Testing persuasive messages about booster doses of COVID-19 vaccines on intention to vaccinate in Australian adults: A randomised controlled trial.

INTRODUCTION: Achieving high COVID-19 vaccine booster coverage is an ongoing global challenge. Health authorities need evidence about effective communication interventions to improve acceptance and uptake. This study aimed to test effects of persuasive messages about COVID-19 vaccine booster doses on intention to vaccinate amongst eligible adults in Australia. METHODS: In this online randomised controlled trial, adult participants received one of four intervention messages or a control message. The control message provided information about booster dose eligibility. Intervention messages added to the control message, each using a different persuasive strategy, including: emphasising personal health benefits of booster doses, community health benefits, non-health benefits, and personal agency in choosing vaccination. After the intervention, participants answered items about COVID-19 booster vaccine intention and beliefs. Intervention groups were compared to the control using tests of two proportions; differences of ≥5 percentage points were deemed clinically significant. A sub-group analysis was conducted among hesitant participants. RESULTS: Of the 487 consenting and randomised participants, 442 (90.8%) completed the experiment and were included in the analysis. Participants viewing messages emphasising non-health benefits had the highest intention compared to those who viewed the control message (percentage point diff: 9.0, 95% CI -0.8, 18.8, p = 0.071). Intention was even higher among hesitant individuals in this intervention group compared to the control group (percentage point diff: 15.6, 95% CI -6.0, 37.3, p = 0.150). Conversely, intention was lower among hesitant individuals who viewed messages emphasising personal agency compared to the control group (percentage point diff: -10.8, 95% CI -33.0, 11.4, p = 0.330), although evidence in support of these findings is weak. CONCLUSION: Health authorities should highlight non-health benefits to encourage COVID-19 vaccine booster uptake but use messages emphasising personal agency with caution. These findings can inform communication message development and strategies to improve COVID-19 vaccine booster uptake. Clinical trial registration: Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622001404718); trial webpage: https://www.anzctr.org.au/ACTRN12622001404718.aspx.

FlexiTeam: Flexible Team and Work Organization using Process-Oriented Case-Based Reasoning

During crises such as COVID-19, there is a need to adapt existing work processes and teams to the changing environment in a very flexible and dynamic way in many business and healthcare organizations. In this paper, we conceptualize the advances required for Process-Oriented Case-Based Reasoning to flexibly and dynamically organize human resources in a team and work processes. The novel contributions of this paper include an extended case representation to represent resources, profiles, and key performance indicators (KPIs) of processes, a query definition which covers the "context”, and an overall process to flexibly and dynamically organize work processes and human resources. We evaluate the FlexiTeam process using a cooking recipe casebase and analyze the quality of the retrieval using a quality measure. We also derive the research questions that need to be addressed to fully explore this approach and the specific difficulties involved in solving this problem. © 2022 Copyright for this paper by its authors. Use permitted under Creative Commons License Attribution 4.0 International (CC BY 4.0). CEUR Workshop Proceedings (CEUR-WS.org)

Understanding the factors that influence communication about COVID-19 vaccines with patients: Perspectives of Australian immunisation providers.

Background: COVID-19 immunisation providers have been at the forefront of the pandemic, and their ability to communicate effectively with patients is key to encouraging COVID-19 vaccine acceptance and uptake. This study explored providers' perspectives on the factors influencing communication with patients about COVID-19 vaccines. Methods: We used an explanatory-sequential mixed-methods approach to conduct the study between December 2021 and March 2022. Phase I involved a cross-sectional survey with immunisation providers in New South Wales (n = 341; 189 general practitioners, 118 nurses and 34 pharmacists), followed by Phase II: semi-structured, in-depth qualitative interviews (n = 19; 10 nurses, 9 pharmacists). We generated descriptive results for the survey. We analysed the qualitative data thematically using an inductive approach. Results: Almost half of survey participants reported communicating often with people who were hesitant about COVID-19 vaccines (49 %; 166/341), however, 21 % (71/341) reported inadequate time to address concerns during consultations. Interview participants reported communication challenges, including time constraints, difficulties addressing and eliciting patient concerns, and keeping up to date with changing information. Conversely, interview participants reported that easy access to government information resources, time to learn about COVID-19 vaccines proactively, knowing about and being able to use tailored strategies to support Aboriginal and Torres Strait Islander and CALD patients were helpful when communicating with patients. Conclusions: Immunisation providers play an important role in patient vaccine acceptance and uptake. Our findings indicate that whilst providers were largely confident in their interactions with patients, further communication support would strengthen providers' skills in communicating with patients who have questions and concerns about COVID-19 vaccines.

The scope and vulnerabilities of the internet of medical things (IoMT)

The year 2020 witnessed a major shift in our society and the global economy due to the onset of COVID-19. Many newer trends are expected to surface as people grow more digitally savvy and embrace technology while working from home. This has also impacted the medical industry worldwide and has made healthcare preventive, predictive, and personalized. In healthcare, the Internet of Things (IoT) refers to a network of connected medical devices that can generate, collect, and store data as well as connect to a network, analyze data, and transmit data of various types such as medical images, physiological and vital body signatures, and genomics data. Real-time monitoring, improved diagnostics, robotic surgical interventions, and other medical IoT applications can all help improve outcomes in healthcare. Medical IoT refers to IoT devices and applications tailored to healthcare demands and environments. It includes sensors and apps for monitoring healthcare remotely, telemedicine consultation, and delivery. Medical IoT also uses AI and machine learning to assist life-transforming advancements in existent medical devices, such as the smart inhaler for asthma sufferers. IoT devices offer a lot of new opportunities for patient monitoring, both by the doctors and by the patients themselves. This is made possible by a variety of wearable IoT devices that promise an array of benefits but also pose challenges for all stakeholders in the healthcare industry. Medical IoT devices enable the collection of patient data in real-time, which is processed and evaluated thereafter. The information gathered is centralized for computing, processing, and storage. Centralization can be hazardous as it is vulnerable to multiple threats: failure at one point, mistrust, manipulation, tampering of data, and privacy evasion. Blockchain can address such critical issues by offering decentralized computation and storage for IoT data. COVID-19 brought out the benefits of technology and has reinforced the need to develop and secure more advanced applications including Medical IoT. We have advanced much, but there is a huge scope to explore, expand, and establish. © 2022 Nova Science Publishers, Inc. All rights reserved.

Effect of persuasive messaging about COVID-19 vaccines for 5- to 11-year-old children on parent intention to vaccinate.

AIM: Uptake of COVID-19 vaccines for children aged 5-11 years old in Australia has plateaued. Persuasive messaging is an efficient and adaptable potential intervention to promote vaccine uptake, but evidence for its effectiveness is varied and dependent on context and cultural values. This study aimed to test persuasive messages to promote COVID-19 vaccines for children in Australia. METHODS: A parallel, online, randomised control experiment was conducted between 14 and 21 January 2022. Participants were Australian parents of a child aged 5-11 years who had not vaccinated their child with a COVID-19 vaccine. After providing demographic details and level of vaccine hesitancy, parents viewed either the control message or one of four intervention texts emphasising (i) personal health benefits; (ii) community health benefits; (iii) non-health benefits; or (iv) personal agency. The primary outcome was parents' intention to vaccinate their child. RESULTS: The analysis included 463 participants, of whom 58.7% (272/463) were hesitant about COVID-19 vaccines for children. Intention to vaccinate was higher in the community health (7.8%, 95% confidence interval (CI) -5.3% to 21.0%) and non-health (6.9%, 95% CI -6.4% to 20.3%) groups, and lower in the personal agency group (-3.9, 95% CI -17.7 to 9.9) compared to control, but these differences did not reach statistical significance. The effects of the messages among hesitant parents were similar to the overall study population. CONCLUSION: Short, text-based messages alone are unlikely to influence parental intention to vaccinate their child with the COVID-19 vaccine. Multiple strategies tailored for the target audience should also be utilised.

Increased belief in vaccination conspiracy theories predicts increases in vaccination hesitancy and powerlessness: Results from a longitudinal study.

RATIONALE: Vaccinations are an important part of a public health strategy against preventable diseases, and uptake is influenced by factors including hesitancy. The belief of vaccine related misinformation including anti-vaccination conspiracy theories has been found to be associated with increased vaccine hesitancy. OBJECTIVE: While research suggests that these conspiracy theory beliefs may arise to satisfy unmet needs such as restoring loss of personal control, somewhat ironically these anti-vaccination conspiracy theories may frustrate these needs. This study examined the causal relationships between vaccination hesitancy, vaccination conspiracy theories, and vaccination related powerlessness. METHODS: Using a stationary random intercepts cross lagged panel model, we investigated the temporal ordering of vaccination hesitancy, powerlessness, and vaccination conspiracy theory beliefs in a sample of Australian adults (N = 500) in a longitudinal study with 5-timepoints over 4-months between June and October 2021. RESULTS: Results from a random intercept cross-lagged model, that separates between-person stability from within-person change, suggested that increased belief in vaccination conspiracy theories was associated with future increases in vaccination hesitancy and powerlessness (but not vice versa). Findings also showed that increases in vaccination hesitancy and conspiracy theory beliefs predicted respective increases from a person's trait-level mean at subsequent timepoints. CONCLUSIONS: Vaccination conspiracy theories appear to increase vaccination powerlessness and hesitancy, rather than satisfying an unmet need for personal control.

Democracy and belief in conspiracy theories in New Zealand

The COVID-19 pandemic supercharged the spread of fake news, misinformation, and conspiracy theories worldwide. Using a national probability sample of adults from the New Zealand Attitudes and Values Study during 2020 (17–99 years old;M = 48.59, SD = 13.86;63% women, 37% men;N = 41,487), we examined the associations between agreement with general conspiracy beliefs and political indicators of intention to vote and satisfaction with government, alongside political factors including trust in politicians, political efficacy, identity centrality, and political ideology. Left-wing political ideology, trust in politicians, and political efficacy accounted for most of the explained variance in satisfaction with the government. General conspiracy belief was also a unique contributor to lower satisfaction with the government. We also found a curvilinear relationship between political ideology with heightened belief in conspiracies at both ideological extremes and the centre. Findings are discussed in terms of the consequences of conspiracy belief on democratic engagement. [ FROM AUTHOR] Copyright of Australian Journal of Political Science is the property of Routledge and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Shining a spotlight on the dangerous consequences of conspiracy theories.

The COVID-19 pandemic has illuminated how conspiracy beliefs-that explain important events as the secret actions of the powerful-can severely impact health choices (such as reduced infection-prevention behaviours). However, the consequences of conspiracy beliefs span far beyond the topic of COVID-19. This review shines a spotlight on how conspiracy beliefs could impact public and personal health (e.g., vaccine uptake), democratic citizenship (e.g., political engagement), intergroup relations (e.g., prejudice and discrimination), and may inspire violence and extremism. We argue that conspiracy beliefs are likely to have the power to mobilise citizens in ways detrimental to a smooth-running society. We conclude the review by offering a range of fruitful avenues for future investigation.

Dyadic Analysis of Fragile Middle Eastern States and Humanitarian Implications of Restrictive COVID-19 Policies

The COVID-19 pandemic has pressured governments to respond with restrictive and health resource-oriented policies to contain the spread of the virus. The aim of this paper is to assess differential policy implementation due to state fragility with a spatial scope of the Middle Eastern region. The policies implemented by the four strongest and six most fragile Middle Eastern countries were extracted from the CoronaNet Government Response Database and grouped into restrictive and resource-oriented categories. Clustering based on these categories informed dyadic analysis. Drawing from the Oxford Government Response Policy Tracker and COVID-19 World Symptom Survey, we found that fragile states tended to be characterized by a higher proportion of restrictive policies, lower government stringency, and lower compliance. The results identify sectors that would benefit most from humanitarian aid and raise the issue of whether restrictions are disproportionately implemented due to covert political agendas or lack of political and economic power.

Evaluation of the Educational Impact of the Urology Collaborative Online Video Didactics Lecture Series.

OBJECTIVE: To assess the impact of the Urology Collaborative Online Video Didactic (COViD) lecture series series on resident knowledge as a supplement to resident education during the coronavirus disease 2019 pandemic. METHODS: One hundred thirty-nine urology residents were voluntarily recruited from 8 institutions. A 20-question test, based on 5 COViD lectures, was administered before and after watching the lectures. Pre- and posttest scores (percent correct) and score changes (posttest minus pretest score) were assessed considering demographic data and number of lectures watched. Multiple linear regression determined predictors of improved scores. RESULTS: Of residents recruited, 95 and 71 took the pre- and posttests. Median number of lectures watched was 3. There was an overall increase in correct scores from pretest to posttest (45% vs 57%, P < .01). Watching any lectures vs none led to higher posttest scores (60% vs 44%, P < .01) and score changes (+16% vs +1%, P < .01). There was an increase in baseline pretest scores by post-graduate year (PGY) (P < .01); however there were no significant differences in posttest or score changes by PGY. When accounting for lectures watched, PGY, and time between lecture and posttest, being a PGY6 (P = .01) and watching 3-5 lectures (P < .01) had higher overall correct posttest scores. Watching 3-5 lectures led to greater score changes (P < .001-.04). Over 65% of residents stated the COViD lectures had a large or very large impact on their education. CONCLUSIONS: COViD lectures improved overall correct posttest scores and increased knowledge base for all resident levels. Furthermore, lectures largely impacted resident education during the coronavirus disease 2019 pandemic.

Impact of immunotherapy on COVID-19immunity: Insights from checkpoint blockade in cancer

Over the last few years, we have gained insights into how immunotherapy, including checkpoint blockade, modulates key CD4 and CD8 T cell subsets in anti-tumor immunity. This information can now give us insights intohow immunotherapy can impact immunity in the setting of COVID-19. Indeed, we recently demonstrated that cancerpatients with T cell depletion have high COVID-19 mortality despite adequate B cell and antibody production, highlighting the importance of cellular immunity. Conversely, in the setting of B cell depletion by anti-CD20 therapy, CD8 T cells can compensate for impaired humoral immunity. PD-1 blockade increases the activation and proliferation of CD4 T follicular-helper cells, which plays a key role in promoting B cell responses and qualityantibody production. Thus, it is possible that PD-1 blockade enhances the efficacy of SARS-CoV-2 vaccination. However, PD-1 blockade in melanoma patients was actually associated with at 2-fold decrease in SARS-CoV-2specific antibodies and neutralizing antibodies, compared to a healthy donor cohort. PD-1 blockade was alsoassociated with depletion of memory CD4 T cells, suggesting there may be consequences to prolonged PD-1blockade.

A Nucleic Acid-Based Orthopoxvirus Vaccine Targeting the Vaccinia Virus L1, A27, B5, and A33 Proteins Protects Rabbits against Lethal Rabbitpox Virus Aerosol Challenge.

In the age of COVID, nucleic acid vaccines have garnered much attention, at least in part, because of the simplicity of construction, production, and flexibility to adjust and adapt to an evolving outbreak. Orthopoxviruses remain a threat on multiple fronts, especially as emerging zoonoses. In response, we developed a DNA vaccine, termed 4pox, that protected nonhuman primates against monkeypox virus (MPXV)-induced severe disease. Here, we examined the protective efficacy of the 4pox DNA vaccine delivered by intramuscular (i.m.) electroporation (EP) in rabbits challenged with aerosolized rabbitpox virus (RPXV), a model that recapitulates the respiratory route of exposure and low dose associated with natural smallpox exposure in humans. We found that 4pox-vaccinated rabbits developed immunogen-specific antibodies, including neutralizing antibodies, and did not develop any clinical disease, indicating protection against aerosolized RPXV. In contrast, unvaccinated animals developed significant signs of disease, including lesions, and were euthanized. These findings demonstrate that an unformulated, nonadjuvanted DNA vaccine delivered i.m. can protect against an aerosol exposure. IMPORTANCE The eradication of smallpox and subsequent cessation of vaccination have left a majority of the population susceptible to variola virus or other emerging poxviruses. This is exemplified by human monkeypox, as evidenced by the increase in reported endemic and imported cases over the past decades. Therefore, a malleable vaccine technology that can be mass produced and does not require complex conditions for distribution and storage is sought. Herein, we show that a DNA vaccine, in the absence of a specialized formulation or adjuvant, can protect against a lethal aerosol insult of rabbitpox virus.

Humoral and cell-based responses following SARS-CoV-2 mRNA vaccination of patients with multiple sclerosis on B-cell depleting therapy

Introduction: Anti-CD20 treated MS patients may have higher risk of severe SARS-CoV-2. Early reports indicate they mount attenuated antibody responses to SARS-CoV-2 vaccines, raising significant concerns about their protection, and the merit of aCD20 infusion delay to enable more robust vaccine responses. Little is known about cellular responses (particularly spike-antigen-specific T-cell responses) to these vaccines in B cell-depleted state. Aims: To characterize the magnitude and kinetics of both antibody-and cell-based responses to SARS-CoV-2 mRNA vaccines in aCD20 treated MS patients, compared to healthy controls (HC). Methods: Both humoral IgG responses to Spike (S) protein and its receptor-binding-domain (RBD), as well as Spike-reactive B cells (flow cytometry) and S-protein-specific CD4+ and CD8+ T-cell responses (activation-induced marker/AIM assays), were serially assessed in 21 MS patients on aCD20 therapy and 10 HC, pre-and post-SARS-CoV-2 mRNA vaccination (pre-vaccine-T1;10 days post primary-T2, pre-booster-T3;10-day post-booster-T4 and 30 days post-booster-T5). Results: Antibodies to both S-protein and RBD were induced in 100% of HC by T4 and, with some lag (by T5), in 89% and 50% of MS patients, respectively. Mean Spike-IgG concentrations for HC and MS patients at T5 were 165.3± 201.9 units/mL (u/ml) and 22.3± 58.2 u/mL respectively (p=0.0004);and 97± 136 u/ mL(HC) and 10.2± 29 u/mL (MS) (p<0.0001) for RBD-IgG. All 6 patients vaccinated longer than 20 weeks after the last aCD20 treatment exhibited partial B-cell reconstitution, and all had measurable spike-specific memory B-cells at T5. All MS patients and HC mounted CD4+ and CD8+ T-cell responses to vaccine. Expansion of activated (Ki67+CD38+) CD4+ T-cells was robust in HC and somewhat attenuated in MS patients (p= 0.03), while expansion of activated (Ki67+CD38+) CD8+ T cells was robust in both cohorts. In AIM assays, spike-antigen-specific responses of CD4+ T-cells of patients were similarly mildly attenuated compared to HC, while those of CD8+ T cells were similarly robust for both patients and HC. Conclusion: In spite of attenuated humoral SARS-CoV-2 mRNA vaccine responses, aCD20 treated patients mount robust CD8+ and mildly attenuated CD4+ T-cell responses. Longer time from last aCD20 infusion may enable more robust humoral and cell-based responses. It will be important to study how cell-based responses relate to protection, complications and risk of infecting others.

Impact of early fluid administration on inpatient mortality and acute kidney injury in patients with COVID-19 disease

BACKGROUND AND AIMS: Initial WHO guidance advised cautious fluid administration for patients with COVID-19 due to concern about the development of acute respiratory distress syndrome (ARDS). However, as the pandemic unfolded it became apparent that patients who were admitted to hospital had high rates of AKI and this initiated a change in local clinical guidelines during early April 2020. We aimed to ascertain the impact of judicious intravenous fluid use on mortality, length of hospitalisation and AKI. METHOD: An observational cohort study of 158 adults admitted with confirmed SARS-Cov-2 between 18th March and 9th May 2020 was conducted in a teaching hospital and designated centre for infectious diseases, London, UK. Key clinical and demographic data collected included clinical severity markers on admission, biochemical and haematological parameters as well as radiological findings. Primary outcomes were inpatient mortality, mortality at 6-weeks post discharge, length of hospitalisation and intensive care (ICU) admission. We also measured requirement for kidney replacement therapy (KRT) and AKI recovery rate at discharge. Using tests of difference, we compared key outcomes between patients treated with varying fluid regimens and then identified risk factors for AKI and mortality using multivariate logistic regression with results expressed as odds ratios (OR) with corresponding 95% confidence interval (CI). RESULTS: The median age was 74.4 (IQR 59.90 - 84.35) years, 66% were male, 53% white with hypertension and diabetes being the commonest co-morbidities. The median duration of illness prior to admission was 7 days (IQR 2 - 10) with respiratory symptoms and fever most prevalent. The people who presented with AKI on admission were more likely to receive fluids (34% vs 15%, p=0.02). 118 patients (75%) received fluids within 24-hours of admission with no difference in volume administered after local guidance change (p=0.78). Comparing patients receiving fluids with those who did not, we observed no difference in mortality (p=0.97), duration of hospital stays (p=0.26) or requirement for ICU admission (p=0.70). 18% died as an inpatient, and 52 patients were either admitted with or developed AKI. Of these 52 patients, 43 received fluids and 9 did not with no difference in KRT requirement (p=0.34), mortality (p=0.50) or AKI recovery (p=0.63). Peak AKI stage was greater among participants who received fluids though stage of AKI at presentation was also greater (p=0.04). Mortality rate in patients with an AKI is higher compared to overall inpatient mortality (31% vs 18%). Of the 36 patients with AKI (Figure Presnted) who were discharged home, 25 patients (69.4%) had renal recovery by the time of discharge. Increasing age and clinical severity on admission were associated with higher mortality (see Figure 1). Older age was associated with 34 - 53 times higher risk of death compared with those aged ≥ 65 years (age 76 - 85 years: OR 34.26, 95% CI: 3.94 - 297.48, p=0.001;age > 85 years: OR 53.07, 95% CI: 5.23 - 539.03, p=0.001). Patients with NEWS2 >4 on admission has 5-fold increased risk of death than those with a score ≥4 (OR 5.26, 95% CI: 1.32 - 20.92). Black ethnicity was associated with a 16-fold increased risk of developing AKI (OR 15.86, 95% CI: 1.67 - 150.99). CONCLUSION: To our knowledge, this is the first study to examine the impact of fluid management on inpatient mortality as well as on renal-associated outcomes of COVID-19 admission. Fluid administration regimen did not have an impact on mortality, length of hospitalisation or ICU admission, nor did it affect renal outcomes. Given the high rates of AKI and KRT in COVID-19 disease, early fluid administration is likely to be an important cornerstone of future management. Further adequately powered prospective studies are required to identify whether early fluid administration can reduce renal injury.

Patient perceptions about virtual clinical consultations during current covid-19 pandemic: A multi-city survey across india

Introduction: COVID-19 has prevented many patients from accessing health care through traditional face-to-face clinic visits. Consequently, online consultations have gained popularity. Aim: To explore patient perceptions regarding virtual consultations. Methods: A voluntary online survey using a mix of quantitative and qualitative questions was administered to patients across selected cities in India using a social media platform. Responses were used to explore the characteristics of users, perceived advantages and disadvantages of online consultations and patient satisfaction. Results: There were 679 respondents (M 52.4%: F 47.6%) that had consulted doctors online;91.8% were from 8 major metro cities. Interestingly, over 80% had never sought online consultation before the COVID-19 pandemic. 46% consultations were via videocalls, 26% through WhatsApp and 21% via telephone calls. The main advantages of online consultations cited by patients included a lower risk of infection (78.8%), reduced waiting time (56.8%) and travel time (58.3%). The main disadvantages included a lack of physical examination (73.4%), a perception that this was not as satisfying as a face-to face consultation (37.9%) and difficulty in communication (24.5%). 78.6% patients rated their online consultations as either good or very good. However, given the choice, almost two-thirds felt they would still prefer face-face consultations. Conclusion: High levels of satisfaction from this survey suggests that teleconsultation has the potential to become a complementary method to access clinical care even after restrictions from the pandemic cease. The disadvantages of online consultations could be mitigated through evolving technologies such as digital stethoscopes and improvement in communication tools. © 2021, Indian Association of Preventive and Social Medicine. All rights reserved.

Plasma resistin levels are associated with acute kidney injury in hospitalized COVID-19 patients

Rationale: Obesity is a strong risk factor for acute kidney injury (AKI) in patients with COVID-19, but underlying mechanisms are unknown. Resistin is an immunomodulatory adipokine with elevated circulating levels in obese outpatients that could contribute to inflammatory kidney injury. We hypothesized that plasma resistin levels would be associated with AKI and BMI, and correlated with the inflammatory markers IL6 and MCP1 in hospitalized COVID-19 patients. Methods: We conducted a prospective cohort study of 134 patients admitted to the Hospital of the University of Pennsylvania with a primary diagnosis of COVID-19. Plasma samples were collected within 48 hours of admission and analyzed using the Olink Proximity Extension Assay, with biomarker levels expressed using normalized protein expression (NPX) values relative to common pooled control plasma. We tested the association of each biomarker with AKI, defined by Kidney Disease Improving Global Outcomes creatinine and dialysis criteria, using the Wilcoxon rank-sum test as well as multivariable logistic regression to adjust for confounders. Spearman's rho and correlation coefficients were calculated for the correlation of biomarker levels with each other. We used causal mediation models to investigate effects of BMI on AKI mediated by plasma resistin. Results: Of 134 patients enrolled, 43 (32.1%) developed AKI: 25 with stage 1, 5 with stage 2, and 13 with stage 3. Plasma resistin levels ranged from 5.26-13.01 NPX units and were strongly associated with AKI: odds ratio 2.13 (95% CI 1.43-3.17) per NPX unit. This association was diminished but remained significant after adjustment for age and APACHE III score (OR 1.69 (1.09-2.63)). Body mass index was higher in patients with AKI than without (median 31.4 (IQR 27.1-37.6) kg/m2 v. 28.3 (25.1-34.9) kg/m2, respectively), but the difference was not statistically significant (p=0.082). There was no significant correlation of BMI with resistin levels (rho 0.05, p=0.562), and causal mediation models failed to detect significant mediation of BMI-AKI association through resistin. Plasma IL6 and MCP1 were associated with AKI (p=0.044 and p=0.003, respectively) and correlated with resistin levels (rho=0.32, p<0.001 and rho=0.40, p<0.001, respectively). Conclusion: In patients hospitalized with COVID-19, plasma levels of the adipokine resistin were strongly associated with the development of AKI, and correlated with circulating inflammatory markers IL6 and MCP1. We did not detect a mediation effect of the obesity-AKI association by plasma resistin but had limited sample size to adequately power this analysis.

Proteomic analysis of COVID-19 plasma reveals dysregulated trem-1, I-17, and tumor microenvironment pathways associated with disease severity

Rationale: To utilize high-dimensional proteomic data to identify dysregulated pathways that are associated with COVID-19 disease severity and suggest potential therapeutic targets. Methods: We enrolled 161 COVID-19 inpatients admitted at two tertiary care hospitals. Plasma samples collected within 48 hours of admission were analyzed with the Olink Proximity Extension Assay;713 unique proteins were assayed. The WHO COVID-19 ordinal severity scale at enrollment was dichotomized into moderate (levels 3-4) and severe (levels 5-7). Normalized protein expression (NPX) values were generated in relation to a common pooled control plasma on each plate. The association between NPX values and disease severity on admission was estimated with logistic regression (LR) after adjustment for age, sex, race, and select comorbidities. Ingenuity Pathway Analysis (IPA) was employed after application of the Benjamini-Hochberg procedure with a false discovery rate of 5% to all proteins for which the NPX difference was +/-0.8 between groups. Predictive models of disease severity on hospital day 7 using all proteins as potential features were fit using elastic net LR (ENLR) and gradient boosting (GBM). Performance was estimated on a held-out test set (40% of the data) with area under the receiveroperator characteristic curve (AUROC). Results: Of 161 subjects, 85 (53%) were classified as having severe COVID-19. A total of 552 proteins were differentially expressed (Figure 1), and 31 of these proteins met criteria for inclusion in pathway analysis. IPA identified the triggering receptor expressed on myeloid cells 1 (TREM-1) signaling pathway (4 members, p=3.8E-3), the tumor microenvironment (TME) pathway (5 members, p=4.1E-3), and the interleukin 17 (IL-17) signaling pathway (4 members, p=1.8E-2). Interleukin 1 receptor-like 1, a member of the TREM-1 pathway, was the protein most associated with disease severity (OR=3.18, p=1.82E-08). Tumor necrosis factor ligand superfamily member 11 (TNFSF11), a member of the IL-17 signaling pathway was the only factor whose enrichment was associated with less severe disease (OR=0.39, p=2.3E-05). ENLR and GBM predicted disease severity on day 7 with AUROC values of 0.908 (0.828, 0.968) and 0.882 (0.788, 0.957), respectively. Conclusion: We identified pathways differentially expressed between patients with severe and nonsevere COVID-19 associated with immune function and angiogenesis. Several agents currently being investigated to treat severe COVID-19 act on these dysregulated pathways, and future investigations could test whether these proteins act as enrichment markers or response indicators. Integrating protein expression with cellular immune phenotype may help explain COVID-19 pathophysiology.