A Review on Saliva-Based Health Diagnostics: Biomarker Selection and Future Directions

The human body has a unique way of saying when something is wrong with it. The molecules in the body fluids can be helpful in the early detection of diseases by enabling health and preventing disease progression. These biomarkers enabling better healthcare are becoming an extensive area of research interest. Biosensors that detect these biomarkers are becoming the future, especially Point Of Care (POC) biosensors that remove the need to be physically present in the hospital. Detection of complex and systemic diseases using biosensors has a long way to go. Saliva-based biosensors are gaining attention among body fluids due to their non-invasive collection and ability to detect periodontal disease and identify systemic diseases. The possibility of saliva-based diagnostic biosensors has gained much publicity, with companies sending home kits for ancestry prediction. Saliva-based testing for covid 19 has revealed effective clinical use and relevance of the economic collection. Based on universal biomarkers, the detection of systemic diseases is a booming research arena. Lots of research on saliva-based biosensors is available, but it still poses challenges and limitations as POC devices. This review paper talks about the relevance of saliva and its usefulness as a biosensor. Also, it has recommendations that need to be considered to enable it as a possible diagnostic tool. Graphical

Tolerance of ETD001, a long-acting inhaled epithelial sodium channel blocker, in humans

Background: To assess the safety, tolerability, and pharmacokinetic (PK) profile in humans of the novel inhaled epithelial sodium channel blocker ETD001. Method(s): Inhaled ETD001 or placebo, delivered via nebulizer, have been administered in a 3:1 ratio to 96 healthy subjects in a blinded, first-inhuman clinical trial (ClinicalTrials.gov Identifier: NCT04926701). The study consisted of two parts. Part A evaluated single ascending doses (SADs) up to 10.8 mg, and Part B evaluated multiple ascending doses (MADs) up to 3.1 mg once daily (QD) for 7 days and 4.65 mg twice daily (BID) for 14 days. Safety was assessed by monitoring for adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG), and spirometry. Systemic exposurewas assessed using serial pharmacokinetic blood draws. Result(s): Therewere no serious AEs. Twenty-four subjects reported 38 AEs, all of mild to moderate intensity and all resolved. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs, or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B;all withdrawals were considered unrelated to study drug: one on day 6 from the 3.1-mg QD cohort for personal reasons, one after the first dose of the 3.1-mg BID cohort because of vasovagal syncope at time of venipuncture triggering atrial fibrillation that spontaneously resolved, and one on Day 4 of the 3.1- mg BID cohort because of a positive COVID-19 test. Pharmacokinetic parameters were approximately dose proportional in Part A, with peak concentrations 1 to 2 hours after dose and exposure out to 12 to 24 hours at all doses, indicating good lung retention. Part B plasma concentrations displayed dose-independent kinetics and showed minimal accumulation, with a mean of 1.11-fold observed over 14 days. Conclusion(s): ETD001 was well tolerated at single doses up to 10.8 mg and multiple doses of 3.1 mg QD for 7 days and 4.65 mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Dipeptidyl Peptidase-1 Inhibition in Patients Hospitalized with COVID-19: a Multicentre Randomized Double-Blind Placebo Controlled Trial

Background: Neutrophil serine proteases (NSPs) are involved in the pathogenesis of COVID19 and are increased in severe and fatal infection. We investigated whether treatment with Brensocatib, an inhibitor of dipeptidyl peptidase-1, an enzyme responsible for the activation of NSPs, would improve outcomes in hospitalized patients with COVID19. Method(s): In a randomized, double-blind, placebo-controlled trial, 406 hospitalized patients with COVID19 with at least one risk factor for severe disease were randomized 1:1 to once-daily Brensocatib 25mg (n=192) or placebo (n=214) for 28 days. Primary outcome was the 7-point World Health Organisation Clinical Status scale at day 29. Secondary outcomes included time to clinical improvement, national early warning score, new oxygen and ventilation use, neutrophil elastase activity in blood and mortality. Finding(s): Brensocatib treatment was associated with worse clinical status at day 29 (adjusted odds ratio 0 72, 95%CI 0 57-0 92) compared to placebo. The adjusted hazard ratio (aHR) for time to clinical improvement was 0 87 (95%CI 0 76-1 00) and time to hospital discharge was 0 98 (95%CI 0 84-1 13). During the 28-day follow-up period, 23 (11%) and 29 (15%) patients died in the placebo and Brensocatib treated groups respectively). Oxygen and new ventilation use were greater in the Brensocatib treated patients. Neutrophil elastase activity in blood was significantly reduced in the Brensocatib group from baseline to day 29. Prespecified subgroup analyses of the primary outcome supported the primary results.

The impact of age and gender on mortality from COVID19 at A UK Hospital

Rationale: Age poses greater mortality risk to COVID-19 patients. This may be due to co-morbidities and age-related impairment of immunity. It has been shown that females are more likely to be infected however, severe disease is more often seen in males, which could be explained by greater levels of interferon-gamma promoter activity driven by oestrogen in females in addition to higher levels of IgG antibody providing more protection. We aim to investigate the effects of age and gender on the mortality rate in patients with COVID-19. Method(s): A retrospective study of all in-patients aged >= 18 years with a confirmed diagnosis of COVID-19 during the first and second waves of the pandemic. Admission CXRs were analysed. Statistical analysis was performed using the Chi-Squared Test for independence. Result(s): 1759 COVID-19 patients were included in the study, of which 481 were aged <65 years and 982 were aged > 65 years. The study had 967 males and 792 females. We found a higher mortality rate in those aged > 65 (41%) compared to those aged <65 years (18%) (P<0.001). There were no significant differences in the mortality rates between both genders. However, interestingly males had a greater severity of pneumonitis (22%) on CXRs compared to females (13%) (P=0.01). Conclusion(s): Our study demonstrated a positive correlation between increasing age and mortality with males showing a greater disease severity. This data should be considered when stratifying at risk groups and prioritising them for early intervention.

To assess the diagnostic and prognostic ability of CXRs in COVID-19 pneumonitis

Rationale: The COVID-19 pandemic has led to the deaths of millions with its ability to cause severe pneumonia. Diagnosis is based on PCR testing which has many limitations: lengthy turnaround times, lack of universal availability and variance in sensitivity. Imaging such as CXR could be a valuable and faster aid in diagnosing COVID-19 compared to PCR. It is widely available, cheap and can be performed at the bedside- enabling a rapid turnover of patients whilst minimising cross-link infection. However only a few studies have assessed its prognostic value. We aim to analyse the diagnostic accuracy of CXR in COVID-19 and to assess if severity of COVID pneumonitis on CXR correlated with mortality. Method(s): A retrospective study of all in-patients aged >= 18 years with a confirmed diagnosis of COVID-19 during the first and second waves of the pandemic. Admission CXRs and in-patient CT Thorax scans were analysed. Statistical analysis was performed using the Chi-Squared Test for independence. Result(s): 999 COVID-19 patients were included in the study. Severity of COVID pneumonitis on CXR correlated with mortality when patients were grouped into the following categories: normal (n=161, mortality=42%), mild (n=220,mortality=33%) moderate, (n=328, mortality=42%) and severe (n=290, mortality=58%) (P<0.001). 251 patients had both CT and CXRs. CT scans were superior in diagnosing COVID pneumonitis (63%) compared to CXR (47%) (P<0.001). Conclusion(s): Our study showed a positive correlation between the severity of COVID pneumonitis on CXR and mortality, supporting the use of CXR in the ED to help rapidly identify and treat patients at high risk of death.

Comparing the mortality of COPD and non-COPD patients with COVID-19 in a UK hospital

Rationale: Initial reports during the pandemic have shown that COPD patients with COVID-19 have a poorer prognosis due to an increased risk of respiratory failure. It is well known that in COPD, there is an increased expression of angiotensin converting enzyme-2 (ACE2), the receptor which plays a role in SARS-CoV-2 entry into cells. In the absence of infection, ACE2 converts angiotensin-2 (AngII) to angiotensin-1-7- helping regulate inflammation. During COVID-19 infection, ACE2 activity is reduced due to receptor occupancy, resulting in greater levels of AngII- leading to a pro-inflammatory state. We aim to investigate the impact of COPD and COVID-19 on mortality, length of in-patient stay and gender. Method(s): A retrospective study of all in-patients aged >= 18 years with a confirmed diagnosis of COVID-19 during the first wave of the pandemic. Statistical analysis was performed using the Chi-Squared Test for independence. Result(s): 445 COVID-19 patients were included in the study, out of whom 52 (12%) had COPD. Mortality in COPD patients (65%) was found to be significantly higher than non-COPD patients (49%) (P=0.03) There were no significant differences in mortality between COPD and non-COPD patients when grouped for male and female (P=0.68). Furthermore, there were no significant differences in length of in-patient stays of >7 days between COPD and non-COPD patients (P=0.79). Conclusion(s): Our study demonstrated how COPD increases mortality in COVID-19. This data should be considered when highlighting at risk groups- prioritising them for treatment, isolation, and preventative public health measures such as the COVID-19 vaccination programme.

Current Challenges and Solutions for Clinical Management and Care of People with HIV: Findings from the 12th Annual International HIV and Aging Workshop.

People with HIV on combination antiretroviral therapy (ART) have longer life expectancy and are increasingly experiencing age-related comorbidities. Thus, aging with HIV has become a central issue in clinical care and research, which has been particularly challenging with the intersection of the ongoing coronavirus (COVID)-19 pandemic. Since 2009, the International Workshop on HIV and Aging has served as a multidisciplinary platform to share research findings from cross-disciplinary fields along with community advocates to address critical issues in HIV and aging. In this article, we summarize the key oral presentations from the 12th Annual International Workshop on HIV and Aging, held virtually on September 23rd and 24th, 2021. The topics ranged from basic science research on biological mechanisms of aging to quality of life and delivery of care under the COVID-19 pandemic. This workshop enriched our understanding of HIV and aging under the COVID-19 pandemic, identified challenges and opportunities to combat the impact of COVID-19 on HIV communities, and also provided updated research and future directions of the field to move HIV and aging research forward, with the ultimate goal of successful aging for older people with HIV.

Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9- NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9- CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.

Impact of statin therapy on mortality and morbidity in patients with COVID-19

S40 Figure 1Mortality rates of high-, medium- and low-dose statin patient groups, converted to Atorvastatin equivalent2, and those not prescribed a statin. Medium-dose statin patients featured independent association with greater mortality rates (*p=0.039)[Figure omitted. See PDF]ConclusionWe highlight a cohort of patients who demonstrated greater mortality from COVID-19 when prescribed medium-dose statins, with an otherwise non-significant effect on mortality of statins of all doses when compared to non-statin patients. Medium-dose statin patients may be those at highest risk of cardiovascular sequelae of COVID-19 with multiple comorbidities, but unable to tolerate maximum doses. We advocate caution when prescribing statins with established COVID-19 therapies until specific groups are identified from prospective clinical trials that may benefit from their use.ReferencesZhang XJ, et al. Cell Metab 2020;32(2):176–187.e4. doi:10.1016/j.cmet.2020.06.015Hu D, et al. Zhonghua Nei Ke Za Zhi 2015;54:467–477

Monitoring of SARS-CoV-2 antibodies using dried blood spot for at-home collection.

The utilization of vaccines to fight the spread of SARS-CoV-2 has led to a growing need for expansive serological testing. To address this, an EUA approved immunoassay for detection of antibodies to SARS-CoV-2 in venous serum samples was investigated for use with dried blood spot (DBS) samples. Results from self-collected DBS samples demonstrated a 98.1% categorical agreement to venous serum with a correlation (R) of 0.9600 while professionally collected DBS samples demonstrated a categorical agreement of 100.0% with a correlation of 0.9888 to venous serum. Additional studies were performed to stress different aspects of at-home DBS collection, including shipping stability, effects of interferences, and other sample-specific robustness studies. These studies demonstrated a categorical agreement of at least 95.0% and a mean bias less than ± 20.0%. Furthermore, the ability to track antibody levels following vaccination with the BioNTech/Pfizer vaccine was demonstrated with serial self-collected DBS samples from pre-dose (Day 0) out to 19 weeks.

SARS-CoV-2 infections in patients with autoimmune blistering disorders: A case series and retrospective analysis.

BACKGROUND: Autoimmune blistering disorders (AIBDs) are rare, potentially life-threatening conditions often requiring immunosuppression. Throughout the SARS-CoV-2 pandemic, infection risk and mortality in patients with AIBDs are unknown. OBJECTIVE: We report the outcomes of SARS-CoV-2 infections in patients with AIBDs and determined if patients on rituximab have an increased risk of SARS-CoV-2 infection. METHODS: We examined clinical outcomes in 10 patients with AIBDs who developed SARS-CoV-2 infections at an American hospital. We performed a retrospective analysis of 132 patients with AIBDs enrolled in a clinical trial. RESULTS: Patients with severe SARS-CoV-2 (n = 4) or death (n = 2) trended to be older. These patients had higher mortality than the national average (20% vs 1.6%). Our cohort included 52 patients with a history of rituximab treatment, 35 of whom were immunosuppressed by rituximab during the pandemic, and 45 patients never treated with rituximab. We found no difference between the rates of SARS-CoV-2 positivity in patients with AIBDs immunosuppressed by rituximab and those not on rituximab (9.1% vs 12.1%). LIMITATIONS: Testing for SARS-CoV-2 was performed on demand rather than surveillance. Overall transmission varied over time, and outcomes depended on accepted treatments. The small sample size of our cohort limits the generalizability of our results. CONCLUSION: This study suggests that rituximab does not increase the risk of SARS-CoV-2 test positivity in patients with AIBDs. However, these results should be interpreted with caution due to our relatively small sample size.

ADAPTING SOCIAL DESIGN RESEARCH METHODS for SOCIALLY DISTANCED PRACTICE

Social Design Research, due to its interactive and democratic nature, typically requires access to participants at all stages of the Design process (enquiry, insight gathering, ideation, and testing). This ensures that the designers’ practice is informed with contextual knowledge gained through relationship-building and ethnography, which are key features of Social Design Research [1]. Due to the impact of the COVID-19 pandemic, the delivery of Design education, and the approaches taken by lecturers and students had to adapt. The methods, attitudes and approaches to Design research and practice have evolved due to these changes due to the use of newly adopted digital collaborative environments. This paper presents the adaptations to existing Social Design Research methods and new ones which have been generated by the students through the undertaking of a project aimed at designing for social value delivered to first year Product Design students at The University of Derby. © PDE 2021.

Impact of empirical antibiotic use in patients with COVID-19 on morbidity and mortality during the first and second UK SARS-CoV-2 waves

S53 Figure 1Rates of mortality against cumulative number of antibiotics received per patient during inpatient spell.[Figure omitted. See PDF]ConclusionIn both COVID-19 waves, antibiotic administration correlated to increased inpatient morbidity and mortality. Given a near-linear relationship of mortality and cumulative antibiotic numbers, antimicrobial stewardship is essential, and tapering an appropriate therapy for likely responsible pathogens will yield lower mortality compared to overlapping coverage and inappropriate escalation. We strongly discourage the use of empirical antibiotics without supporting biochemical evidence of bacterial co-infection for possible future COVID-19 waves.ReferenceRussell C, et al. Lancet Microbe. 2021 Jun 2. https://doi.org/10.1016/S2666-5247(21)00090-2

Impact of bacterial infections in patients with COVID-19 on morbidity and mortality during the second UK SARS-CoV-2 wave

P91 Table 1(a) Most frequently observed bacterial species (b) Culture type positivity with relation to rates of mortality(a) Bacteria Number isolated (b) Culture Type Number of positives Number of deaths Positivity mortality Enterococcus 67 Urine 104 28 26.9% Escherichia 65 Blood 76 28 36.8% Staphylococcus 64 Skin 40 16 40% Pseudomonas 24 Sputum & BAL 33 20 60.6% Klebsiella 12 Stool 13 5 38.5% Streptococcus 12 Central venous line 8 4 50% ConclusionBacterial infection is observed far more frequently in COVID-19 patients than previously reported and adversely affects morbidity and mortality. Multiple sites of bacterial infection prolongs inpatient stay and increases mortality. Thorough culture collection should be encouraged in COVID-19 patients with biochemical evidence of bacterial infection to identify responsible pathogens and respective antimicrobial sensitivity. Given the higher mortality rates, empirical use of antibiotics in COVID-19 patients without supporting evidence of bacterial infection is strongly discouraged.ReferencesLansbury, et al. J Infect. 2020 Aug;81(2):266–2.Russell C, et al. Lancet Microbe. 2021 Jun 2. https://doi.org/10.1016/S2666-5247(21)00090-2

COVID-19 mortality in cancer patients on systemic anti-cancer treatments during the second UK SARS-CoV-2 wave

P104 Table 1Mortality rate after presentation of COVID-19 by: tumour type, time from cancer diagnosis, cancer stage, progression of disease, and systemic anti-cancer treatment (SACT). Number mortality number mortality% odds ratio Cancer type Solid organ 75 28 37.3 1.32 Lung 18 11 61.1 4.66** Haematological 29 11 37.9 1.47 Time from diagnosis <12 months 55 25 45.5 2.32** >12 months 67 25 37.3 1.25 STAGE AT DIAGNOSIS 4 46 23 50.0 2.82*** 3 26 13 50.0 2.17 2 14 5 35.7 1.22 1 31 8 25.8 0.77 0 5 1 20.0 0.46 disease progression (<3 months BEFORE COVID-19) Yes 38 22 57.9 4.60*** No 84 28 33.3 1.07 SACT (<3 months BEFORE COVID-19) Yes 53 69 34.0 1.49 No 69 32 46.4 1.80** *p<0.05 **p<0.01 ***p<0.001ConclusionAmong patients with cancer and COVID-19, mortality was high and associated with cancer-specific features. There was no evidence cancer patients on systemic anti-cancer treatments possessed higher mortality from COVID-19 disease, which correlates with findings from COVID-19 and cancer registries1. Patients that did not receive SACT within 3 months before COVID-19 and therefore more likely to have palliative treatment did demonstrate high mortality. Larger studies are needed to confirm the risk of mortality and timing of SACT before COVID-19 disease.ReferenceLee AJ, et al. British Journal of Cancer 2021;124:1777–1784.

Vitamin D deficiency increases susceptibility to COVID-19 infection

BackgroundVitamin D plays a vital part in modulating the immune system, with Vitamin D deficiency leading to increased susceptibility to infection.1 There is some evidence to suggest Vitamin D may play a protective role in the prevention of COVID-19 infection in hospitalised patients,2 but the topic remains controversial. Our study aims to investigate if low Vitamin D levels correlate with increased risk of COVID-19 infection, thereby representing a modifiable risk factor for COVID-19 infection.MethodA retrospective observational study was conducted on 3198 health care workers of a Greater London District General Hospital, who had undergone testing for 25-OH Vitamin D levels and COVID-19 antibody in June 2020. In accordance with NICE guidelines, Vitamin D deficiency was defined as less than 25 nmol/L, insufficiency as 25–50 nmol/L, and those with levels over 50 nmol/L were used as control comparisons. Evidence of previous SARS-CoV-2 infection was assessed by detection of SARS-CoV-2 IgG antibodies. Regression analysis was performed to determine independent significance, accounting for age and gender.Results3191 participants were included in this study, with age ranging from 19–78 years (mean 42.9) of which 78.2% were female. Both age and gender were not independently associated with positive SARS-CoV-2 IgG antibodies. 1997 (62.6%) participants had Vitamin D levels within the normal range, 899 (28.2%) participants had insufficient levels and 302 (9.4%) had Vitamin D deficiency. Both Vitamin D deficiency (OR 1.61, p=0.002) and insufficiency (OR 1.33, p=0.006) independently correlated with significantly increased incidence of positive COVID-19 antibodies than personnel with normal Vitamin D levels.ConclusionsWe report the largest single-centre study investigating the impact of low Vitamin D levels within healthcare workers to date. Significant correlation between low levels of Vitamin D and previous COVID-19 infection was identified. Oral Vitamin D supplementation to maintain levels >50 nmol/L may play a protective role against COVID-19. Larger studies are needed to investigate the role of Vitamin D supplementation in healthcare workers for further COVID-19 waves.ReferencesAranow C, et al. Journal of Investigative Medicine 2011;59:881–886.Nogues X, et al. J Clin Endocrinol Metab. 2021 Jun 7:dgab405.