The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce-randomised controlled trial.

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.

Morphoproteomic Features of Pulmonary Influenza A (H1N1) with Therapeutic Implications: A Case Study

Objective. Influenza pandemic of the human lung was caused by the Influenza A (H1N1) over 100 years ago in 1918, but it recurred in pandemic fashion in 2009. Understanding the pathobiology of this infectious agent in the human lung could lead to adjuvant therapies that are relatively non-toxic and reduce the mortality of the human host. Overall, our objective was to apply morphoproteomics to pulmo-nary lung sections from an autopsied victim so that we may better define its biology from the perspective of its interaction with the host and provide options for therapeutic targets. Methods. Morphoproteomic analysis from a case study of this Influenza A (H1N1) pulmonary infection included immunohistochemical probes to detect the expressions of fatty acid synthase (FAS), CD163+ (M2 polarized monocytes/macro-phages), and programmed death-ligand 1 (PD-L1) expression as part of the host response to interaction with the Influenza A (H1N1) virus.Results. Representative sections of the Influenza A (H1N1) victim's lung showed: cytoplasmic expression of FAS in most of the sloughed and atypical alveolar pneumocytes;abundance of intra-alveolar and alveolar interstitial CD163+ macrophages/monocytes;and PD-L1 expres-sion on occasional macrophages, and focally on collections of alveolar pneumocytes and the alveolar inter-stitium.Conclusion. Morphoproteomics and microanatomical features coincide with the etiopathogenic features of pulmonary Influenza A (H1N1) infection and the host response. This plus data mining of the medical literature suggests that adjunctive, targeted therapy such as metformin and vitamin D3 could ad-dress the biology of Influenza A (H1N1) pneumonia, enhance the host immune response, and prevent its progression to a life-threatening, ventilator-dependent clinical situation.

COVID-19 IN MS: CLINICALLY REPORTED OUTCOMES FROM THE UK MS REGISTER

Background The UK MS Register (UKMSR) has been capturing longitudinal clinical and patient reported outcomes (PROs) since 2011. As the UK population 'locked-down' in March 2020 it became important that clinicians could record hospitalised MS patients due to COVID-19 and record outcome. The UKMSR provided an electronic case return form, designed collaboratively by the community. Aim Impacts of disability, age and treatment on mortality in pwMS with COVID-19 Method Linear modelling and standardised hypothesis testing were performed on an outcome of died or not, impact of disability (EDSS), disease modifying therapies and age. Results N=132 PCR confirmed COVID-19 patients submitted, 14 missing EDSS, leaving n=118. Female n=80, n relapsing =74, n progressive = 44, mean age 49.2. Median EDSS = 5.0. Linear regression for age was found to be most significant for outcome (p=0.002). Univariate analysis found that the outcome was not independent of EDSS (ChiSq p=0.0008), DMT (ChiSq p=0.006) and MSType (ChiSq p=0.0006). In the multivariate model only, age remained significant. Conclusions Only age remained as a marker of poor outcome multivariate analysis. No MS Specific characteristics were found to be significant. We would encourage continued data collection from UK neurology centres to increase the utility of this data.

COVID-19 AND MULTIPLE SCLEROSIS: AN UPDATED REPORT OF THE COMMUNITY-BASED LONGITUDINAL UK MS REGISTER STUDY

COVID-19 is a concern in people with multiple sclerosis (MS), mostly because of their long-term physical disabilities and immunomodulatory disease-modifying therapies (DMTs). In this community-based pro-spective longitudinal study, we have been monitoring a cohort of people with MS via the web-based platform of the UK MS Register since the start of the COVID-19 outbreak. We report our findings from 17/03/2020 to 15/01/ 2021. Out of 7344 participants, 883 (12%) have reported a selfdiagnosis of COVID-19 of whom 211 had a confirmed clinical or laboratory-based (n=114) diagnosis. No individual DMT increased the likelihood of contracting COVID-19 (with any of the diagnoses as the outcome). Gender (male: female, adjusted OR: 95% CI [0.94: 0.68'1.3]), web-based Expanded Disability Status Scale score (webEDSS;one-point increase, 0.92: 0.84'1.01), and MS duration (one-year increase, 1: 0.98'1.02) were not associated with contracting COVID-19. Younger age (one-year decrease, 1.04: 1.03'1.06), ethnicities other than white (1.95: 1.13'3.34), and relapsing-remitting MS (versus progressive, 1.72: 2.56'1.16) increased the likelihood of contracting COVID-19. Within a median (interquartile range) of 26 (0'72) days follow-up of participants with COVID-19 (n=532), 69% reported full recovery. A higher webEDSS (one-point increase, 0.84: 0.74'0.96) lowered the likelihood of full recovery. Overall, MS-specific factors do not predispose people with MS to contracting COVID-19, but physical disability can delay recovery.

Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease.

The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CLpro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CLpro and MERS-CoV 3CLpro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.

Contact With Nature as a Mental Health Buffer for Lower Income Communities During the COVID-19 Pandemic

Despite a growing number of research outputs on the importance of nature contact during the COVID-19 pandemic, we know of no longitudinal research conducted prior to and during the pandemic among low-income and minority ethnicity populations, i.e., those that might be most affected. Furthermore, we have scant information about how and to what degree contact with nature might protect mental health or mitigate worsening of mental health during the pandemic. We filled these gaps using a subset of a longitudinal study of n = 86 individuals in low-income, predominantly African American, neighborhoods in Detroit, MI, USA. The study addressed the following research questions: (1) did self-reported use and perceived value of nature change during, vs. prior to, the pandemic;(2) did perceived access to outdoor spaces buffer people against mental health issues such as stress, anxiety and depression symptoms;or (3) did objectively measured quality of nature views from home buffer people against mental health issues, taking into account relevant covariates and pandemic experiences (e.g., loss of employment, death of a friend/relative)? While attitudes to nature improved slightly from pre- to during the pandemic, we also observed significant decreases in most types of outdoor physical activity and passive enjoyment of nature (e.g., smelling plants/rain). We found a positive association between visibility of greenspace and perceived stress and anxiety, which not only contradicts previous research findings, but was especially surprising given that overall there was a decrease in perceived stress from 2019-2020. We did not detect associations between perceived access/use of nature and mental health. However, higher depressive symptoms were associated with exposure to more COVID-19-related stressors (lost employment, death of friends from COVID-19, etc.). Taken together, our results indicate that COVID-19 may serve to prolong or exacerbate mental health issues, rather than create them, in this population and that low quality greenspace may perhaps limit the ability for nature view to buffer mental health during the pandemic.

Self-diagnosed COVID-19 in people with multiple sclerosis: a community-based cohort of the UK MS Register

The COVID-19 study (clinicaltrials.gov:NCT04354519) is a prospective observational cohort launched on 17 March 2020 as part of the UKMSR. As of 24 April, out of 3910 participants, 237 (6.1% (95% CI 5.3% to 6.8%)) reported self-diagnosed COVID-19 among whom 54 (22.8% (17.5% to 28.2%)) also had a diagnosis by a healthcare professional based on symptoms and 37 (15.6% (11.2% to 20.6%)) a confirmed diagnosis by testing. Three participants reported hospitalisation due to COVID-19. No deaths were reported. Among 1283 siblings without MS, 79 (6.2%) had a reported diagnosis of COVID-19. Adjusting for age and gender, the likelihood of contracting COVID-19 in pwMS was similar to siblings (OR 1.180 (0.888 to 1.569)). Seven hundred and fifty-nine of 3812 participants reported that they were self-isolating and that they had been self-isolating for at least 2 weeks before symptom onset if they had COVID-19. Of these, 2 (0.3% (0% to 0.7%)) had self-diagnosed COVID-19 whereas 137 of 3053 participants not self-isolating (4.5% (3.8% to 5.2%)) had the disease. Participants on DMTs were less likely to have self-diagnosed COVID-19 (OR 0.640 (CI 0.428 to 0.957)), which remained significant after removing self-isolating participants (OR 0.633 (0.402 to 0.998)). High-efficacy DMTs reduced the likelihood of self-diagnosed COVID-19 compared with no DMTs (OR 0.540 (0.311 to 0.938)) but not compared with moderate-efficacy DMTs. Including webEDSS (n=2808) and physical MSIS-29v2 (n=3192) as additional predictors in the analysis showed no significant association with the likelihood of contracting COVID-19. The gender distribution was similar between participants with and without COVID-19. More participants with self-diagnosed COVID-19 reported themselves as having any ethnicity other than white compared with those without the disease (6.9% (3.9% to 10.1%) vs 3.8% (3.2% to 4.4%), p=0.019). Gender and ethnicity did not affect the likelihood of having COVID-19.

COVID-19 in Multiple Sclerosis: Clinically reported outcomes from the UK Multiple Sclerosis Register.

BACKGROUND: In March 2020, the United Kingdom Multiple Sclerosis Register (UKMSR) established an electronic case return form, designed collaboratively by MS neurologists, to record data about COVID-19 infections in people with MS (pwMS). OBJECTIVES: Examine how hospital admission and mortality are affected by disability, age and disease modifying treatments (DMTs) in people with Multiple Sclerosis with COVID-19. METHODS: Anonymised data were submitted by clinical teams. Regression models were tested for predictors of hospitalisation and mortality outcomes. Separate analyzes compared the first and second 'waves' of the pandemic. RESULTS: Univariable analysis found hospitalisation and mortality were associated with increasing age, male gender, comorbidities, severe disability, and progressive MS; severe disability showed the highest magnitude of association. Being on a DMT was associated with a small, lower risk. Multivariable analysis found only age and male gender were significant. Post hoc analysis demonstrated that factors were significant for hospitalisation but not mortality. In the second wave, hospitalisation and mortality were lower. Separate models of the first and second wave using age and gender found they had a more important role in the second wave. CONCLUSIONS: Features associated with poor outcome in COVID-19 are similar to other populations and being on a DMT was not found to be associated with adverse outcomes, consistent with smaller studies. Once in hospital, no factors were predictive of mortality. Reassuringly, mortality appears lower in the second wave.

Determinants of recovery from the coronavirus disease 2019 in people with multiple sclerosis: The UK MS Register COVID-19 prospective cohort study

Objective: To assess factors associated with recovery from the coronavirus disease 2019 (COVID-19) among people with multiple sclerosis (pwMS) Background: It is important to understand the recovery process from COVID-19 among pwMS to identify those who are most vulnerable to the long-term sequelae of infection. Design/Methods: The UK MS Register COVID-19 study is a community-based prospective cohort of pwMS launched on March 17th, 2020. We have been collecting data from participants (n=6,618 as of October 5th, 2020) every two weeks from the time of their enrolment in the study. We ask participants about COVID-19 and follow them through their recovery. The UK MS Register holds pre-COVID-19 longitudinal and prospectively collected patient-reported data including web-based Expanded Disability Status Scale (webEDSS), MS Impact Scale (MSIS-29), and Hospital Anxiety and Depression Scale (HADS) scores. Results: Out of 709 participants with self-diagnosed COVID-19, 391 responded to the follow-up questionnaires. 76% (n=297) had fully recovered, 15.9% (n=62) had mostly recovered, and 8.2% (n=32) were still experiencing symptoms at the time of their latest follow-up. Among participants with full recovery, the median (IQR) duration of disease was 10 (6-21) days. Participants who had not recovered completely had been followed up for a median (IQR) duration of 105 (35-131) days. PwMS who had a higher webEDSS score (OR 0.78, 95%CI 0.65-0.93) or physical component of MSIS-29 score (OR 0.97, 95%CI 0.96-0.98) were less likely to report a full recovery. The presence of anxiety (HADS-anxiety ≥11), recorded the year before the pandemic, was associated with a lower probability of complete recovery (OR 0.26, 95%CI 0.10-0.66). Demographics, diseasemodifying therapies, MS duration, or type of MS were not associated with recovery. Conclusions: Physical disability and anxiety prior to the pandemic are the main determinants of persistent COVID-19 symptoms among people with MS.

Impact of Packaging Film and Beef Trimmings on Ground Beef Shelf Life.

Fresh beef storage in the retail setting can be presented in a variety of packaging methods, and identifying an alternative such as vacuum packaging to current traditional methods could potentially increase shelf life and reduce meat waste. The objective of this study was to identify the influence of packaging film and lean trimming sources on fresh ground beef surface color during a simulated retail display period. There were no differences (p > 0.05) in surface color redness (a*), yellowness (b*), chroma, or hue angle regardless of packaging film or lean trimmings. However, thiobarbituric acid reactive substances (TBARS) were greater (p < 0.05) for packages containing a greater percentage of CULL beef trimmings regardless of packaging film. In addition, pH values of ground beef packages did not differ (p > 0.05) among packaging film or lean trimming blends. Visual color did not differ (p > 0.05) throughout the simulated retail display period regardless of beef trimmings or packaging film. Microbial spoilage organisms were greater (p < 0.05) after the simulated display period. These results suggest that ground beef presented in a simulated retail setting using an alternative packaging platform, such as vacuum packaging, is plausible.

Impact of COVID-19 on ventricular tachycardia and atrial tachycardia events in patients with transvenous devices

Background: Covid-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has resulted in a significant number of increased hospitalizations and excess deaths worldwide. Though reports regarding myocardial injury/inflammation relating to Covid-19 are known, little is known about larger scale effects of the virus on cardiac arrhythmias. Additionally, it is known that autonomics play a large role in the incidence of cardiac arrhythmias, and the temporal relationship of the national lockdown on cardiac arrhythmias has not well characterized. We aimed to assess the temporal trends of cardiac arrhythmias seen in the Barts device clinic and compare it to the previous year. Hypothesizing that there had been a decrease in the burden of Ventricular Tachycardia (VT). Methods: We exported all arrhythmia events that have been transmitted to the Latitude remote monitoring platform (Boston Scientific) retrospectively between January 2020 to May 2020 and January 2019 to May 2019. We will compare trends against the previous year to exclude any seasonal variation. Results: From the cohort of 2,110 patients on latitude remote monitoring, this produced 28,005 arrhythmia episodes in the study period. From January to 21 May 2019 there were 7,940 Ventricular events (Mean 56/day;SD ± 20) vs 7,017 events (Mean 49/day;SD ± 19) in the same time period in 2020. Figure 1A shows a lowess regression curve of ventricular events in 2019 vs 2020 with confidence intervals. It can be seen that events are largely similar until after lockdown when there are fewer ventricular events, Annova with Turkey post hoc correction (p=0.01, mean difference 19 events per day). From January to 21 May 2019 there were 6,380 atrial events (Mean 45/day;SD ± 13) compared with 6,690 events during the same time period in 2020 (Mean 49/day;SD ± 16). Figure 1B shows a lowess regression curve of atrial events in 2019 vs 2020 with confidence intervals. It can be seen that events are largely similar until lockdown there is an increase on atrial events, Anova with Tukey post hoc correction (p=0.02, mean difference 12 events per day). Conclusion: These data suggest that ventricular events were largely similar pre-lockdown but decreased during the lockdown, while atrial events increased during the period of the lockdown before normalizing. This suggests that autonomic and psychological impacts of lockdown had an important effect on the frequency of atrial and ventricular events that presented to our joint VT clinic, and underlines the important role of the autonomic nervous system in arrhythmia. [Image Omitted]

Clinical COVID19 data collection from the UK multiple sclerosis register

Background: The UK MS Register captures longitudinal data directly from people with MS (pwMS) as patient reported outcome measures but also from NHS Trusts via electronic Case Return Form (eCRF). As part of our response to the COVID19 pandemic we designed an anonymised clinical capture instrument to allow clinicians from non affiliated NHS hospitals capture important clinical data on incident cases. Here we outline our current clinicians reported findings from these collected data. Objectives: Report on patients with Multiple Sclerosis and COVID as reported by UK National Health Service MS clinicians to the UK MS Register Methods: Data were captured using the RedCap platform to design forms and were stored on secured databases at Swansea University Medical School. The URL for data capture was shared on social media and via clinician groups to encourage as many clinicians as possible to report hospitalised pwMS and confirmed COVID. Variables included: Age, Gender, MS Type, Expanded Disability Status Score (EDSS), Disease Modifying Therapy (DMT) Details, COVID clinical treatment and outcomes. Results: Between 27/03/2020 and 14/07/2020, 93 patients with COVID were reported. Their mean Age was 53.38 (±14.2) and median EDSS 6.0. Of these 11 patients died with mean Age 63.7(±10.9). Median EDSS 8.0. Multivariate regression showed increased EDSS score to be the most significant factor for mortality (P <0.01) with the other variables (age, gender, disease type, DMT,) not influencing mortality. All the patients that died had progressive MS and only one was on a DMT. Conclusions: Here we present the UK PwMS, with laboratory confirmed COVID19 as reported by hospital clinicians. We found increased disability rather than age or MS type to be the only predictor of mortality. These results are strikingly different from the patients reported UK MS register COVID study (separate abstract) that had a much milder COVID illness that led to hospitalisation in only 3% of the cases.

Complementary reporting by patients and clinicians offers a more thorough picture of the impact of COVID-19 on people with multiple sclerosis

Introduction: The Coronavirus disease 2019 (COVID-19) pandemic has created uncertainties about different aspects of the lives of people with multiple sclerosis (PwMS). We intend to understand the impact of the virus and the risks of the infection in PwMS. Methods: The study was launched on 17 March 2020 as part of the United Kingdom (UK) MS Register (UKMSR), a research project with 13,916 PwMS registered as of 22 April 2020 which holds longitudinal data about patients' demographics, MS related and other medical information, and patient-reported outcome measures since 2011. All patients on the UKMSR were asked to participate in the study by completing COVID-19 related questionnaires fortnightly. Telephone interviews by a neurologist confirmed the suspected diagnosis of COVID-19 based on symptoms. We also asked healthcare professionals to provide anonymised data on MS patients with COVID-19 using a separate questionnaire. Results: As of 22 April 2020, 3,702 PwMS participated in the study and recruitment is on-going. A total of 196 (5.29%) participants reported that they had suspected COVID-19 out of which 41 (20.92%) reported having been diagnosed by a healthcare professional. Only three (1.53%) of the patients with suspected COVID-19 required hospitalisation. On the contrary, out of the 26 suspected COVID-19 cases reported by clinicians, 21 have positive polymerase chain reaction tests and 3 have died. Conclusion: These contrasting results emphasise the need to supplement clinician-reported outcomes with community- based studies to understand the true impact of COVID-19 in PwMS.