RETHINKING REMDESIVIR: ENHANCING ANTI-SARS-CoV-2 ACTIVITY OF ORAL LIPID RVn PRODRUGS

Background: SARS-CoV-2 evolution has contributed to successive waves of infections and severely compromised the efficacy of available SARS-CoV-2 monoclonal antibodies. Decaying vaccine-induced immunity, vaccine hesitancy, and limited vaccine protection in older and immunocompromised populations further compromises vaccine efficacy at the population level. Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease due to COVID-19. An orally bioavailable RDV analog could facilitate earlier widespread administration to non-hospitalized COVID-19 patients. Method(s): We synthesized monoalkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. We evaluated the in vivo efficacy of our lead compound, 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (V2043), in an oral treatment model of murine SARS-CoV-2 infection. We then synthesized numerous phospholipid analogs of RVn and determined which modifications enhanced in vitro antiviral activity and selectivity. The most effective compounds against SARS-CoV-2 were then evaluated for antiviral activity against other RNA viruses. Result(s): Oral treatment of SARS-CoV-2 infected BALB/c mice with V2043 (60 mg/kg once daily for 5 days, starting 12 hrs after infection) reduced lung viral load by more than 100-fold versus vehicle at day 2 and to below the LOD at day 5. V2043 inhibited previous and contemporary SARS-CoV-2 Variants of concern to a similar degree, as measured by the half maximal effective concentration (EC50) in a human lung epithelial cell line (Calu-3). Evaluation of multiple RVn analogs with hydrophobic esters at the sn-2 of glycerol revealed that in vitro antiviral activity was improved by the introduction of a 3-fluoro-4-methoxysubstituted benzyl or a 3-or 4-cyano-substituted benzyl. These compounds showed a 2-to 6-fold improvement in antiviral activity compared to analogs having an unsubstituted benzyl, such as V2043, and were more active than RDV. These compounds also showed enhanced antiviral activity against multiple contemporary and emerging RNA viruses. Conclusion(s): Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections and as preparation for future outbreaks of pandemic RNA viruses.

Examiner perceptions of the MRCGP recorded consultation assessment for general practice licensing during COVID-19: cross-sectional study.

BACKGROUND: The Recorded Consultation Assessment (RCA) was developed rapidly during the COVID-19 pandemic to replace the Clinical Skills Assessment (CSA) for UK general practice licensing. Our aim was to evaluate examiner perceptions of the RCA. METHODS: We employed a cross-sectional design using a questionnaire survey of RCA examiners with attitudinal (relating to examiners thoughts and perceptions of the RCA) and free text response options. We conducted statistical descriptive and factor analysis of quantitative data with qualitative thematic analysis of free text responses. RESULTS: Overall, 182 of 260 (70%) examiners completed the questionnaire. Responders felt that consultations submitted were representative of the work of a typical GP during the pandemic and provided a good sample across the curriculum. They were also generally positive about the logistic, advisory and other support provided as well as the digital platform. Despite responders generally agreeing there was sufficient information available in video or audio consultations to judge candidates' data gathering, clinical management, and interpersonal skills, they were less confident about their ability to make judgments of candidates' performance compared with the CSA. The qualitative analysis of free text responses detailed the problems of case selection and content, explained examiners' difficulties when making judgments, and detailed the generally positive views about support, training and information technology. Responders also provided helpful recommendations for improving the assessment. CONCLUSION: The RCA was considered by examiners to be feasible and broadly acceptable, although they experienced challenges from candidate case selection, case content and judgments leading to suggested areas for improvement.

The impact of the first United Kingdom COVID-19 lockdown on environmental air pollution, digital display device use and ocular surface disease symptomatology amongst shielding patients.

Worldwide lockdown reduced air pollution during the first phase of the COVID-19 pandemic. The relationship between exposure to ambient air pollution, digital display device use and dry eye symptoms amongst patients with severe ocular surface disease (OSD) were considered. Symptoms and air pollutant concentrations for three different time periods (pre, during and post COVID-19 lockdown) were analysed in 35 OSD patients who achieved an immunosuppression risk-stratification score > 3 fulfilling the UK Government criteria for 12-week shielding. OSDI symptoms questionnaire, residential postcode air pollution data obtained from the Defra Automated Urban and Rural monitoring network for concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter (PM) with diameters below 10 µm and 2.5 µm, and English Indices of Deprivation were analysed. Significant reductions in NO2 and NOx concentrations were observed between pre- and during-lockdown periods, followed by a reversal in the post-lockdown period. Changes were linked to the Living Environment outdoor decile. A 12% increase (p = 0.381) in symptomatology during-lockdown was observed that reversed post-lockdown by 19% (p = 0.144). OSDI scores were significantly correlated with hours spent on digital devices (r2 = 0.243) but not with air pollutant concentrations. Lockdown measures reduced ambient air pollutants whilst OSD symptomatology persisted. Environmental factors such as increased time indoors and use of bluescreen digital devices may have partly played a role.

Hematologic findings and complications of SARS-COV- 2 in children and young adults

Background: Thrombotic coagulopathy is a predictor of SARS-CoV- 2 infection related mortality in adults (1-4). Incidence of venous thromboembolic events (VTE) in children seems to be lower (5), but there remains paucity of data on this in children. The current study describes the coagulation and inflammatory disturbances occurring in children <21 years with SARS-CoV- 2 infection and multisystem inflammatory syndrome in children (MIS-C) and evaluates risk factors for hematologic complications. Aim(s): 1. Report hematological and inflammatory abnormalities and hemorrhagic/thrombotic outcomes, in pediatric patients with SARS-CoV- 2 or MIS-C. 2. Identify risk factors for hematologic adverse outcomes with SARS-CoV- 2 or MIS-C. Method(s): Single-institution, retrospective study of in children <21 years with SARS-CoV2 acute infection or MIS-C between March 1, 2020, and February 28, 2021. Laboratory parameters were collected at presentation, and during hospitalization. Bleeding was graded using the modified World Health Organizations (WHO) grading system. VTEs were diagnosed radiographically, or by strong clinical suspicion. Correlation studies were done to assess hematologic and inflammatory laboratory markers. (Figure Presented) Results: In pediatric patients with SARS-COV- 2 infection and MIS-C (n = 127), we identified thrombotic and bleeding complications incidences at 6.3% and 6.3%, respectively. VTEs and bleeding events occurred mainly in females. All thrombotic events occurred in patients not previously on anticoagulation. No patients in our study received post-discharge thromboprophylaxis;one VTE occurred 3 days after discharge for COVID-19 pneumonia. Adolescent age (>13 years) and indwelling central venous-access device (CVAD) increased thrombotic risk, while MIS-C diagnosis did not. Obesity was not a risk factor for VTE but was associated with increased bleeding risk. Seven of eight bleeding events (5.5%) were WHO grade 3. Conclusion(s): SARS-CoV- 2 thrombotic complications in children are occur at lower rates than in adults. Older age, female sex, and CVADs increase thrombotic risk. With higher rates of bleeding events our study, daily risk-assessment of the need for continued thromboprophylaxis is recommended.

Depression, anxiety, substance misuse and self-harm in children and young people with rare chronic liver disease.

The burden of mental illness in young people with chronic liver disease is not known. In this population cohort study in England, we identified 358 individuals (aged ≤25 years) diagnosed with autoimmune hepatitis or liver disease related to cystic fibrosis and 1541 propensity-score-matched controls. By the first year of follow-up, the cumulative burden of psychiatric events in participants with liver disease was high compared with controls: anxiety disorder (6.87 per 100 individuals [95% CI 4.00-9.73] v. 2.22 [95% CI 1.37-3.07]), depression (5.10 [95% CI 2.83-7.37] v. 0.86 [95% CI 0.53-1.19]), substance misuse (10.61 [95% CI 9.50-11.73] v. 1.23 [95% CI 0.71-1.75]) and self-harm (3.09 [95% CI 1.12-5.05] v. 0.20 [95% CI 0.07-0.33]). Participants with liver disease had a 2-fold increase (OR = 1.94, 95% CI 1.45-2.58), a 2.5-fold increase (OR = 2.59, 95% CI 1.91-3.50) and 4.4-fold increase (OR = 4.44; 95% CI 3.46-5.71) in the risk of anxiety, depression and substance misuse, respectively. These findings highlight the need for effective intervention in psychiatric disorders in young people with rare liver disease.

A Longitudinal Comparison of Ambulatory Neurology Patient Experiences with Telehealth during the COVID-19 Pandemic: How have telehealth interest and satisfaction changed over time?

Objective: To compare patient satisfaction and preference for future telemedicine following in-person and virtual visits (telephone and video) in an ambulatory neurology practice. Background: During the COVID-19 pandemic, care shifted from exclusively telemedicine to hybrid models with in-person, video, and telephone visits. We sought to understand how patient satisfaction and visit preferences have changed. Design/Methods: Patients who completed a virtual visit in March 2020 (early pandemic, exclusive telemedicine), May 2020 (mid pandemic, in-person optional), and March 2021 (late pandemic, hybrid model) were contacted by telephone. Assenting patients were assessed for visit satisfaction (% reporting “all needs met”) and desire for future telemedicine (% reporting “definitely interested”). Results: 3,991 ambulatory visits were performed (1,004 early;478 mid;2,509 late);1,725 patients (43%) assented to post-visit feedback;mean age 45.8±24.4 years, 42% male, 79% white, and 56% with Medicare/Medicaid insurance. Patient satisfaction significantly increased (73% early, 79% mid, 81% late pandemic, p=0.008). Interest in telemedicine also increased for patients completing telephone visits (40% early, 50% mid, 59% late, p=0.027) and video visits (52% early, 59% mid, 62% late, p=0.035). Patients reporting “all needs met” were younger (44 years vs 51, p<0.001). There was no difference in satisfaction by race (p=0.09), sex (p=0.82), or insurance (p=0.82). However, white patients were more interested in future telemedicine (p=0.037). Multivariable analysis showed that older, male, black patients, with Medicare/Medicaid insurance were less likely to complete a video visit early pandemic. Male sex was no longer a predictor late pandemic whereas older patients were 2% less likely (for each 1 year older), black patients 45% less likely, and patients with Medicare/Medicaid 54% less likely to complete a video visit. Conclusions: Patients, especially younger ones, have become more satisfied and more interested in hybrid care models. Barriers to conducting video visits persist including for older, black patients with Medicare or Medicaid insurance.

A Comparison of Telehealth and In-Person Visits in Ambulatory Neurology:What are the factors that patients consider when selecting future visit type?

Objective: To identify factors that patients consider when selecting future visit type (in-person vs video vs telephone). Background: Telehealth has rapidly integrated into ambulatory medicine in response to the COVID-19 pandemic. In our clinic, telemedicine comprises approximately 30% of visits. Design/Methods: Consecutive patients who had an ambulatory neurology visit in March 2021 were contacted by telephone. Assenting patients completed (1) a survey quantifying likelihood of scheduling a future telemedicine visit and (2) a semi-structured interview. Qualitative responses were analyzed using principles of thematic analysis. Results: 2,493 ambulatory visits were performed;962 patients (39%) assented to post-visit feedback;74% were in-person visits, 13% video, and 13% telephone. Patients with video and telephone visits were more likely than in-person to consider telemedicine in the future (59% vs 62% vs 36% respectively, p<0.001). Five themes were identified that influence patient visit preferences: “Pros of Visit Type,” “Barriers to Telehealth,” “Situational Context,” “Inherent Patient Beliefs,” and “Extrinsic Variables.” Telemedicine patients considered convenience as “Pros of Visit Type,” while in-person patients valued improved communication and quality of medical care. “Barriers to Telehealth” such as accessibility and user familiarity were prevalent among in-person and telephone patients, whereas system limitations such as poor internet connection were prevalent among video patients. “Situational Context” varied: all patients agreed that stable conditions can be monitored via telemedicine;all patients considered physical examination a driving factor for in-person visits;telephone patients cited worsening symptoms as warranting in-person visits more frequently than video patients. The “Inherent Belief” that telemedicine is equivalent to in-person care was cited more by telephone than video patients. “Extrinsic Variables” such as patient awareness of telemedicine must be addressed. Conclusions: Patients view telemedicine as an adjunct to, and not replacement for, in-person visits. Future care delivery models should incorporate patient perspectives to guide improved access to care and reduction of healthcare spending.

Differences in Ambulatory Neurology Patient Experiences According to Distance Traveled: How do telephone and video visits compare to in-person?

Objective: To compare patient satisfaction and preference for future telemedicine visit following in-person and virtual visits (telephone and video) based on distance from a neurology ambulatory clinic. Background: Due to the COVID-19 pandemic, ambulatory neurology shifted to both in-person and telemedicine visits. Understanding how patient satisfaction and visit preferences differ by distance traveled can inform care post-pandemic. Design/Methods: Patients who completed a virtual visit in March 2020 (early pandemic) and virtual or in-person visit in March 2021 (late pandemic) were contacted by telephone within 3 months. Assenting patients completed quantitative assessment of satisfaction and desire for future telemedicine visit. Distance was measured “as-the-crow-flies” between patients' home and clinic zip-codes. Patients were stratified into groups: >60mi, 60-30mi, 30-15mi, and <15mi away. Results: 3,610 ambulatory visits were performed (1,101 early, 2,509 late);1,235 patients (34%) assented to feedback. Of these, 57% were in-person, 18% video, and 23% telephone. In general, >70% of patients reported “all needs met” regardless of visit type. Patient satisfaction was significantly greater with in-person visits for intermediate distances (60-15mi) and with telemedicine visits for the closest (<15mi) and farthest distances (>60mi, p<0.048). Satisfaction with in-person visits exceeded video and telephone visits only for patients at 30-15mi (89%, 76%, and 69% respectively;p<0.011). In the late pandemic, patients desired future virtual visits significantly less following in-person visits compared to video and telephone at all distances (p<0.037). Satisfaction did not change from early to late pandemic;however, desire for future virtual visits significantly increased for telephone visits (29-39% early to 58-71% late, p<0.05) and remained high for video (50-67% early and 54-67% late, P>0.05). Conclusions: Patients have become more receptive to telemedicine and in particular to telephone visits. Satisfaction with virtual visits is comparable to in-person visits at all distances and is particularly high for patients traveling the longest and shortest distances.

Mental health of people with multiple sclerosis during the COVID-19 outbreak: A prospective cohort and cross-sectional case-control study of the UK MS Register.

BACKGROUND: People with MS (pwMS) have had higher rates of anxiety and depression than the general population before the COVID-19 pandemic, placing them at higher risk of experiencing poor psychological wellbeing during the pandemic. OBJECTIVE: To assess mental health and its social/lifestyle determinants in pwMS during the first wave of the outbreak in the United Kingdom. METHODS: This is a community-based, prospective longitudinal cohort and cross-sectional case-control online questionnaire study. It includes 2010 pwMS from the UK MS Register and 380 people without MS. RESULTS: The Hospital Anxiety and Depression Scale scores of pwMS for anxiety and depression during the outbreak did not change from the previous year. PwMS were more likely to have anxiety (using General Anxiety Disorder-7) and/or depression (using Patient Health Questionnaire-9) than controls during the outbreak (OR: 2.14, 95% CI: 1.58-2.91). PwMS felt lonelier (OR: 1.37, 95% CI: 1.04-1.80) reported worse social support (OR: 1.90, 95% CI: 1.18-3.07) and reported worsened exercise habits (OR: 1.65, 95% CI: 1.18-2.32) during the outbreak than controls. CONCLUSION: Early in the pandemic, pwMS remained at higher risk of experiencing anxiety and depression than the general population. It is important that multidisciplinary teams improve their support for the wellbeing of pwMS, who are vulnerable to the negative effects of the pandemic on their lifestyle and social support.

Immunogenicity of Covid-19 vaccination in patients with myelodysplastic syndromes

Many patients with haematological cancers remain incompletely protected from SARS-CoV-2 following two doses of vaccine with Pfizer-BioNTech BNT162b2 nCoV-19 or ChAdOx1. Myelodysplastic syndrome (MDS) represents a spectrum of clonal bone marrow neoplasms. The response of patients with MDS to the COVID-19 vaccines remains unknown. Here, we report the humoral and T-cell responses of patients with low-and high-risk myelodysplastic syndrome (MDS), 2 weeks following completion of the second-dose schedules of ChAdOx1 or BNT162b2 nCoV-19 vaccines. Patients with MDS ( n = 38) followed up at Kings College Hospital, London were vaccinated with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccine. Written informed consent was provided. Eligibility criteria included the diagnosis of MDS as per the WHO classification and age ≥18 years. Healthy volunteers (HV;n = 30) served as a reference group. Blood samples were collected 2 weeks after the second vaccine dose. Plasma samples were tested for SARS-CoV-2-specific antibody aimed at the SARS-CoV-2 spike (S) protein receptor-binding domain and neutralisation assays against pseudotypes with SARS-CoV-2 Wuhan strain (WT), VOC.B.1.1.7 (alpha) or VOC.B.1.617.2 (delta) Spike. Cellular responses were assessed using IFNγ ELISPOT and flow cytometry (CD25 and CD69 expression) after 24 h peptide stimulation. IFNγ ELISpot analysis was performed ex vivo for assessment of T-cell response. 32% of the MDS patients received BNT162b2 and 58% received ChAdOx1 nCoV-19 vaccines. All HV received BNT162b2. Overall serological responses were as follows: HV BNT162b2 100% (26/26);MDS BNT162b2 100% (15/15) and MDS ChAdOx1 76.2% (16/21). Notably, the MDS ChAdOx1 cohort demonstrated significantly decreased serological titres to the MDS BNT162b2 cohort. The functional implications of seroconversion were assessed by neutralisation assays for SARS-CoV-2 WT and VOC alpha and delta. All but four MDS patients could neutralise all variant strains, but MDS cohorts showed significantly reduced median neutralisations for all three variant strains compared to HV. Five MDS ChAdOx1 patients who did not have a serological response were able to mount T-cell responses. Additionally, treatment with either azacytidine or calcineurin inhibitor cyclosporin did not impair appropriate T-cell responses. The numbers of individuals who were both serological and T-cell responders were as follows: HV 95% (20/21), MDS BNT162b2 71.4% (10/14) and MDS ChAdOx1 52.9% (9/17). Overall serological responses in the MDS cohorts were 100% for those who had completed the two-dose BNT162b2 vaccine schedule compared to 76.2% of patients vaccinated with the ChAdOx1 vaccine. It may be advisable that MDS patients are boosted with an mRNA-based vaccine to promote enhanced immunity in this specific population. We observed that neutralisation in seroconverted patients was significantly weaker for both the ChAdOx-1 and BNT162b2 MDS cohorts compared to HV. This highlights the continued need for a third primary dose for this clinically vulnerable patient group and our further work will analyse the cohort's response to this.

A Case-Control Autopsy Series of Liver Pathology Associated with Novel Coronavirus Disease (COVID-19)

Background: COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a global health emergency. Although well-known for pulmonary injury, COVID-19 is a systemic process. Previous autopsy case series have speculated about, although not clearly defined, patterns of hepatic injury, with steatosis being reported in many patients. This retrospective study is the first case-control study investigating hepatic pathology in a large cohort of deceased COVID-19 patients. Design: Consented autopsy cases at two institutions, between 4/2020 and 2/2021, were retrospectively searched for documentation of COVID-19 as a contributing cause of death. A control group of 40 consecutive consented COVID-19(-) autopsy cases during the same period was identified. The autopsy report and electronic medical records were reviewed for clinical information. H&E-stained liver sections were examined for selected histologic features. Results: 54 COVID-19(+) (mean age 72, M:F=3.2:1) were included in the study. The 40 control cases had a mean age of 64 years and a M:F=1.4:1. The study group was significantly older (p=0.0095) but there was no significant difference in sex. The control group had a higher rate of chronic alcoholism and underlying malignancy, with no difference noted in BMI or other comorbidities. The study group was more likely to have received steroid (72.2% vs. 30%, p<0.0001) and anticoagulation therapy (75.9% vs. 47.5%, p=0.009). Histologically, the study group showed a higher incidence of clinically insignificant steatosis (≤5%), (33.3% vs 12.5%;P = 0.03). Presence of clinically relevant (>5%) steatosis or zonal distribution of steatosis was not significantly different between the groups. Mild nonspecific lobular inflammation and acidophil bodies were also more common in COVID-19 cases (51.9% vs 30.0%;P = 0.04). No significant difference was noted among other histologic features, including vascular changes (Table 1). Conclusions: Mild nonspecific lobular necroinflammatory activity is a common finding in deceased COVID-19 patients, suggestive of COVID-19 hepatitis. COVID-19 is unlikely a cause of clinically significant steatosis. However, patients with COVID-19 are more likely to have low levels of steatosis (≤5%) compared to controls. The high rate of steroid therapy in this population may be a possible source of this minor component of steatosis.

Targeting vimentin impacts multiple cellular processes, blocks the spike protein-ACE2-mediated pseudoviral infection in vitro and reduces the symptom and lung injury in aged mice with mouse-adapted SARS-CoV-2 infection in vivo

Vimentin intermediate filament is involved in multiple steps of viral infection such as viral entry, trafficking and egress, as well as in various mechanisms of hyperinflammation such as the restraint of Treg cell functions and the activation of NLRP3 inflammasome. We evaluated a vimentin-binding small molecule compound ALD-R491 for its effects on cellular processes related to viral infection and for its efficacy in treating SARS-CoV2 infection in vitro and in vivo. In cultured cells, the compound could reduce endocytosis by 10%, endosomal trafficking by 40% and exosomal release by over 30%. In an infection system consisting of a lentiviral pseudotype bearing the SARS-CoV-2 spike protein and HEK293 cells over-expressing the human ACE2 receptor with multiplicity of infection (MOI) of 1, 10 and 100, the compound inhibited the infection up to a maximum of over 90%, with IC 50 < 50 nM, CC50 > 10 μM, and SI > 200. After oral administration of ALD-R491 in rats, the plasma concentration of the compound reached the peak (Tmax) at around 5 h with a half-life (T1/2) of about 5 h. The compound was widely distributed and enriched in tissues in vivo in rats with a volume of distribution (Vd) of over 2,000 ml/kg. The lung and the lymph nodes were among the tissues with high drug exposures. In rats receiving oral gavage of the compound at 30 mg/kg, the drug exposure in the lung and the lymph nodes maintained at levels over 1 μM from 1 h to 6 h after the oral dosing. In the syngeneic mouse tumor CT26 model, ALD-R491 was found to activate regulatory T cells (Tregs) in vivo and enhance de novo generation of Tregs in lymph nodes of the mice. In the Mouse-Adapted SARS-CoV2 model, aged mice (11-12 months) were used to provide a harder test of recovery from infection that reflects the severeness of COVID-19 in old patients. For therapeutic treatment, the mice were orally administered with the compound 24 h after the SARS-CoV2 infection once per day on Day 1, Day 2 and Day 4. At 10 mg/kg, ALD-R491 significantly reduced the body weight loss of the mice (p<0.01 on Day 5 post-infection). At both 3 mg/kg and 10 mg/kg, the compound significantly reduced the hemorrhagic score for the lungs (p<0.01 and p<0.05, respectively, on Day 5). These results indicate that vimentin intermediate filament is an effective host-directed antiviral target. Importantly, the vimentin-binding small molecule ALD-R491 impacts multiple aspects of SARS-CoV2 infection, has a favorable oral pharmacokinetics and a wide therapeutic window, and therefore may be a promising therapeutic candidate for treating COVID-19. Statement: Aluda Pharmaceuticals, Inc. has utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases.

Immunogenicity of Covid-19 Vaccination in Subjects with Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) represent a spectrum of clonal bone marrow neoplasms from low risk disease through to those transforming into acute myeloid leukaemia. The COVID-19 pandemic has presented a great risk to those with hematological malignancies who are at higher risk of severe disease and death than the general population. Previous studies looking at the immune response to influenza vaccination in those with MDS had shown promising results, with immune responses not differing from those of healthy family members. Whilst some data exist to reassure the MDS community that majority of patients show seroconversion following Covid-19 vaccination, little data exists on their neutralizing capacity or post vaccination T-cell responses in this cohort. In addition, the majority of patients in these studies received BNT162b2 and there is little published data on vaccine response to the ChAdOx1 nCoV-19 vaccine. We have investigated the humoral and T-cell response of 39 patients with MDS two to four weeks following Covid-19 booster vaccination with BNT162b2 or ChAdOx1 nCoV-19 through the SOAP study (Sars-cov-2 fOr cAncer Patients, IRAS project ID:282337). Plasma and PBMCs from MDS cases and healthy controls have been collected, and are being assessed for both humoral and cellular responses to SARS_CoV_2, the alpha (B.1.1.7) and delta (B.1.617.2) variants. Humoral responses will be assessed using ELISA (peptide binding) and functional viral neutralization assays. Cellular responses will be assessed using IFNy ELISPOT and flow cytometry (CD25 and CD69 expression) after 24h peptide stimulation. All data at time point 1 (2 - 4 weeks following booster vaccination) have been collected and will subsequently be collected at 6 months and 12 months post-vaccination. We also report on the safety data for these vaccines within this patient population. Of this cohort 64% were male with a median age of 65 years (range 21-84). 54% received vaccination with ChAdOx1 nCoV-19 and 44% received BNT162b2 (2% unrecorded). The vaccines were well tolerated with no serious adverse events to date. The mean interval between doses was 70.7 days (range 50 - 90 days). 71% of the cohort were receiving no disease modifying therapy at the time of vaccination, half of whom were receiving supportive therapy and the other half no intervention for their MDS. Of those receiving disease modifying therapy;5 were receiving azacitidine, (1 in conjunction with low-dose cytarabine) and 3 ciclosporin. We will report the largest study of the humoral and T-cell mediated response to the Covid-19 vaccine in MDS patients to date. This will include cellular response to the delta variant and immunogenicity of both the BNT162b2 and ChAdOx1 nCoV-19 vaccines. Given the vulnerability of these patients to severe disease, investigating the immune response to the vaccines begins to build an evidence base for advising MDS patients on their ongoing risk of infection during the pandemic and going forward. The SOAP study will reassess the immune response at 6 and 12 months post-vaccination to continue to investigate post-vaccine immunity in this cohort. Disclosures: Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau;Apellis: Consultancy;Akari: Consultancy, Honoraria, Speakers Bureau;Biocryst: Consultancy, Honoraria, Speakers Bureau;Achilleon: Consultancy, Honoraria, Speakers Bureau;Alexion: Consultancy, Honoraria, Speakers Bureau;Ra Pharma: Consultancy, Honoraria, Speakers Bureau;Amgen: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau;Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Patten: JANSSEN: Honoraria;NOVARTIS: Honoraria;GILEAD SCIENCES: Honoraria, Research Funding;ROCHE: Research Funding;ASTRA ZENECA: Honoraria;ABBVIE: Honoraria.

Engineering Education: Resiliance And Purposeful Change

Engineering education is undergoing rapid change. Programs across the world have instituted route-and-branch reforms and are navigating a path towards new educational models. This transition has been proactive, carefully planned and rolled out over time frames determined by the institution. Over the past eighteen months, the COVID-19 pandemic has necessitated major changes to program design and delivery. Here, changes have been reactive, unexpected, and introduced at speed. The timing of the Special Issue places it at the conjuncture of these two contrasting change processes. The editorial considers global developments in engineering education in this unique context. It begins by looking back to 2018. It then moves forward to the present and considers how programs have progressed along their planned change pathways, despite the sudden program changes instituted by the pandemic © 2021, Advances in Engineering Education.All Rights Reserved.

Ambulance attendance for substance and/or alcohol use in a pandemic: Interrupted time series analysis of incidents.

INTRODUCTION: The ambulance attendance for substance and/or alcohol use in a pandemic (ASAP) study explores incidents during the COVID-19 lockdown in the East Midlands region of the United Kingdom (23 March-4 July 2020). METHOD: Retrospective cross-sectional count per day of ambulance attendances from the East Midlands Ambulance Service Trust. Ambulance attendances relating to alcohol or other drug use in the year prior, during lockdown and weeks following, were examined using interrupted time series analysis by patient demographics and geographical location. RESULTS: A total of 36 104 records were identified (53.7% male, 84.5% ethnicity classified as White, mean age 38.4 years). A significant drop in the number of attendances per day at the start of lockdown (-25.24, confidence interval - 38.16, -12.32) was observed, followed by a gradual increase during the ongoing lockdown period (0.36, confidence interval 0.23, 0.46). Similar patterns were found across genders, age groups 16-64 and urban/rural locations. DISCUSSION AND CONCLUSION: The pattern of ambulance attendances for alcohol or other drug use changed during the COVID-19 lockdown period. Lockdown significantly affected the use of ambulances for incidents involving alcohol or other drug use, impacting on health-care services. Further research into hazardous use of alcohol or other drugs during the lockdown periods is needed to inform policy, planning and public health initiatives.

A Systematic Literature Review of Indoor Air Disinfection Techniques for Airborne Bacterial Respiratory Pathogens.

Interrupting the transmission of airborne (<≈5 µm) respiratory pathogens indoors is not a new challenge, but it has attracted unprecedented interest due to the COVID-19 pandemic during 2020-2021. However, bacterial respiratory pathogens with known or potential airborne transmission account for an appreciable proportion of the communicable disease burden globally. We aimed to systematically review quantitative, laboratory-based studies of air disinfection techniques for airborne respiratory bacteria. Three databases (PubMed, Web of Science, Scopus) were searched, following PRISMA guidelines. A total of 9596 articles were identified, of which 517 were assessed in detail and of which 26 met the inclusion and quality assessment criteria. Seven air disinfection techniques, including UV-C light, filtration, and face masks, among others, were applied to 13 different bacterial pathogens. More than 80% of studies suggested that air disinfection techniques were more effective at inactivating or killing bacteria than the comparator or baseline condition. However, it was not possible to compare these techniques because of methodological heterogeneity and the relatively small number of the studies. Laboratory studies are useful for demonstrating proof-of-concept and performance under controlled conditions. However, the generalisability of their findings to person-to-person transmission in real-world settings is unclear for most of the pathogens and techniques we assessed.

Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England.

BACKGROUND: Contradicting assumptions have been made about the effectiveness of SARS-CoV-2 vaccines in patients with multiple sclerosis (MS) receiving immunomodulatory disease-modifying therapies (DMTs) based on the quantification of humoral and cellular immune responses. This study aimed to understand changes in the risk of SARS-CoV-2 infection among the total population of patients receiving MS DMTs in England following mass vaccination. METHODS: This is a retrospective analysis of national data collected prospectively and longitudinally. National Health Service (NHS) England and NHS Improvement (NHSE/I) hold prescribing data on all commissioned MS DMTs in England. United Kingdom Health Security Agency (UKHSA) has been collecting data on all registered SARS-CoV-2 test results, including polymerase chain reaction and rapid antigen tests. All patients receiving MS DMTs were identified using NHSE/I datasets. All patients receiving MS DMTs with SARS-CoV-2 infection (i.e., positive test) from March 2020 to August 2021 were identified by merging NHSE/I and UKHSA datasets. Similar data for the general population were captured using publicly available datasets of the United Kingdom government. The incidence rate ratios (IRR) of SARS-CoV-2 infection among patients receiving MS DMTs compared to the general population during the pre-vaccination (November 2020 to January 2021) and post-vaccination (June to August 2021) periods were calculated. RESULTS: A mean (standard deviation) of 41,208 (4,301) patients received an MS DMT in England during each month from March 2020 to August 2021. The IRR (95% confidence interval) of infection in patients taking ocrelizumab versus the general population increased from 1.13 (0.97-1.31) during the pre-vaccination period to 1.79 (1.57-2.03) during the post-vaccination period. For patients on fingolimod, it increased from 0.87 (0.73-1.02) to 1.40 (1.20-1.63) during the same periods. There were no significant changes for patients on other MS DMTs. CONCLUSION: SARS-CoV-2 vaccines offer less protection against infection to patients taking ocrelizumab or fingolimod, who have an impaired immune response to vaccines, than the general population. These findings will have implications for vaccination policies.