The impact of pandemic-related measures on COVID-negative dementia inpatients

Background During the COVID-19 pandemic, infection control measures and changes to patient flow have drastically altered the care provided to inpatients with dementia. Some of these emergency steps mainly affected COVID-19 positive patients, whereas others had an impact on all. This project aimed to examine the pandemic?s impact on the demographics, care and outcomes of inpatients with dementia who did not test positive for the virus. Methods This analysis formed a part of an overarching initiative at Stoke Mandeville Hospital, which leveraged the National Audit of Dementia (NAD) framework to assess care during the pandemic. A tailor-made questionnaire was composed of the relevant NAD elements and additional items, including questions on capacity assessment. The full sample included 100 patients with dementia admitted between April and July 2020. In this project, data from patients who tested negative for COVID-19 (n=75) were compared to the local results of the last available NAD (2018;n=50). A combination of student?s t, binomial, and Chi-squared statistical tests was applied to numerical, two-answer categorical, and multiple-answer categorical data respectively (with FDR correction where appropriate). Results Demographics of dementia patients admitted during the pandemic were different, with fewer males (27% vs. 40% in 2018), fewer ethnic minorities (13% vs. 36%) and fewer patients admitted from their own home (45% vs 63%). During admission, fewer functional assessments were carried out and less patient-specific information made available. Inpatient falls were less frequent (19% vs. 64%), presumably due to decreased opportunities for mobility. Admissions were shorter overall, but discharges appeared less well planned and coordinated. Rates of delirium and mortality were unaffected. Conclusions While major outcomes appear unchanged, the real impact may be masked by limited, selective admissions. The findings highlight the need to preserve assessment and discharge planning for COVID-negative patients with dementia during future crisis response measures.

Exploring dynamics and network analysis of spike glycoprotein of SARS-COV-2.

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 continues to rage with devastating consequences on human health and global economy. The spike glycoprotein on the surface of coronavirus mediates its entry into host cells and is the target of all current antibody design efforts to neutralize the virus. The glycan shield of the spike helps the virus to evade the human immune response by providing a thick sugar-coated barrier against any antibody. To study the dynamic motion of glycans in the spike protein, we performed microsecond-long molecular dynamics simulation in two different states that correspond to the receptor binding domain in open or closed conformations. Analysis of this microsecond-long simulation revealed a scissoring motion on the N-terminal domain of neighboring monomers in the spike trimer. The roles of multiple glycans in shielding of spike protein in different regions were uncovered by a network analysis, in which the high betweenness centrality of glycans at the apex revealed their importance and function in the glycan shield. Microdomains of glycans were identified featuring a high degree of intracommunication in these microdomains. An antibody overlap analysis revealed the glycan microdomains as well as individual glycans that inhibit access to the antibody epitopes on the spike protein. Overall, the results of this study provide detailed understanding of the spike glycan shield, which may be utilized for therapeutic efforts against this crisis.

Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by Molecular Simulations

The novel coronavirus (nCOV-2019) outbreak has put the world on edge, causing millions of cases and hundreds of thousands of deaths all around the world, as of June 2020, let alone the societal and economic impacts of the crisis. The spike protein of nCOV-2019 resides on the virion's surface mediating coronavirus entry into host cells by binding its receptor binding domain (RBD) to the host cell surface receptor protein, angiotensin converter enzyme (ACE2). Our goal is to provide a detailed structural mechanism of how nCOV-2019 recognizes and establishes contacts with ACE2 and its difference with an earlier coronavirus SARS-COV in 2002 via extensive molecular dynamics (MD) simulations. Numerous mutations have been identified in the RBD of nCOV-2019 strains isolated from humans in different parts of the world. In this study, we investigated the effect of these mutations as well as other Ala-scanning mutations on the stability of RBD/ACE2 complex. It is found that most of the naturally-occurring mutations to the RBD either strengthen or have the same binding affinity to ACE2 as the wild-type nCOV-2019. This may have implications for high human-to-human transmission of coronavirus in regions where these mutations have been found as well as any vaccine design endeavors since these mutations could act as antibody escape mutants. Furthermore, in-silico Ala-scanning and long-timescale MD simulations, highlight the crucial role of the residues at the interface of RBD and ACE2 that may be used as potential pharmacophores for any drug development endeavors. From an evolutional perspective, this study also identifies how the virus has evolved from its predecessor SARS-COV and how it could further evolve to become more infectious.

Mitigating Surgical Skill Decay in Orthopaedics Using Virtual Simulation Learning.

BACKGROUND: The COVID-19 pandemic has interrupted orthopaedic training structures for both surgeons and trainees. The concept of skill decay must be considered during inactivity of elective practice. The purpose of this study was to provide an evidence-based curriculum in association with immersive virtual reality (iVR) to prevent skill decay during periods of training cessation and beyond. METHODS: A review of pertinent literature for orthopaedic surgical skill decay was performed. Early experience by faculty instructors and residency and fellowship program directors was gathered from multiple institutions with experience in virtual training methods including iVR. A proposed curriculum for cognitive and manual skill acquisition during COVID-19 was produced from qualitative narrative group opinion. RESULTS: Skill decay can occur on the order of days to months and is dependent on the initial skill level. A novel curriculum for structured continuing medical education during and after periods of surgical disruption including e-learning, virtual meetings, and iVR simulators was produced from expert opinion and based on competency-based curriculum standards. CONCLUSION: Skill decay mitigation strategies should use best available evidence technologies and course structures that satisfy advanced learning concepts. The virtual curriculum including iVR simulators may provide cost-effective solutions to training.

Safety and Tolerability of Intra-Venous Ascorbic Acid in Allogeneic Hematopoietic Cell Transplant Recipients: A Matched Historical Control Study

Intravenous (IV) ascorbic acid (AA) improves organ function and reduces inflammation in sepsis, an inflammatory state similar to the post-hematopoietic cell transplant (HCT) milieu. This salutary effect is mediated by antioxidant activity as well transcriptional modulation by AA. HCT recipients are deficient in AA, therefore we evaluated the safety and efficacy of patients receiving parenteral AA after myeloablative conditioning for allogeneic HCT compared to similarly treated historical controls who did not receive AA. Methods: Patients with hematologic malignancies, AML (48% of patients), ALL (28%), and CML+MDS (25%) were enrolled in an IRB approved prospective phase 2 clinical trial (NCT03613727). IV AA 50 mg/kg/d divided in 3 doses was given on days 1-14 after HCT, followed by oral AA 500 mg bid from day 15 until 6 months post HCT (FDA-IND 138924). Conditioning regimens utilized included;fludarabine & melphalan (45%), cyclophosphamide with either busulfan (30%) or total body irradiation (25%). GVHD prophylaxis included calcineurin inhibitors and methotrexate or cellcept along with anti-thymocyte globulin (ATG). Primary endpoint was reduction in TRM at 1 year. Propensity score matching was used for matching study patients with similarly treated historical controls, matching for diagnosis, conditioning regimen, and CIBMTR disease risk category for comparison of clinical outcomes. Cox-proportional hazard models were used to estimate adjusted hazard ratios (AHR) between the time-to-event outcomes and study group, adjusted for patient age, donor type, stem cell source, diagnosis, conditioning regimen, and CIBMTR disease risk. Results of an interim analysis following a period of COVID 19 mandated suspension of study accrual are reported. Results: As of March 2020, 40 patients have received IV AA: these include HLA-matched related donor (MRD;n=11), and either 10/10 or 9/10 HLA- matched unrelated donor (MUD;n=22 & 7 respectively) recipients. Graft source was either peripheral blood (n=38) or bone marrow (n=2);88% patients had CIBMTR high risk disease. Median age was 55 years;males (19). All patients enrolled were deficient in AA at day 0, median AA level 0.3 mg/dL (range: 0.1-0.5);post AA infusion level was normal at 1.6 (1.2-5.7) on day 14. Median neutrophil and platelet recovery was by 12 days (range: 9-15 & 8-21 days respectively) with sustained donor engraftment. Median absolute CD3+ cell count at day 30 was 330 cells/microL. With a median follow up of 220 days in AA recipients, no statistically significant difference was observed in transplant related mortality between propensity matched historical controls and study patients (AHR 0.6, 95% CI: 0.2-1.5;p-value = 0.27);univariate survival analysis is depicted in Figure 1. Relapse was also similar (AHR 1.2, 95% CI: 0.3-4.5;p-value = 0.82), and despite a larger number of HLA mismatched unrelated donor recipients, acute GVHD (Grade II-IV) rates were similar in the two groups for both grade II-IV (AHR 0.8, 95% CI: 0.7-1.7;p-value = 0.65) and grade III-IV disease (AHR 0.6, 95% CI: 0.2-1.6;p-value = 0.32). Chronic GVHD rates were also similar (AHR 0.4, 95% CI: 0.1-2.7;p-value = 0.74). There are no attributable grade 3 - 4 toxicities from AA;CMV and EBV reactivation rates were not different in the two groups. Conclusions: In patients undergoing myeloablative allogeneic HCT the administration of IV ascorbic acid is safe and does not negatively impact myeloid engraftment or immune reconstitution. In this interim analysis, transplant related mortality, relapse and GVHD are not increased in IV AA recipients compared to historical controls. Thus, given its safety and tolerability, and possible salutary impact on survival and relapse in these high-risk patients, we posit the feasibility of a randomized phase 3 trial with IV AA in the post-transplant setting to determine its effect on relapse and TRM. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Outcomes and Surgical Considerations for Neurosurgical Patients Hospitalized with COVID-19-A Multicenter Case Series.

OBJECTIVE: Neurosurgical patients are at a higher risk of having a severe course of coronavirus disease 2019 (COVID-19). The objective of this study was to determine morbidity, hospital course, and mortality of neurosurgical patients during the coronavirus disease 2019 (COVID-19) pandemic in a multicenter health care system. METHODS: A retrospective observational study was conducted to identify all hospitalized neurosurgical patients positive for COVID-19 from March 11, 2020 to November 2, 2020 at Mayo Clinic and the Mayo Clinic Health System. RESULTS: Eleven hospitalized neurosurgical patients (0.68%) were positive for COVID-19. Four patients (36.6%) were men and 7 (63.3%) were women. The mean age was 65.7 years (range, 35-81 years). All patients had comorbidities. The mean length of stay was 13.4 days (range, 4-30 days). Seven patients had a central nervous system malignancy (4 metastases, 1 meningioma, 1 glioblastoma, and 1 schwannoma). Three patients presented with cerebrovascular complications, comprising 2 spontaneous intraparenchymal hemorrhages and 1 ischemic large-vessel stroke. One patient presented with an unstable traumatic spinal burst fracture. Four patients underwent neurosurgical/neuroendovascular interventions. Discharge disposition was to home in 5 patients, rehabilitation facility in 3, and hospice in 3. Five patients had died at follow-up, 3 within 30 days from COVID-19 complications and 2 from progression of their metastatic cancer. CONCLUSIONS: COVID-19 is rare among the inpatient neurosurgical population. In all cases, patients had multiple comorbidities. All symptomatic patients from the respiratory standpoint had complications during their hospitalization. Deaths of 3 patients who died within 30 days of hospitalization were all related to COVID-19 complications. Neurosurgical procedures were performed only if deemed emergent.

A hybrid asynchronous-synchronous learning network (HASLN) flipped-classroom approach in engineering education

This paper describes a technique in use at the Faculty of Engineering, UWI (Mona), to offer undergraduate engineering classes by combining collaborative Asynchronous Learning Networks (ALNs) and synchronous group interactions, in a flipped classroom setting. The ALN component involves access to online class materials such as recorded lectures, class notes, assigned and reference books and study guides so that students may watch lectures, write their own notes and consult supplemental materials as needed. A multimedia social network group including the instructors, instructional assistants and all students in the class then provides a forum to pose and answer questions and facilitate collaborative discussions of online material. The ALN class lectures and group interaction are complemented by a Synchronous Learning Network (SLN), using face-to-face meetings where possible and optionally, as necessitated over the past year during the on-going Covid-19 pandemic, using synchronous video conferencing tools. This face-to-face or videoconference enabled SLN component essentially constitutes a 'flipped-class room' approach, where lectures are watched at home and homework and problems are done at school. In person or virtually by interactive videoconference, fully exploiting the collaborative benefits of real-time, teacher-student and studentstudent interactions. The synchronous 'flipped-class room' sessions are used for group discussions, collaborative problem solving as well as supervised student assessment purposes. The flipped classroom sessions serve several important purposes in achieving key goals of effective teaching and learning. First, a moderated content specific question and answer discussion and by a mini-quiz with full access to personally authored lecture motivate and ensure diligence in student assimilation of the online class lectures. This sound foundation then empowers students to use the ALN lecture and supplemental material to successfully complete class assignments and projects in an interactive and collaborative setting. The in-person session also allows the for progressive and rigorous evaluation of learning via periodic tests based on personally completed class-assignments, comprehensive in-term examination(s) with no notes or textbook allowed, and a cumulative closed book, closed notes final examination based on the entire course material covered. The paper also provides general observations on the overall teaching and learning effectiveness and student performance as well as preliminary anecdotal student feedback on the HASLN approach. Finally, we motivate the benefit of implementing the HASLN techniques in High School and pre-college education for Science, Technology, Engineering and Math (STEM) classes. Copyright © 2021 by the International Institute of Informatics and Systemics.

Critical Sequence Hotspots for Binding of Novel Coronavirus to Angiotensin Converter Enzyme as Evaluated by Molecular Simulations.

The novel coronavirus (nCOV-2019) outbreak has put the world on edge, causing millions of cases and hundreds of thousands of deaths all around the world, as of June 2020, let alone the societal and economic impacts of the crisis. The spike protein of nCOV-2019 resides on the virion's surface mediating coronavirus entry into host cells by binding its receptor binding domain (RBD) to the host cell surface receptor protein, angiotensin converter enzyme (ACE2). Our goal is to provide a detailed structural mechanism of how nCOV-2019 recognizes and establishes contacts with ACE2 and its difference with an earlier severe acute respiratory syndrome coronavirus (SARS-COV) in 2002 via extensive molecular dynamics (MD) simulations. Numerous mutations have been identified in the RBD of nCOV-2019 strains isolated from humans in different parts of the world. In this study, we investigated the effect of these mutations as well as other Ala-scanning mutations on the stability of the RBD/ACE2 complex. It is found that most of the naturally occurring mutations to the RBD either slightly strengthen or have the same binding affinity to ACE2 as the wild-type nCOV-2019. This means that the virus had sufficient binding affinity to its receptor at the beginning of the crisis. This also has implications for any vaccine design endeavors since these mutations could act as antibody escape mutants. Furthermore, in silico Ala-scanning and long-timescale MD simulations highlight the crucial role of the residues at the interface of RBD and ACE2 that may be used as potential pharmacophores for any drug development endeavors. From an evolutional perspective, this study also identifies how the virus has evolved from its predecessor SARS-COV and how it could further evolve to become even more infectious.

Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by Molecular Simulations.

The novel coronavirus (nCOV-2019) outbreak has put the world on edge, causing millions of cases and hundreds of thousands of deaths all around the world, as of June 2020, let alone the societal and economic impacts of the crisis. The spike protein of nCOV-2019 resides on the virion's surface mediating coronavirus entry into host cells by binding its receptor binding domain (RBD) to the host cell surface receptor protein, angiotensin converter enzyme (ACE2). Our goal is to provide a detailed structural mechanism of how nCOV-2019 recognizes and establishes contacts with ACE2 and its difference with an earlier coronavirus SARS-COV in 2002 via extensive molecular dynamics (MD) simulations. Numerous mutations have been identified in the RBD of nCOV-2019 strains isolated from humans in different parts of the world. In this study, we investigated the effect of these mutations as well as other Ala-scanning mutations on the stability of RBD/ACE2 complex. It is found that most of the naturally-occurring mutations to the RBD either strengthen or have the same binding affinity to ACE2 as the wild-type nCOV-2019. This may have implications for high human-to-human transmission of coronavirus in regions where these mutations have been found as well as any vaccine design endeavors since these mutations could act as antibody escape mutants. Furthermore, in-silico Ala-scanning and long-timescale MD simulations, highlight the crucial role of the residues at the interface of RBD and ACE2 that may be used as potential pharmacophores for any drug development endeavors. From an evolutional perspective, this study also identifies how the virus has evolved from its predecessor SARS-COV and how it could further evolve to become more infectious.

Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by Molecular Simulations (preprint)

The novel coronavirus (nCOV-2019) outbreak has put the world on edge, causing millions of cases and hundreds of thousands of deaths all around the world, as of June 2020, let alone the societal and economic impacts of the crisis. The spike protein of nCOV-2019 resides on the virions surface mediating coronavirus entry into host cells by binding its receptor binding domain (RBD) to the host cell surface receptor protein, angiotensin converter enzyme (ACE2). Our goal is to provide a detailed structural mechanism of how nCOV-2019 recognizes and establishes contacts with ACE2 and its difference with an earlier coronavirus SARS-COV in 2002 via extensive molecular dynamics (MD) simulations. Numerous mutations have been identified in the RBD of nCOV-2019 strains isolated from humans in different parts of the world. In this study, we investigated the effect of these mutations as well as other Ala-scanning mutations on the stability of RBD/ACE2 complex. It is found that most of the naturally-occurring mutations to the RBD either strengthen or have the same binding affinity to ACE2 as the wild-type nCOV-2019. This may have implications for high human-to-human transmission of coronavirus in regions where these mutations have been found as well as any vaccine design endeavors since these mutations could act as antibody escape mutants. Furthermore, in-silico Ala-scanning and long-timescale MD simulations, highlight the crucial role of the residues at the interface of RBD and ACE2 that may be used as potential pharmacophores for any drug development endeavors. From an evolutional perspective, this study also identifies how the virus has evolved from its predecessor SARS-COV and how it could further evolve to become more infectious.