual orientations and determines the binding affinity. An innovative method was used to identify the low-entropy regions of the hydration shells of the RBDs of multiple SARS-CoV-2 variants and the ACE2. We observed integral low-entropy regions of hydration shells covering the binding sites of the RBDs and matching in shape to the low-entropy region of hydration shell at the binding site of the ACE2. The RBD-ACE2 binding is thus found to be guided by hydrophobic collapse between the shape-matched low-entropy regions of the hydration shells. A measure of the low-entropy of the hydration shells can be obtained by counting the number of hydrophilic groups expressing hydrophilicity within the binding sites. The low-entropy level of hydration shells at the binding site of a spike protein is found to be an important indicator of the contagiousness of the coronavirus.

Hydrophobic interaction determines docking affinity of SARS CoV 2 variants with antibodies (preprint)

Preliminary epidemiologic, phylogenetic and clinical findings suggest that several novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have increased transmissibility and decreased efficacy of several existing vaccines. Four mutations in the receptor-binding domain (RBD) of the spike protein that are reported to contribute to increased transmission. Understanding physical mechanism responsible for the affinity enhancement between the SARS-CoV-2 variants and ACE2 is the "urgent challenge" for developing blockers, vaccines and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. Based on a hydrophobic-interaction-based protein docking mechanism, this study reveals that the mutation N501Y obviously increased the hydrophobic attraction and decrease hydrophilic repulsion between the RBD and ACE2 that most likely caused the transmissibility increment of the variants. By analyzing the mutation-induced hydrophobic surface changes in the attraction and repulsion at the binding site of the complexes of the SARS-CoV-2 variants and antibodies, we found out that all the mutations of N501Y, E484K, K417N and L452R can selectively decrease or increase their binding affinity with some antibodies.

Anatomic Repair of Left Main Coronary Artery Atresia: Coronary Ostioplasty With Autologous Pulmonary Artery.

BACKGROUND: Left main coronary arterial (LMCA) atresia is a rare coronary arterial anomaly with extremely limited data on the optimal management. We aimed to report our single-surgeon experience of the ostioplasty in patients with LMCA atresia. METHODS: From July 2018 to December 2019, pediatric patients who presented with LMCA atresia and subsequently underwent surgical coronary ostioplasty were recruited into this retrospective study. Concomitant mitral repair was applied when the regurgitation was moderate or more severe. RESULTS: A total of 9 patients diagnosed with LMCA atresia were included. Mitral regurgitation was found in all of them, including 6 (66.7%) severe, 1 (11.1%) moderate, and 2 (22.2%) mild. In addition to ischemic lesions, which were found in 7 (77.8%) patients, structural mitral problems were also common (presented in 7 [77.8%] patients). All the patients underwent coronary ostioplasty with autologous pulmonary arterial patch augmenting the anterior wall of the neo-ostium. Mean aortic cross clamp time and cardiopulmonary bypass time was 88.1 ± 18.9 and 124.6 ± 23.6 minutes, respectively. During a median of 10.9 (range: 3.3 to 17.2) months' follow-up, there was only 1 death at 5 months after surgery. All survivors were recovered uneventfully with normal left-ventricular function; however, with 4 (50.0%) having significant recurrence of mitral regurgitation. CONCLUSIONS: With favourable surgical outcomes, coronary ostioplasty for LMCA atresia may be an option of revascularization. Structural mitral problems presented in majority patients, resulting in the requirement of concomitant mitral repair. However, the optimal technique of mitral repair remains unclear.

A hydrophobic-interaction-based mechanism trigger docking between the SARS CoV 2 spike and angiotensin-converting enzyme 2 (preprint)

A recent experimental study found that the binding affinity between the cellular receptor human angiotensin converting enzyme 2 (ACE2) and receptor-binding domain (RBD) in spike (S) protein of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is more than 10-fold higher than that of the original severe acute respiratory syndrome coronavirus (SARS-CoV). However, main-chain structures of the SARS-CoV-2 RBD are almost the same with that of the SARS-CoV RBD. Understanding physical mechanism responsible for the outstanding affinity between the SARS-CoV-2 S and ACE2 is the "urgent challenge" for developing blockers, vaccines and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. Considering the mechanisms of hydrophobic interaction, hydration shell, surface tension, and the shielding effect of water molecules, this study reveals a hydrophobic-interaction-based mechanism by means of which SARS-CoV-2 S and ACE2 bind together in an aqueous environment. The hydrophobic interaction between the SARS-CoV-2 S and ACE2 protein is found to be significantly greater than that between SARS-CoV S and ACE2. At the docking site, the hydrophobic portions of the hydrophilic side chains of SARS-CoV-2 S are found to be involved in the hydrophobic interaction between SARS-CoV-2 S and ACE2. We propose a method to design live attenuated viruses by mutating several key amino acid residues of the spike protein to decrease the hydrophobic surface areas at the docking site. Mutation of a small amount of residues can greatly reduce the hydrophobic binding of the coronavirus to the receptor, which may be significant reduce infectivity and transmissibility of the virus.

Number of Pre-Existing Comorbidities and Prognosis of COVID-19: A Retrospective Cohort Study (preprint)

Background: Though many studies have described the association of COVID-19 and different kinds of noncommunicable chronic diseases, information with the combine effects of comorbidities to COVID-19 patients have not been well characterized yet. The aim of this study was to examine the associations of numbers of comorbidities with critical type and death of COVID-19.Methods: This was a single-centered retrospective study among patients with COVID-19. All patients with COVID-19 enrolled in this study were diagnosed according to World Health Organization interim guidance. Six different kinds of noncommunicable chronic diseases were included in this study. The logistic regression model was used to estimate the fixed effect of numbers of comorbidities on critical type or death, adjusting for potential confounders.Results: In total, 475 COVID-19 patients were enrolled in our study, included 234 females and 241 males. Hypertension was the most frequent type (162 [34.1%] of 475 patients). Patients with two or more comorbidities have higher risk of critical type (OR 3.072, 95% CI [1.581, 5.970], p=0.001) and death (OR 5.538, 95% CI [1.577, 19.451], p=0.008) compared to patients without comorbidities. And the results were similar after adjusting for age and gender in critical type (OR 2.021, 95% CI [1.002–4.077], p=0.049) and death (OR 3.653, 95% CI [0.989, 13.494], p=0.052).Conclusions: The number of comorbidities was an independent risk factor for critical type and death in COVID-19 patients.

Temporal Dynamics in Clinical and Laboratory Manifestations During COVID-19 Progression (preprint)

BAckground Severe COVID-19 patients account for most of the mortality of this disease. Early detection of severe cases of the disease remains a major challenge. Here, we performed clinical and laboratory profiling of COVID-19 to explore the early warning indicators of severe cases.Methods An analysis of the evolution during the hospitalization of clinical and laboratory findings from 78 confirmed COVID-19 patients and the associated risk factors.Results Of the 78 patients who were classified as un-severe at admission, 60 patients(stable group) were stable as mild cases until discharge, and the remaining 18 patients progressed to severe cases(exacerbated group) during hospitalization. Compared with stable patients, exacerbated patients exhibited older, higher BMI values and higher proportion of smokers. In the exacerbated patients, the median time from onset to deterioration was 7.5 days. Before the time point(days 0–7 from onset), we observed higher-levels of White blood cells(WBC), neutrophil, Neutrophi-Lymphocyte-Ratio(NLR), Lactose-dehydrogenase(LDH), D-dimer, and lower-levels of albumin in the exacerbated group, compared with the stable group. In the second week after the time point, the exacerbated patients displayed lower numbers of lymphocytes, CD3+, and CD8+T-cells, and higher-levels of C-reactive protein(CRP), erythrocyte-sedimentation-rate(ESR), Alanine-aminotransferase(ALT),Aspartate-aminotransferase(AST), and Interleukin-6. In the third week, the highest temperature and the proportion of febrile patients declined. All of the laboratory indicators gradually improved.Conclusions Advanced age and smoking history could be risk factors for COVID-19 progression. In the early stage, high-levels of WBC and neutrophils, with noticeably increased LDH and D-dimer, could be early indicators of the disease’s conversion from mild to severe, followed by elevated inflammatory markers, liver enzymes, and decreased T-lymphocytes in the next week.

Number of Pre-Existing Comorbidities and Prognosis of COVID-19: A Retrospective Cohort Study (preprint)

Background: Though many studies have described the association of coronavirus disease 2019 (COVID-19) and different kinds of noncommunicable chronic diseases, information with the combine effects of comorbidities to COVID-19 patients have not been well characterized yet. The aim of this study was to examine the associations of numbers of comorbidities with critical type and death of COVID-19.Methods: This was a single-centered retrospective study among patients with COVID-19. All patients with COVID-19 enrolled in this study were diagnosed according to World Health Organization interim guidance. Six different kinds of noncommunicable chronic diseases were included in this study. The logistic regression model was used to estimate the fixed effect of numbers of comorbidities on critical type or death, adjusting for potential confounders.Results: In total, 475 COVID-19 patients were enrolled in our study, included 234 females and 241 males. Hypertension was the most frequent type (162 [34.1%] of 475 patients). Patients with two or more comorbidities have higher risk of critical type (OR 3.072, 95% CI [1.581, 5.970], p=0.001) and death (OR 5.538, 95% CI [1.577, 19.451], p=0.008) compared to patients without comorbidities. And the results were similar after adjusting for age and gender in critical type (OR 2.021, 95% CI [1.002–4.077], p=0.049) and death (OR 3.653, 95% CI [0.989, 13.494], p=0.052).Conclusions: The number of comorbidities was an independent risk factor for critical type and death in COVID-19 patients.

Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis.

The outbreak of the novel coronavirus disease (COVID-19) quickly spread all over China and to more than 20 other countries. Although the virus (severe acute respiratory syndrome coronavirus [SARS-Cov-2]) nucleic acid real-time polymerase chain reaction (PCR) test has become the standard method for diagnosis of SARS-CoV-2 infection, these real-time PCR test kits have many limitations. In addition, high false-negative rates were reported. There is an urgent need for an accurate and rapid test method to quickly identify a large number of infected patients and asymptomatic carriers to prevent virus transmission and assure timely treatment of patients. We have developed a rapid and simple point-of-care lateral flow immunoassay that can detect immunoglobulin M (IgM) and IgG antibodies simultaneously against SARS-CoV-2 virus in human blood within 15 minutes which can detect patients at different infection stages. With this test kit, we carried out clinical studies to validate its clinical efficacy uses. The clinical detection sensitivity and specificity of this test were measured using blood samples collected from 397 PCR confirmed COVID-19 patients and 128 negative patients at eight different clinical sites. The overall testing sensitivity was 88.66% and specificity was 90.63%. In addition, we evaluated clinical diagnosis results obtained from different types of venous and fingerstick blood samples. The results indicated great detection consistency among samples from fingerstick blood, serum and plasma of venous blood. The IgM-IgG combined assay has better utility and sensitivity compared with a single IgM or IgG test. It can be used for the rapid screening of SARS-CoV-2 carriers, symptomatic or asymptomatic, in hospitals, clinics, and test laboratories.