Impact of a six-month COVID-19 travel moratorium on Plasmodium falciparum malaria prevalence on Bioko Island, Equatorial Guinea (preprint)

Importation of malaria infections has long been suspected as a driver of sustained malaria prevalence on areas of Bioko Island, Equatorial Guinea. However, quantifying the impact of imported infections is difficult because of the dynamic nature of the disease and the complexity of designing a randomized trial. Here, we leverage a six-month travel moratorium in and out of Bioko Island during the initial COVID-19 pandemic response to evaluate the contribution of imported infections to Pf prevalence on Bioko Island. Using a difference in differences design and data from island wide household surveys conducted before (2019) and after (2020) the travel moratorium, we compared the change in prevalence between areas of low historical travel to those with high historical travel. We found that prevalence increased in low travel areas after the moratorium compared to before, while prevalence decreased in high travel areas. In the absence of a travel moratorium, the prevalence of infection in high travel areas was expected to be 5% higher than what was observed. The observed decrease in prevalence can be directly attributed to the lack of imported cases, highlighting the importance of control measures that target these types of infections.

The Seasonality of Respiratory Syncytial Virus in Western Australia Prior to Implementation of SARS-CoV-2 Non-Pharmaceutical Interventions (preprint)

Background: Respiratory syncytial virus (RSV) seasonality is dependent on the local climate. We assessed the stability of RSV seasonality prior to the SARS-CoV-2 pandemic in Western Australia (WA), a state spanning temperate and tropical regions. Method RSV laboratory testing data were collected from January 2012 to December 2019. WA was divided into three regions determined by population density and climate; Metropolitan, Northern and Southern. Season threshold was calculated per region at 1.2% annual cases, with onset the first of ≥2 weeks above this threshold and offset as the last week before ≥2 weeks below. Results The incidence of RSV in WA was 6.3/10,000. The Northern region had the highest incidence (15/10,000), more than 2.5 times the Metropolitan region (IRR 2.7; 95% CI, 2.6-2.9). Test percentage positive was similar in the Metropolitan (8.6%) and Southern (8.7%) regions, with the lowest in the Northern region (8.1%). RSV seasons in the Metropolitan and Southern regions occurred annually, with a single peak and had consistent timing and intensity. The Northern tropical region did not experience a distinct season. Proportion of RSV A to RSV B in the Northern region differed from the Metropolitan region in 5 of the 8 years studied. Conclusions Incidence of RSV in WA is high, especially in the Northern region, where climate, an expanded at-risk population, and increased testing may have contributed to greater numbers. Before the SARS-CoV-2 pandemic, RSV seasonality WA was consistent in timing and intensity for the Metropolitan and Southern regions.

Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for Hepatitis C: a single arm mechanistic pilot study (preprint)

ABSTRACT Background WHO has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct acting antiviral (DAA) therapy for Hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4 or 8 weeks treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on day 0 and 28. Results Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and one withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance associated substitutions (RAS), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS or DCV levels. SOF metabolite levels were higher in those failing 4-week therapy. Conclusions Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4 weeks treatment. Funding Funded by the Medical Research Council (grant MR/P025064/1) and The Global Challenges Research Fund (Wellcome Trust Grant 206/296/Z/17/Z).) Clinical trial number ISRCTN17100273

Robust expansion of phylogeny for fast-growing genome sequence data (preprint)

Massive sequencing of SARS-CoV-2 genomes has led to a great demand for adding new samples to a reference phylogeny instead of building the tree from scratch. To address such challenge, we proposed an algorithm ‘TIPars’ by integrating parsimony analysis with pre-computed ancestral sequences. Compared to four state-of-the-art methods on four benchmark datasets (SARS-CoV-2, Influenza virus, Newcastle disease virus and 16S rRNA genes), TIPars achieved the best performance in most tests. It took only 21 seconds to insert 100 SARS-CoV-2 genomes to a 100k-taxa reference tree using near 1.4 gigabytes of memory. Its efficient and accurate phylogenetic placements and incrementation for phylogenies with highly similar and divergent sequences suggest that it will be useful in a wide range of studies including pathogen molecular epidemiology, microbiome diversity and systematics.

Filtration efficiency and differential pressure of fabrics used in non-medical masks based on SARS COVID-19 particle size

Non-medical fabric masks, recommended by the Centers for Disease Control and Prevention and the World Health Organization, are available in various fabrics. There is limited research on the overall effectiveness of fabrics used to make masks. The purpose of this study was to assess fabrics commonly used in non-medical masks against their ability to mitigate the spread of COVID-19 based on the size and throughput of aerosols and particles (<1??m). Seven different fabrics were evaluated on filtration efficiency (FE), differential pressure (dP), and filtration quality (Q factor). Results indicate <16% FE against particles the size of COVID-19, dP <0.51 in w.c., and Q factor <0.004?Pa?1. FE results are lower than previously reported research with dP and Q factors within international guidelines. Using non-medical fabric masks as the sole mitigation strategy is not effective. It is critical to combine non-medical fabric masks with physical distancing to slow the spread of COVID-19 further.

A whole health care system review of the effects from changes to pre-hospital emergency care pathways during the COVID-19 pandemic

BackgroundThe United Kingdom COVID-19 pandemic response included large scale changes to emergency healthcare delivery across primary care, secondary care and ambulance services without fully understanding potential unintended effects. Our aim was to ascertain themes within the emergency response that could be modified to mitigate against future excess deaths.MethodsA structured judgement review of the entire care pathway (primary care, secondary care, 111 and 999 calls) for deaths registered in Salford during weeks 12-19 of 2020, creating a single integrated record of all Healthcare interactions and outcomes between 1stMarch 2020 and death for all patients. An expert panel judged avoidability of death against the National Mortality Case Record Review Programme scale, and themes associated with potential harm.Results522 deaths (197 hospital, 190 care homes): 51% female, 81% Caucasian, 35% dementia, age 79±9 years, 44% COVID-19 cause of death.18% of deaths contained avoidability themes. In people aged ≥75 years who lived at home this was 53%, in care home residents 29%, in learning disability patients 44%. For COVID-19 and non-COVID-19 deaths the figures were 49% and 23%. 15 deaths were judged more than 50:50 avoidable. For higher avoidability (score 2 or 3), 44% had >2 themes.Common themes were delays in patients presenting to care providers (10%, n=53), delays in testing (27%, 139), avoidable exposure to COVID-19 (29%, 149), delays in provider response (6%, 32), and sub-optimal care (34%, 177).Pre-hospital healthcare contact frequently was primary care 81%, 999 56%, NHS 111 11%. The most common outcome of 111 calls was advice to contact GP (34%). 46 patients (9%) had healthcare appointments cancelled (median 1 cancellation, range 1-9).ConclusionsThe initial emergency response to COVID-19 was associated with late presentation, sub-optimal assessments, and delays in receiving care. The effects had multifaceted impacts and will require complex remedy.

Peptide Scanning of SARS-CoV and SARS-CoV-2 Spike Protein Subunit 1 Reveals Potential Additional Receptor Binding Sites (preprint)

The binding of SARS-CoV and SARS-CoV-2 to the ACE2 receptor on human cells is mediated by the spike protein subunit 1 (S1) on the virus surfaces, while the receptor binding domains (RBDs) of S1 are the major determinants for the interaction with ACE2 and dominant targets of neutralizing antibodies. However, at the virus-host interface, additional biomolecular interactions, although being relatively weak in affinity and low in specificity, could also contribute to viral attachment and play important roles in gain- or loss-of-function mutations. In this work, we performed a peptide scanning of the S1 domains of SARS-CoV and SARS-CoV-2 by synthesizing 972 16-mer native and mutated peptide fragments using a high throughput in situ array synthesis technology. By probing the array using fluorescently labelled ACE2, a number of previously unknown potential receptor binding sites of S1 have been revealed. 20 peptides were synthesized using solid phase peptide synthesis, in order to validate and quantify their binding to ACE2. Four ACE2-binding peptides were selected, to investigate whether they can be assembled through a biotinylated peptide/neutravidin system to achieve high affinity to ACE2. A number of constructs exhibited high affinity to ACE2 with Kd values of pM to low nM.

Direct comparison of venipuncture serum draws versus whole blood finger-stick specimens by anti-COVID-19 IgG/IgM rapid lateral flow immunoassay and ELISA (preprint)

During the COVID-19 pandemic, manufacturers have developed several diagnostic test kits that include lateral flow immunoassays (LFIA) also known as rapid cassette testing. Rapid cassette testing provides qualitative test results indicating the presence or absence of IgG and IgM antibodies to determine COVID-19 (SARS-CoV-2) infection among individuals. Venipuncture blood draws have been the traditional and widely proposed sample collection method but is costly and not applicable to point-of-care testing (POC) and in remote settings. Whole blood finger-stick blood collections traditionally used by diabetics for glucose level testing is an ideal scenario, but raises concerns regarding the outcome of test results in regards to specificity and sensitivity. In this study we directly compare simultaneous collections of venipuncture serum (SST) blood draws and whole blood finger-sticks (n = 75) to detect human Anti-COVID-19 IgG and IgM antibodies using an EUA-approved lateral flow immunoassay, showing equal to enhanced performance characteristics for this specimen type.

Genomics-Informed Responses in the Elimination of COVID-19 in Australia (preprint)

BACKGROUND: A cornerstone of Australia’s ability to control COVID-19 has been effective border control, using an extensive supervised quarantine program. However, a rapid recrudescence in COVID-19 cases was observed in the state of Victoria in June 2020. Here, we describe the genomic findings that located the source of this second wave as a breach in supervised hotel quarantine and demonstrate the successful elimination of COVID-19 for a second time in Australia.METHODS: Genome sequencing was performed on all available SARS-CoV-2-positive samples in Victoria and integrated genomic and epidemiological investigation undertaken.RESULTS: At 31st January 2021, 20,451 COVID-19 cases were reported in Victoria; samples were sequenced from 75% of cases (15,431/20,451). Genomics revealed 98% (10,426/10,646) of locally-acquired cases during the second wave were derived from a single incursion from hotel quarantine, with the outbreak strain rapidly detected in other Australian states and territories. Phylodynamic analyses indicated an epidemic growth rate comparable to emerging variants, such as B.1.1.7 in the United Kingdom. Strict public health interventions resulted in the elimination of the outbreak strain by 29th October 2020. Subsequent cases represented independent international or interstate introductions, with limited local spread.CONCLUSIONS: Rapid escalation of clonal outbreaks can occur from even a single breach of control practices, as revealed through our genomic ‘enhanced outbreak-detection' system. The subsequent elimination and rapid control of new SARS-CoV-2 incursions reinforce that decisive public health responses to emergent cases are effective even with high epidemic growth rates, and “elimination” should be favored in settings where this is achievable.FUNDING STATEMENT: The Microbiological Diagnostic Unit Public Health Laboratory (MDU PHL) and the Victorian Infectious Diseases Reference Laboratory (VIDRL) at The Doherty Institute are funded by the Victorian Government. This work was supported by the National Health and Medical Research Council, Australia (NHMRC); Partnership Grant (APP1149991), Investigator Grant to BPH (APP1196103), Investigator Grant to DAW (APP1174555), Research Fellowship to TPS (APP1105525), MRFF COVID-19 Genomics Grant (MRF9200006).DECLARATION OF INTERESTS: None to declare. ETHICS APPROVAL STATEMENT: Data were collected in accordance with the Victorian Public Health and Wellbeing Act 2008. Ethical approval was received from the University of Melbourne Human Research Ethics Committee (study number 1954615.3).

Determining the Role of Natural SARS-CoV-2 Infection in the Death of Ten Domestic Pets (preprint)

Transmission of SARS-CoV-2, the virus that causes COVID-19, from people to companion animals has been reported globally. Between March 2020 and January 2021, the United States reported 94 companion animals with SARS-CoV-2. While most animals with SARS-CoV-2 have mild illness, 10 animals (5 dogs, 5 cats) died around the time of SARS-CoV-2 diagnosis. In one dog, histopathologic changes suggest SARS-CoV-2 exacerbated a severe chronic respiratory disease and contributed to death. In one cat, SARS-CoV-2 was associated with histopathologic changes suggesting the virus caused clinical signs that resulted in euthanasia. In the remaining eight animals, SARS-CoV-2 infection was an incidental finding (4 dogs, 4 cats). This report provides evidence that in rare circumstances, SARS-CoV-2 can contribute to or cause death in companion animals with underlying conditions. 

Vitamin C—An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19 (preprint)

There are limited proven therapies for the treatment of COVID-19. Vitamin C’s antioxidant, anti-inflammatory and immunomodulating effects, make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19, supporting anti-inflammatory treatment. This literature review focuses on vitamin C deficiency in respiratory infections including COVID-19; the mechanism of action in infectious disease and adrenal function supporting the anti-inflammatory actions of glucocorticosteroids: its role in preventing and treating colds and pneumonia and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8g/d) may reduce incidence and duration of respiratory infections and intravenous vitamin C (2-24g/d) has been shown to reduce mortality, Intensive Care Unit and hospital stays, time on mechanical ventilation in severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and frequency of vitamin C deficiency in respiratory infections it may be worthwhile testing patients’ vitamin C status and treating accordingly with intravenous use within ICUs and orally with doses between 2 and 8g/day in hospitalised and infected persons.

Vitamin C—An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19 (preprint)

There are limited proven therapies for the treatment of COVID-19. Vitamin C’s antioxidant, anti-inflammatory and immunomodulating effects, make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19, supporting anti-inflammatory treatment. This literature review focuses on vitamin C deficiency in respiratory infections including COVID-19; the mechanism of action in infectious disease and adrenal function supporting the anti-inflammatory actions of glucocorticosteroids: its role in preventing and treating colds and pneumonia and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8g/d) may reduce incidence and duration of respiratory infections and intravenous vitamin C (2-24g/d) has been shown to reduce mortality, Intensive Care Unit and hospital stays, time on mechanical ventilation in severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and frequency of vitamin C deficiency in respiratory infections it may be worthwhile testing patients’ vitamin C status and treating accordingly with intravenous use within ICUs and orally with doses between 2 and 8g/day in hospitalised and infected persons.

Corporate Capital Raising During the COVID Crisis (preprint)

In the midst of the COVID-19 pandemic that led to a record slowdown in economic activity, financial capital raising by U.S. public companies surged to record levels. Using company-level data through the second quarter of 2020, we show that capital raising has been particularly strong among firms most affected by the pandemic, confirming that much of the new issuance reflects demand for capital to replace cash flows lost to the economic disruption from the pandemic. Although debt overhang, information asymmetries, or other frictions have the potential to limit the supply of such liquidity, we find no evidence that firms traditionally viewed as financially constrained have raised less capital than other firms. During the first half of 2020, the full range of public companies –from the smallest, youngest, and riskiest to the largest, oldest, and safest– have been able to raise financing at similar levels, suggesting no constraints on the supply of capital during the pandemic. While companies issue record amounts of bonds during this period, it is equity, at the margin, that finances the negative shocks to cash flow and large cash infusions into the smaller and riskier companies in the sample.

Modelling oral adrenal cortisol support (preprint)

A simplified mathematical model of oral hydrocortisone delivery in adrenal insufficiency is described; the model is based on three components (gastric hydrocortisone, free serum cortisol and bound serum cortisol) and is formulated in terms of linear kinetics, taking into account the dynamics of glucocorticoid–protein binding. Motivated by the need to optimise cortisol replacement in the situations of COVID-19 infection, the model is fitted to recently-published data on 50 mg dosing and earlier data on 10 mg dosing. The fitted model is used to predict typical responses to standard dosing regimes, which involve a larger dose in the morning and 1 or 2 smaller doses later in the day, and the same regimes with doses doubled. In all cases there is a circadian-like response, with early morning nadir. The model is also used to consider an alternative dosing strategy based on four equal and equally-spaced doses of 10, 20 or 30 mg per 24 h, resulting in a more even response resembling a response to sustained inflammatory stress.

A University Based Social Services Parent Training Model: A Telehealth Adaptation During the COVID-19 Pandemic (preprint)

With the COVID-19 pandemic resulting in social distancing recommendations many service providers find themselves altering the way they must provide medically necessary therapy. Even with the advent of more advanced telehealth technology, implementation of behavioral programming falls mainly on the caregivers of the clients that are served. This crisis brings to question ethical dilemmas and upends the current ways many programs may have been implemented across the world. As a result, a re-evaluation of how these services are delivered is in order. This paper reviews how a University-Based, State-funded Service Delivery Program (USSDP) provided essential and necessary services during the COVID-19 pandemic. Specifically, the purpose of this paper is to describe how the USSDP quickly adopted a telehealth care model in a program that previously had not delivered services in this modality. Ethical, contextual, and competency-based factors are reviewed in the context of this organization followed by a dialogue on broader generalization suggestions utilizing an active support model of care within telehealth restrictions.