Correlation between vitamin D and anosmia in post acute Covid syndrome clinic

Introduction: Anosmia has emerged as a clinical feature of Covid-19. It is estimated over half of patients with Covid19 report anosmia. It is primarily transient, but can persist over a month in around 20% of cases. There is a hypothetical interaction between hypovitaminosis D and diminished smell. A deficiency may lead to neurologic decline in cranial nerves, including the olfactory nerve. Few studies investigating this are available. Loss of smell is a common occurrence through adulthood, with many physiologic and anatomic contributing factors. Limited data is available addressing anosmia post Covid-19. Aim(s): To assess the correlation between vitamin D (VD) and anosmia, in patients referred to post acute COVID syndrome (PACS) clinic, and to assess the variation of data across age groups. Method(s): A "Sniffin' Sticks" test was undertaken for all patients referred to the PACS clinic. This was correlated with a recent serum VD level. Result(s): 143 patients presented to the PACS clinic over a 10 month period. 84% were under 65 years. 60% of these patients who developed anosmia were found to have VD insufficiency. A similar proportion of patients with hyposmia, and patients with normal smell were found to be VD insufficient (36% vs 34.7%). Within the older cohort, none of the patients with anosmia were deficient in VD, and 7.7% of patients with smell dysfunction had insufficiency. Conclusion(s): There is an association between anosmia and VD deficiency in patients under 65 years of age seen at PACS clinic. This did not reflect in the cohort with hyposmia. In the older age group, the majority of patients had normal VD levels, which may indicate other contributing factors towards the decrease in smell.

Swiss public health measures associated with reduced SARS-CoV-2 transmission using genome data.

Genome sequences from evolving infectious pathogens allow quantification of case introductions and local transmission dynamics. We sequenced 11,357 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from Switzerland in 2020 - the sixth largest effort globally. Using a representative subset of these data, we estimated viral introductions to Switzerland and their persistence over the course of 2020. We contrasted these estimates with simple null models representing the absence of certain public health measures. We show that Switzerland's border closures de-coupled case introductions from incidence in neighboring countries. Under a simple model, we estimate an 86-98% reduction in introductions during Switzerland's strictest border closures. Furthermore, the Swiss 2020 partial lockdown roughly halved the time for sampled introductions to die out. Last, we quantified local transmission dynamics once introductions into Switzerland occurred, using a phylodynamic model. We found that transmission slowed 35-63% upon outbreak detection in summer 2020, but not in fall. This finding may indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics.

Impact of Covid-19 on the management of patients with metastatic melanoma.

The Covid-19 pandemic created new uncertainties in the management of metastatic melanoma patients. In particular, the impact of immunotherapy, targeted therapy, or chemotherapy on the risk of Sars-CoV-2 infection and severity was debated. In this study, we analyzed all patients with metastatic melanoma receiving therapy who developed Covid-19 between February 2020 and February 2022. We retrospectively collected demographic data, cancer-specific parameters, melanoma treatment regimen, comorbidities and Covid-19-specific parameters in these patients. Of the 350 patients with metastatic melanoma, 25 had Covid-19. The median age at the time of Covid-19 diagnosis was 66 years (range 36-86), 10 patients were female, and 15 patients were male. The treatment regimen during infection was immunotherapy in 12 cases, followed by targeted therapy (n = 8), chemotherapy (n = 2), and TVEC injections, follow-up and palliative therapy in 1 case each. The severity was mild in 17 patients and 8 had a moderate to critical course. Patients with a severe Covid-19 course were often older and had more comorbidities than patients with a mild infection. Many of the patients had a mild Covid-19 course despite having metastatic melanoma and systemic therapy. We therefore recommend continuing systemic therapy whenever possible, even in such exceptional situations as the Covid-19 pandemic.

Effect of the COVID-19 pandemic on treatment metrics for large vessel occlusion stroke at Box Hill Hospital

Background: The COVID-19 pandemic has disrupted modern healthcare and delayed time to acute stroke treatment at some centres internationally. The effect of the pandemic on time metrics in patients with a large vessel occlusion (LVO) at Australian stroke centres is unknown. Aim(s): To evaluate time metrics for patients with an LVO transferred from a primary stroke centre (PSC) to a comprehensive stroke centre (CSC), during and before the coronavirus pandemic. Method(s): Retrospective analysis of consecutive patients with an LVO who were transferred from a single PSC to any of three CSCs were enrolled. The pandemic period was defined as the 24 months following the March 2020 state of emergency declaration in Melbourne, and prepandemic period the preceding 24 months. "Door-in" was the time triaged as a stroke, and "Door-out" was the time ambulance staff departed. Result(s): 159 patients were included, 82 in the pandemic group and 77 in the pre-pandemic group. There were no significant differences between groups in patient age, sex, modified Rankin scale score, or National Institute of Health Stroke Scale score. Door-in to Door-out (DIDO) times were reduced during the pandemic (median 52 vs 66 minutes, IQR 41-66 vs 52-95 minutes, p<0.001). There was no change in time from PSC Door-in to the first CSC DSA images (median 125 vs 125 minutes, p=0.79). Within the DIDO workflow, the only significantly different metric was time from CSC advising of patient acceptance to PSC door-out, which improved (median 8 vs 14 minutes, p=0.016). DIDO times out of hours when the stroke registrar was called in also improved (median 51 vs 87 minutes, p=0.003). Conclusion(s): The median DIDO times at our PSC improved during the pandemic. Further studies are required to determine if this is due to a continued quality improvement program at our centre, or due to other factors.

Scottish COVID CAncer iMmunity Prevalence (SCCAMP): A longitudinal study of patients with cancer receiving active anti-cancer treatment during the COVID-19 pandemic

Background: Cancer and systemic anti-cancer treatment (SACT) have been identified as possible risk factors for infection and related severe illness associated with SARS-CoV-2 virus as a consequence of immune suppression. The Scottish COVID CAncer iMmunity Prevalence (SCCAMP) study aimed to characterise the incidence and outcomes of SARS-Cov-2 infection in patients undergoing active anticancer treatment during the COVID-19 pandemic and their antibody response following vaccination. Methods: Eligible patients were those attending secondary care for active anti-cancer treatment for a solid tumour. Blood samples were taken for total SARS-CoV-2 antibody assay (Siemens) at baseline and after 1.5, 3, 6 and 12 months. Data on COVID-19 infection, vaccination, cancer type, treatment and outcome (patient death) was obtained from routine electronic health records. Results: The study recruited 766 eligible participants between 28th May 2020 and 31st October 2021. During the study period there were 174 deaths (22%). The median age was 63 years, and 67% were female. Most received cytotoxic chemotherapy (79%), with the remaining 14% receiving immunotherapy and 7% receiving another form of anti-cancer therapy (radiotherapy, other systemic anti-cancer treatment). 48 (6.3%) tested positive for SARS-CoV-2 by PCR during the study period. The overall infection rate matched that of the local adult general population until May 2021, after which population levels appeared higher than the study population. Antibody testing detected additional evidence of infection prior to vaccination, taking the total number to 58 (7.6%). There was no significant difference in SARS-CoV-2 PCR positive test rates based on type of anti-cancer treatment. Mortality rates were similar between those who died within 90 days of a positive SARS-CoV-2 PCR and those with no positive PCR (10.4% vs 10.6%). Death from all causes was lowest among vaccinated patients, and of the patients who had a positive SARS-CoV-2 PCR at any time, all of those who died during the study period were unvaccinated. Multivariate analysis correcting for age, gender, socioeconomic status, Charlson co-morbidity score and number of previous medications revealed that vaccination was associated with a significantly lower infection rate regardless of treatment with chemotherapy or immunotherapy with hazard ratios of 0.307 (95% CI 0.144-0.6548) or 0.314 (95% CI 0.041-2.367) in vaccinated patients respectively. Where antibody data was available, 96.3% of patients successfully raised SARSCoV-2 antibodies at a time point after vaccination. This was unaffected by treatment type. Conclusions: SCCAMP provides real-world evidence that patients with cancer undergoing SACT have a high antibody response and protection from SARS-CoV-2 infection following COVID-19 vaccination.

Asia Pacific Fragility Fracture Alliance Primary Care Toolkit: Empowering Fragility Fracture Education

Introduction: The Asia Pacific Fragility Fracture Alliance (APFFA) is a federation committed to reducing the burden of low trauma fracture throughout the region. Education on fracture prevention to those at the forefront of patient care is an important part of this effort. Methods: APFFA has curated educational materials developed by others (https://apfracturealliance.org/education-directory/) and developed a Primary Care Physician (PCP) Education Toolkit (https://apfracturealliance.org/education-toolkit/). Here we describe the toolkit and report its introduction during the COVID-19 pandemic. Results: The PCP Education Toolkit is designed as a half-day educational program together with supporting resources to highlight the role of primary care providers in this effort. The educational program includes a lecture focused on the burden of fracture, a lecture focused on clinical assessment of fracture risk, a discussion kit, and materials to assist with meeting planning. The discussion kit is designed to be adaptable to local practices and constraints. The supporting material features a patient handbook that gives practical advice on nutrition, home safety, and issues to be raised during medical encounters. COVID-19 hampered rollout of these materials. In addition, APFFA has relied on its constituent organizations to provide educational content to promote best practices in acute fracture management, rehabilitation, and secondary fracture prevention through the development of an education directory. The directory includes synopses and links to high quality materials from around the world. Conclusion: The PCP Education Toolkit was designed with the expectation that the program would be presented as live meetings. The pandemic made this infeasible. Despite the restrictions, the PCP Education Toolkit materials have been enthusiastically received in New Zealand and disseminated by Osteoporosis NZ. As the world emerges from the pandemic, we are looking to present this material in more venues in 2022 and beyond. The toolkit is available free of charge at the above address.

Long COVID syndrome and the lung: how long will it last?

The prevalence and duration of the long-term respiratory complications of COVID-19 infection remains to be elucidated. This short commentary reports on recently published studies in patients post-acute COVID-19 infection in terms of symptom prevalence, physiological and radiological sequela and where only symptoms are present despite investigation. Pulmonary function testing, 6-min walk tests, computed tomography chest and more advanced imaging modalities have been incorporated to reveal the underlying pathophysiology that cause such disabling symptoms in patient with post-acute COVID-9 syndrome (PACS). PACS has a serious impact on people's ability to return to work, affecting the physical, mental, social sphere and with significant healthcare and general economic consequences for them, their families and society.

APFFA primary care toolkit: Empowering fragility fracture education

Objective: The Asia Pacific Fragility Fracture Alliance (APFFA) is a federation committed to reducing the burden of low trauma fracture throughout the region. Education on fracture prevention to those at the forefront of patient care is an important part of this effort Methods: APFFA has curated educational materials developed by others (https://apfracturealliance.org/education-directory/) and developed a Primary Care Physician (PCP) Education Toolkit (https:// apfracturealliance.org/education-toolkit/). Here we describe the toolkit and report its introduction during the COVID-19 pandemic Results: The PCP Education Toolkit is designed as a half-day educational program together with supporting resources to highlight the role of primary care providers in this effort. The educational program includes a lecture focused on the burden of fracture, a lecture focused on clinical assessment of fracture risk, a discussion kit, and materials to assist with meeting planning. The discussion kit is designed to be adaptable to local practices and constraints. The supporting material features a patient handbook that gives practical advice on nutrition, home safety, and issues to be raised during medical encounters. COVID-19 hampered rollout of these materials. In addition, APFFA has relied on its constituent organizations to provide educational content to promote best practices in acute fracture management, rehabilitation, and secondary fracture prevention through the development of an education directory. The directory includes synopses and links to high quality materials from around the world Conclusion: The PCP Education Toolkit was designed with the expectation that the program would be presented as live meetings. The pandemic made this infeasible. Despite the restrictions, the PCP Education Toolkitmaterials have been enthusiastically received in New Zealand and disseminated by Osteoporosis NZ. As the world emerges from the pandemic we are looking to present this material inmore venues in 2022 and beyond. The toolkit is available free of charge at the above address Acknowledgements: Development of the PCP Education Toolkit and Education Directory was funded via an unrestricted grant from Amgen Asia to APFFA and its content was developed independently by APFFA.

Swiss public health measures associated with reduced SARS-CoV-2 transmission using genome data (preprint)

Genome sequences allow quantification of changes in case introductions from abroad and local transmission dynamics. We sequenced 11,357 SARS-CoV-2 genomes from Switzerland in 2020 - the 6th largest effort globally. Using these data, we estimated introductions and their persistence throughout 2020. By contrasting estimates with null models, we estimate at least 83% of introductions were adverted during Switzerland's border closures. Further, transmission chain persistence roughly doubled after the partial lockdown was lifted. Then, using a novel phylodynamic method, we suggest transmission in newly introduced outbreaks slowed 36 - 64% upon outbreak detection in summer 2020, but not in fall. This could indicate successful contact tracing over summer before overburdening in fall. The study highlights the added value of genome sequencing data for understanding transmission dynamics.

The cost-effectiveness of what in health and care?

Assessing the value for money offered by new health technologies is playing an increasingly important role in aiding decision-making in health and care. Even in a pre-COVID-19 world, international healthcare systems were struggling to meet the demands of their patient populations and the rising cost of new health technologies, such as pharmaceuticals. With the impact of the coronavirus pandemic on the global economy and the provision of other health and care services more generally, difficult decisions will continue to be required over what basket of health and care services are available to the general population. Health economists have developed methods to aid decision-makers who want to improve population health as the primary goal. Tools such as quality-adjusted life years (QALYs) combine health-related quality of life and quantity of life into a single outcome. QALYs allow for population health to be maximised. However, there is debate over whether the quality of life content captured by QALYs is too narrow. In addition, the aim of maximisation in health may be at odds with other goals of health and care, such as reducing health inequalities. This chapter discusses some of the key steps involved in the construction of the QALY to value patient benefits from health and care interventions, and also how the QALY is commonly used in economic evaluation to aid healthcare decision-making. A critique and an alternative to QALYs is also provided. Evaluating peoples capabilities has been proposed as an alternative to health focused outcomes, such as QALYs, to inform health and care decision-making. Developed initially by nobel prize winning economist and philosopher, Amartya Sen, capabilities represent what a person is able to do and be in life that they have reason to value. Although health functionings are an important component of Sen's Capability Approach, using QALYs does not fully extend the evaluative focus on to how such health outcomes and other non-health functionings are reflective of what people can and cannot do in their life that they have reason to value. Aiming to get people to a decent or sufficient level of capability also provides an alternative to the health maximisation objective commonly pursued in health economic evaluations. Adopting a different quality of life measurement approach in health economic evaluations, as well as a new objective, has important implications for what patients and treatments are prioritised in health and care. Previous research has shown how interventions that improve quality of life for patients with mental health conditions and more severe health conditions will be more favourably treated using a capability measure. It is also recognised that health inequality has largely been neglected in the singular focus of QALY maximisation. Shifting to a "sufficient capability" objective may help address efficiency and equity concerns without the need for more complex economic evaluation frameworks that require dual objectives to deal with population health and health inequality simultaneously.

A Comparative Study of Real-Time RT-PCR-Based SARS-CoV-2 Detection Methods and Its Application to Human-Derived and Surface Swabbed Material.

Real-time RT-PCR remains a gold standard in the detection of various viral diseases. In the coronavirus 2019 pandemic, multiple RT-PCR-based tests were developed to screen for viral infection. As an emergency response to increasing testing demand, we established a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR diagnostics platform for which we compared different commercial and in-house RT-PCR protocols. Four commercial, one customized, and one in-house RT-PCR protocols were evaluated with 92 SARS-CoV-2-positive and 92 SARS-CoV-2-negative samples. Furthermore, economical and practical characteristics of these protocols were compared. In addition, a highly sensitive digital droplet PCR (ddPCR) method was developed, and application of RT-PCR and ddPCR methods on SARS-CoV-2 environmental samples was examined. Very low limits of detection (1 or 2 viral copies/µL), high sensitivities (93.6% to 97.8%), and high specificities (98.7% to 100%) for the tested RT-PCR protocols were found. Furthermore, the feasibility of downscaling two of the commercial protocols, which could optimize testing capacity, was demonstrated. Tested commercial and customized RT-PCR detection kits show very good and comparable sensitivity and specificity, and the kits could be further optimized for use on SARS-CoV-2 viral samples derived from human and surface swabbed samples.

Prolonged Unfrozen Storage and Repeated Freeze-Thawing of SARS-CoV-2 Patient Samples Have Minor Effects on SARS-CoV-2 Detectability by RT-PCR.

Reliable transportation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patient samples from a swabbing station to a diagnostics facility is essential for accurate results. Therefore, cooling or freezing the samples is recommended in case of longer transportation times. In this study, SARS-CoV-2 detectability by RT-PCR was assessed after prolonged unfrozen storage or repetitive freeze-thawing of SARS-CoV-2 samples. SARS-CoV-2-positive patient swabs stored in viral transport medium were exposed to different temperatures (4°C, 25°C, and 35°C) and to repetitive freeze-thawing, to assess the effect of storage conditions on RT-PCR detection. SARS-CoV-2 RNA was still reliably detected by RT-PCR after 21 days of storage in viral transport medium, even when the samples had been stored at 35°C. The maximum observed change in cycle threshold value per day was 0.046 (±0.019) at 35°C, and the maximum observed change in cycle threshold value per freeze-thaw cycle per day was 0.197 (±0.06). Compared with storage at 4°C, viral RNA levels deviated little but significantly when stored at 25°C or 35°C, or after repeated freeze-thawing. The results of this study indicate that viral RNA levels are relatively stable at higher temperatures and repetitive freeze-thawing.

Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2.

Three families of RNA viruses, the Coronaviridae, Flaviviridae, and Filoviridae, collectively have great potential to cause epidemic disease in human populations. The current SARS-CoV-2 (Coronaviridae) responsible for the COVID-19 pandemic underscores the lack of effective medications currently available to treat these classes of viral pathogens. Similarly, the Flaviviridae, which includes such viruses as Dengue, West Nile, and Zika, and the Filoviridae, with the Ebola-type viruses, as examples, all lack effective therapeutics. In this review, we present fundamental information concerning the biology of these three virus families, including their genomic makeup, mode of infection of human cells, and key proteins that may offer targeted therapies. Further, we present the natural products and their derivatives that have documented activities to these viral and host proteins, offering hope for future mechanism-based antiviral therapeutics. By arranging these potential protein targets and their natural product inhibitors by target type across these three families of virus, new insights are developed, and crossover treatment strategies are suggested. Hence, natural products, as is the case for other therapeutic areas, continue to be a promising source of structurally diverse new anti-RNA virus therapeutics.

Quantifying SARS-CoV-2 spread in Switzerland based on genomic sequencing data (preprint)

Pathogen genomes provide insights into their evolution and epidemic spread. We sequenced 1,439 SARS-CoV-2 genomes from Switzerland, representing 3-7% of all confirmed cases per week. Using these data, we demonstrate that no one lineage became dominant, pointing against evolution towards general lower virulence. On an epidemiological level, we report no evidence of cryptic transmission before the first confirmed case. We find many early viral introductions from Germany, France, and Italy and many recent introductions from Germany and France. Over the summer, we quantify the number of non-traceable infections stemming from introductions, quantify the effective reproductive number, and estimate the degree of undersampling. Our framework can be applied to quantify evolution and epidemiology in other locations or for other pathogens based on genomic data.

SARS-CoV-2 viroporin triggers the NLRP3 inflammatory pathway (preprint)

Cytokine storm resulting from a heightened inflammatory response is a prominent feature of severe COVID-19 disease. This inflammatory response results from assembly/activation of a cell-intrinsic defense platform known as the inflammasome. We report that the SARS-CoV-2 viroporin encoded by ORF3a activates the NLRP3 inflammasome, the most promiscuous of known inflammasomes. ORF3a triggers IL-1 beta expression via NFkB, thus priming the inflammasome while also activating it via ASC-dependent and -independent modes. ORF3a-mediated inflammasome activation requires efflux of potassium ions and oligomerization between NEK7 and NLRP3. With the selective NLRP3 inhibitor MCC950 able to block ORF3a-mediated inflammasome activation and key ORF3a residues needed for virus release and inflammasome activation conserved in SARS-CoV-2 isolates across continents, ORF3a and NLRP3 present prime targets for intervention.

Remdesivir Metabolite GS-441524 Efficiently Inhibits SARS-CoV-2 Infection in Mouse Model (preprint)

The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.

Abdominal imaging findings in patients with SARS-CoV-2 infection: a scoping review.

PURPOSE: This scoping review evaluated the currently available data related to abdominal imaging in the SARS-CoV-2 infection. METHOD: A systematic review of MEDLINE, EMBASE, SCOPUS, and Web of Science was performed from inception to July 15, 2020 using PRISMA-ScR guidelines. The review included case reports and series discussing radiologic manifestations of SARS-CoV-2 infection in abdominal imaging studies. Studies published from inception to March 31, 2020, were independently screened and reviewed by one author, and another author reviewed studies published after March 31 to July 15, 2020. Study screening and full-text review for publications before March 31, 2020, was performed by one author, and another author for publications after March 31 to July 15, 2020. RESULTS: Thirty-six studies were included in qualitative synthesis. The prevalence of gastrointestinal symptoms is roughly 18% and includes loss of appetite, nausea, vomiting, diarrhea, and abdominal pain. Sixteen percent of COVID-19 cases may only present with gastrointestinal symptoms. Many patients presenting this way demonstrate evidence of COVID-19 incidentally through abdominal CT imaging at the lung bases. Studies published to date have also reported abdominal imaging findings including small and large bowel wall thickening, fluid-filled colon, pneumatosis intestinalis, pneumoperitoneum, intussusception, and ascites. CONCLUSION: Gastrointestinal manifestations and imaging manifestations of SARS-CoV-2 infection are increasingly reported and warrant specific attention during abdominal imaging.