VOLUME VERSUS PRESSURE TARGETED NON-INVASIVE VENTILATION IN AMYOTROPHIC LATERAL SCLEROSIS (VOP ALS): study protocol for a randomised controlled trial (preprint)

Introduction Amyotrophic lateral sclerosis (ALS) is a rare, idiopathic, progressive, neuromuscular disease. The prevalence in England and Wales is between 4 and 5 cases per 100,000. A significant proportion of ALS cases are complicated by respiratory and sleep impairment which can reduce health related quality of life (HRQOL) and survival. Non-invasive ventilation (NIV) is the standard of care to treat respiratory and sleep symptoms. Patients who are compliant with NIV have improved survival, HRQOL and reduced symptoms. Different modes of NIV are available and broadly fall into two categories: pressure support ventilation (PSV) and volume assured pressure support (VAPS) ventilation. A clinically enhanced version of VAPS in the form of intelligent volume assured pressure support with automatic EPAP (iVAPS-AE) is now widely available and although spontaneous timed (ST) mode is the preferred choice in ALS, to date no one mode has been shown to be superior. In this single-centre randomised controlled trial we will explore the differences in NIV compliance and effect on HRQOL, between ST and iVAPS-AE NIV modes in patients diagnosed with respiratory failure due to ALS. We also want to explore the optimal NIV mode for patients diagnosed with ALS. This trial is still in the data collection phase and has the potential to guide changes in clinical respiratory practice in ALS. Methods and Analysis VOP ALS is a single blinded, single centre, RCT exploring the impact of iVAPS-AE on patient outcomes compared to ST-mode in patients diagnosed with ALS related respiratory impairment. Primary outcome is mean NIV compliance and secondary outcome is health reported quality of life, both measured over 90 days. The study aimed to recruit 40 patients, but it was revised to 15 because of the COVID-19 pandemic. The analysis will be mainly descriptive by treatment arms and summarised with 95% confidence interval. Ethics and Dissemination VOP ALS is sponsored in the UK by University Hospitals Coventry and Warwickshire NHS Trust and has been granted ethical approval by Northwest - Haydock Research Ethics Committee Ethics Committee (REC ref: 21/NW/0326). Publication of results in a peer-reviewed journal and conference presentations are expected. Trial Registration Number: NCT05328492. Registered 4th April 2022 - Retrospectively registered, https://clinicaltrials.gov/study/NCT05328492

BRIEF COMMUNICATION High level of Anti SARS-Co-V2 RBD Antibody one year post booster vaccine hospital workers in Indonesia; Was second booster needed? (preprint)

Healthcare workers in Indonesia acquired a complete 2 doses of Sinovac in early 2021 and first booster dose of Moderna in July 2021. In August 2022, the ministry of health prioritized healthcare workers to acquire the second booster dose of Moderna as antibody levels from the year before may have waned. We conducted a sequential serosurvey aimed to determine the level of SARS CoV2 S-RBD antibody reached by the first vaccine, after the first booster, and before the second booster to understand the dynamics of the antibody level. COVID-19 antibody test was conducted using the FastBioRBDtm test with a maximum limit detection level of 4000 BAU/mL. First serosurvey which was conducted in June 2021, one to six months after Sinovac vaccination, showed a median antibody level of 41.4 BAU/mL (IQR 10 - 629.4 BAU/mL). The second serosurvey was conducted one month (August 2021) after the first Moderna booster vaccine, and showed a median level of 4000 BAU/mL (IQR 3081 - 4000 BAU/mL). While the last serosurvey conducted a year (August 2022) after the booster, showed 4000 BAU/mL (IQR 4000 - 4000 BAU/mL). Only 39 (11.9%) healthcare workers have antibody levels below the maximum level of 4000 BAU./mL We did not see the waning of antibody levels among healthcare workers approximately 1 year after the booster. It increases perhaps due to the natural infection caused by the omicron variant outbreak in early 2022. Based on this fact, we suggest considering if the second booster dose is really necessary. The limited vaccine supply can better be given to the person or other high-risk groups of patients who has a low level of antibody based on serological testing.

Impact of Covid-19 Pandemic on the Effectiveness of Outpatient Counseling in Childhood Obesity Management.

The Covid-19 pandemic drastically modified social life and lifestyle, in particular, among children and adolescents, promoting sedentary behaviors and unhealthy eating habits. The aims of this study were to assess the rate and the factors associated with outpatient drop-out in childhood obesity management, and to evaluate how the Covid-19 pandemic influenced weight status and lifestyle of children and adolescents with obesity. One hundred and forty-five children and adolescents with obesity were identified, including 80 subjects evaluated before the Covid-19 pandemic (group A) and 65 subjects in the period straddling the Covid-19 pandemic (group B). Anamnestic (family history of obesity, dietary habits, physical activity, screen time), socio-cultural (economic status, employment and schooling of parents, household composition, place of living) and clinical (weight, height, BMI, waist circumference) data were retrospectively analyzed for each subject in both groups at baseline (V0) and 12-months (V1) at in-person assessment. Glycemic and lipid profiles were assessed at V0. Drop-out rate did not differ significantly between the two groups. BMI SDS at V0 (OR=2.52; p=0.004), female sex (OR=0.41; p=0.035), and the presence of a single parent in the household (OR=5.74; p=0.033) significantly influenced drop-out in both groups. Weight loss between V0 and V1 was significantly greater among group A patients compared to group B (p=0.031). In group B, hours spent in physical activity significantly decreased from V0 to V1, being significantly lower than group A at V1; on the contrary, screen time significantly increased in the same period. The consumption of sugary drinks and snacks was significantly greater in group B than group A at V1. Our study documented that the Covid-19 pandemic, although not affecting the drop-out rate of obese children in a follow-up program, negatively influenced lifestyle and reduced the effectiveness of outpatient counseling in childhood obesity treatment.

Deep Journalism and DeepJournal V1.0: A Data-Driven Deep Learning Approach to Discover Parameters for Transportation (As A Case Study) (preprint)

We live in a complex world characterised by complex people, complex times, and complex social, technological, and ecological environments. There is clear evidence that governments are failing at most public matters. The recent COVID-19 pandemic is a high example of global governance failure both at preventing such pandemics and managing the COVID-19 pandemic. It is time that all of us take responsibility and look into ways of collaboratively improving the governance of public matters, our matters. While there are many reasons for government failures, we believe the lack of information availability is a fundamental reason that limits the government’s ability to act smartly and allows the lack of transparency to creep into policy and action leading to corruption and failure. To this end, this paper introduces the concept of deep journalism, a data-driven deep learning-based approach for discovering multi-perspective parameters related to a topic of interest. We build three datasets (a newspaper, a technology magazine, and a Web of Science dataset) and discover the academic, industrial, public, governance, and political parameters for the transportation sector as a case study to introduce deep journalism and our tool DeepJournal (Version 1.0) that implements our proposed approach. We elaborate on 89 transportation parameters and hundreds of dimensions reviewing 400 technical, academic, and news articles. The findings related to the multi-perspective view of transportation reported in this paper show that there are many important problems seen by the public that industry and academia seem to not place their focus on. On the other hand, academia produces much broader and deeper knowledge on the subject such as a wide range of pollutions affecting the people and planet do not get to reach the public eye. Our deep journalism approach could find the gaps and highlight them to the public and other stakeholders.

Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19 (preprint)

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

SARS-CoV-2 501Y.V2 (B.1.351) elicits cross-reactive neutralizing antibodies (preprint)

Neutralization escape by SARS-CoV-2 variants, as has been observed in the 501Y.V2 (B.1.351) variant, has impacted the efficacy of first generation COVID-19 vaccines. Here, the antibody response to the 501Y.V2 variant was examined in a cohort of patients hospitalized with COVID-19 in early 2021 - when over 90% of infections in South Africa were attributed to 501Y.V2. Robust binding and neutralizing antibody titers to the 501Y.V2 variant were detected and these binding antibodies showed high levels of cross-reactivity for the original variant, from the first wave. In contrast to an earlier study where sera from individuals infected with the original variant showed dramatically reduced potency against 501Y.V2, sera from 501Y.V2-infected patients maintained good cross-reactivity against viruses from the first wave. Furthermore, sera from 501Y.V2-infected patients also neutralized the 501Y.V3 (P.1) variant first described in Brazil, and now circulating globally. Collectively these data suggest that the antibody response in patients infected with 501Y.V2 has a broad specificity and that vaccines designed with the 501Y.V2 sequence may elicit more cross-reactive responses.

A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity (preprint)

Chloroquine and hydroxychloroquine (H)CQ are well known anti-malarial drugs, while their use against COVID-19 is more controversial. (H)CQ activity was examined in tissue culture cells to determine if their anti-viral benefits or adverse effects might be due to altering host cell pathways. Metabolic analysis revealed (H)CQ inhibit oxidative phosphorylation in mitochondria, likely by sequestering protons needed to drive ATP synthase. This activity could cause cardiotoxicity because heart muscle relies on beta oxidation of fatty acids. However, it might also explain their therapeutic benefit against COVID-19. A new model of SARS-CoV-2 infection postulates virus enters host cell mitochondria and uses its protons for genome release. Oxidative phosphorylation is eventually compromised, so glycolysis is upregulated to maintain ATP levels. (H)CQ could prevent viral infection and/or slow its replication by sequestering these protons. In support of this model other potential COVID-19 therapeutics also targeted mitochondria, as did tobacco smoke, which may underlie smokers protection. The mitochondria of young people are naturally more adaptable and resilient, providing a rationale for their resistance to disease progression. Conversely, obesity and diabetes could exacerbate disease severity by providing extra glucose to infected cells dependent on glycolysis. The description of (H)CQ function presented here, together with its implications for understanding SARS-CO-V2 infection, makes testable predictions about disease progression and identifies new approaches for treating COVID-19.

No evidence for allelic association between Covid-19 and ACE2 genetic variants by direct exome sequencing in 99 SARS-CoV-2 positive patients (preprint)

Background: Coronaviruses (CoV) are a large family of viruses that are common in people and many animal species. Animal coronaviruses rarely infect humans with the exceptions of the Middle East Respiratory Syndrome (MERS-CoV), the Severe acute respiratory syndrome coronavirus (SARS-CoV), and now SARS-CoV-2, which is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19). Many studies suggested that genetic variants in ACE2 gene may influence the host susceptibility/resistance to SARS-CoV-2 virus according to the functional role of ACE2 in human pathophysiology. However, all these studies have been conducted in silico based on epidemiological and population data. We therefore investigated the occurrence of ACE2 variants in a cohort of 99 Italian unrelated individuals clinically diagnosed with coronavirus disease 19 (COVID-19) to experimental demonstrate allelic association with disease severity. Methods: By whole-exome sequencing we analysed 99 DNA samples of severely and extremely severely COVID-19 patients hospitalized at the University Hospital of Rome Tor Vergata and Bambino Gesu Hospital in Rome. Results: We identified three different germline variants, one intronic (c.439+4G>A) and two missense (c.2158A>G, p.Asn720Asp; c.1888G>C, p.Asp630His ), in 26 patients with a similar frequency between male and female and a not statistically different frequency, except for c.1888G>C, (p.Asp630His) with the ethnically matched populations (EUR). Conclusions: Our results suggest that there is not any ACE2 exonic allelic association with disease severity. It is possible that rare susceptibility alleles are located in the non-coding region of the gene able to control ACE2 gene activity. It is therefore of interest, to explore the existence of ACE2 susceptibility alleles to SARS-Co-V2 in these regulatory regions. In addition, we found no significant evidence that ACE2 alleles is associated with disease severity/sex bias in the Italian population.