Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities.

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.

Comparative B cell and antibody responses induced by adenoviral vectored and mRNA vaccines against COVID-19 (preprint)

Both vector and mRNA vaccines were an important part of the response to the COVID-19 pandemic and may be required in future outbreaks and pandemics. However, adenoviral vectored (AdV) vaccines may be less immunogenic than mRNA vaccines against SARS-CoV-2. We assessed anti-spike and anti-vector immunity among infection-naive Health Care Workers (HCW) following two doses of AdV (AZD1222) versus mRNA (BNT162b2) vaccine. 183 AdV and 274 mRNA vaccinees enrolled between April and October 2021. Median ages were 42 and 39 years, respectively. Blood was collected at least once, 10-48 days after vaccine dose 2. Surrogate virus neutralization test (sVNT) and spike binding antibody titres were a median of 4.2 and 2.2 times lower, respectively, for AdV compared to mRNA vaccinees (p<0.001). Median percentages of memory B cells that recognized fluorescent-tagged spike and RBD were 2.9 and 8.3 times lower, respectively for AdV compared to mRNA vaccinees. Titres of IgG reactive with human Adenovirus type 5 hexon protein rose a median of 2.2-fold after AdV vaccination but were not correlated with anti-spike antibody titres. Together the results show that mRNA induced substantially more sVNT antibody than AdV vaccine due to greater B cell expansion and targeting of the RBD. Pre-existing AdV vector cross-reactive antibodies were boosted following AdV vaccination but had no detectable effect on immunogenicity. Key pointsO_LImRNA SARS-CoV-2 vaccine induced higher surrogate neutralizing antibody titres than adenoviral vaccine C_LIO_LImRNA vaccine induced a more potent, RBD-targeted B cell response than AdV vaccine C_LIO_LIAdenoviral vaccine boosted antibodies against human Adenovirus, but titres dont correlate with anti-spike titres C_LI

The Troublesome Ticks Research Protocol: Developing a Comprehensive, Multidiscipline Research Plan for Investigating Human Tick-Associated Disease in Australia.

In Australia, there is a paucity of data about the extent and impact of zoonotic tick-related illnesses. Even less is understood about a multifaceted illness referred to as Debilitating Symptom Complexes Attributed to Ticks (DSCATT). Here, we describe a research plan for investigating the aetiology, pathophysiology, and clinical outcomes of human tick-associated disease in Australia. Our approach focuses on the transmission of potential pathogens and the immunological responses of the patient after a tick bite. The protocol is strengthened by prospective data collection, the recruitment of two external matched control groups, and sophisticated integrative data analysis which, collectively, will allow the robust demonstration of associations between a tick bite and the development of clinical and pathological abnormalities. Various laboratory analyses are performed including metagenomics to investigate the potential transmission of bacteria, protozoa and/or viruses during tick bite. In addition, multi-omics technology is applied to investigate links between host immune responses and potential infectious and non-infectious disease causations. Psychometric profiling is also used to investigate whether psychological attributes influence symptom development. This research will fill important knowledge gaps about tick-borne diseases. Ultimately, we hope the results will promote improved diagnostic outcomes, and inform the safe management and treatment of patients bitten by ticks in Australia.

Extended Interval Dosing of Ocrelizumab Reduces Risk of Developing Hypogammaglobulinaemia

Introduction Disruption to clinical services, triggered by the COVID-19 pandemic, led to extended intervals between ocrelizumab treatments for some patients. Objectives To assess the rates of developing low immunoglobulin levels and timing of CD19+ B-cell count repopulation in a real-world clinical population. To assess for evidence of clinical or radiological MS disease activity with extended interval dosing of ocrelizumab. Methods We audited 712 patients given ocrelizumab by our seven clinical services. All monitoring of immunoglobulin levels and CD19+ cell counts were recorded. Disease activity was defined as on treatment clinical relapse, radiological activity, and EDSS progression. Results Low immunoglobulin levels developed in 102 patients, the odds ratio for developing hypogam- maglobulinaemia comparing extended to standard interval dosing was 0.42 (CI 0.22-0.81). Disease activity included 20 participants with clinical relapses and 72 with new MRI lesions. There was no evidence of excess clinical or radiological disease activity on switching to extended interval dosing. 38 had EDSS progression, giving an odds ratio comparing extended to standard interval dosing of 0.77 (CI 0.38-1.56). Conclusions This real-world data of extended interval dosing of ocrelizumab indicates lower rates of hypogammaglobulinaemia and no detrimental effect on short-term treatment efficacy.

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Immune profiling of SARS-CoV-2 infection during pregnancy reveals NK cell and γδ T cell perturbations.

Pregnancy poses a greater risk for severe COVID-19; however, underlying immunological changes associated with SARS-CoV-2 during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in unvaccinated pregnant and nonpregnant women with acute and convalescent COVID-19, quantifying 217 immunological parameters. Humoral responses to SARS-CoV-2 were similar in pregnant and nonpregnant women, although our systems serology approach revealed distinct antibody and FcγR profiles between pregnant and nonpregnant women. Cellular analyses demonstrated marked differences in NK cell and unconventional T cell activation dynamics in pregnant women. Healthy pregnant women displayed preactivated NK cells and γδ T cells when compared with healthy nonpregnant women, which remained unchanged during acute and convalescent COVID-19. Conversely, nonpregnant women had prototypical activation of NK and γδ T cells. Activation of CD4+ and CD8+ T cells and T follicular helper cells was similar in SARS-CoV-2-infected pregnant and nonpregnant women, while antibody-secreting B cells were increased in pregnant women during acute COVID-19. Elevated levels of IL-8, IL-10, and IL-18 were found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, we demonstrate perturbations in NK cell and γδ T cell activation in unvaccinated pregnant women with COVID-19, which may impact disease progression and severity during pregnancy.

Advocating for individuals and communities

The role of advocating for individuals and communities not only includes advocating for the basic needs and resources of communities and entails conducting policy advocacy. This chapter provides two accounts of how CHWs provide advocacy and advocate for their profession. CHWs in Arizona advocated for their communities and their workforce on the state, local, and federal level to address the social determinants of health and structural issues such as poverty, unemployment, the built environment, and discrimination. The first team explores stories of CHWs who have advocated on multiple levels, including organizational and policy levels, and discusses the factors that support and hinder CHW advocacy efforts. The team describes how local and grassroots advocacy efforts ultimately helped to create a CHW workforce sustainability movement and support the statewide CHW professional association, Arizona Community Health Workers Association (AzCHOW), in advocating for voluntary certification on the state level. The second team provides timely information on how CHWs with Enlace Chicago advocated for their communities during COVID-19 to address social determinants of health, including poverty, unemployment, discrimination, and exploitation of worker rights, and provide basic needs. The CHW stories describe how advocacy efforts were instrumental in directing community members to food banks, personal protection equipment, sources of employment and workers' rights, and emergency rental assistance programs. These stories underscore how CHWs were often the only links connecting their community members to what they needed while facilitating the community's understanding to public health guidelines during COVID-19 and addressing mental health needs. © Springer Nature Switzerland AG 2021.

Trends in Utilization of Vitreoretinal Services Following the Initial Phase of the 2020 COVID-19 Pandemic.

BACKGROUND: To identify vitreoretinal practice patterns in the months following the initial 2020 national shutdown due to the COVID-19 pandemic in the United States (US). STUDY DESIGN: Retrospective analysis of vitreoretinal practice patterns from multiple retinal centers across the US from January 1, 2018 to December 31, 2020. RESULTS: The lowest utilization of retina care occurred during the week of March 23, 2020, after which utilization returned to pre-pandemic levels by July 2020. Patients with retinal detachments (RDs) presented with worse visual acuity during March, April, and May 2020 compared to the same time periods of 2018 and 2019 (P values < 0.05). However, only comparing eyes that presented in March 2018 to March 2020, was the year 1 vision significantly worse (P = 0.008). CONCLUSION: The COVID-19 pandemic significantly impacted vitreoretinal care. The vision of patients with RDs may not have been affected by the delayed presentation. [Ophthalmic Surg Lasers Imaging Retina 2023;54:15-23.].

Associations between COVID-19 and hospitalisation with respiratory and non-respiratory conditions: a record linkage study.

OBJECTIVES: To assess associations between SARS-CoV-2 infection and the incidence of hospitalisation with selected respiratory and non-respiratory conditions in a largely SARS-CoV-2 vaccine-naïve population . DESIGN, SETTING, PARTICIPANTS: Self-control case series; analysis of population-wide surveillance and administrative data for all laboratory-confirmed COVID-19 cases notified to the Victorian Department of Health (onset, 23 January 2020 - 31 May 2021; ie, prior to widespread vaccination rollout) and linked hospital admissions data (admission dates to 30 September 2021). MAIN OUTCOME MEASURES: Hospitalisation of people with acute COVID-19; incidence rate ratios (IRRs) comparing incidence of hospitalisations with defined conditions (including cardiac, cerebrovascular, venous thrombo-embolic, coagulative, and renal disorders) from three days before to within 89 days of onset of COVID-19 with incidence during baseline period (60-365 days prior to COVID-19 onset). RESULTS: A total of 20 594 COVID-19 cases were notified; 2992 people (14.5%) were hospitalised with COVID-19. The incidence of hospitalisation within 89 days of onset of COVID-19 was higher than during the baseline period for several conditions, including myocarditis and pericarditis (IRR, 14.8; 95% CI, 3.2-68.3), thrombocytopenia (IRR, 7.4; 95% CI, 4.4-12.5), pulmonary embolism (IRR, 6.4; 95% CI, 3.6-11.4), acute myocardial infarction (IRR, 3.9; 95% CI, 2.6-5.8), and cerebral infarction (IRR, 2.3; 95% CI, 1.4-3.9). CONCLUSION: SARS-CoV-2 infection is associated with higher incidence of hospitalisation with several respiratory and non-respiratory conditions. Our findings reinforce the value of COVID-19 mitigation measures such as vaccination, and awareness of these associations should assist the clinical management of people with histories of SARS-CoV-2 infection.

Plasma Protein Profiles Correlate Hemophagocytic Lymphohistiocytosis (Hlh) Signature with More Severe Pediatric Covid-19

Purpose: In general, children have less severe disease with SARSCoV2 infection than adults. However, some children do experience life-threatening sequelae from infection. In order to analyze inflammatory responses to SARS-CoV2 and clinical outcomes, this study evaluates the plasma protein profiles of pediatric COVID19 patients compared to HLH, severe sepsis, Kawasaki disease, febrile viral illness and healthy controls Methods: The Luminex platform measured 150 analytes in 108 patients with pediatric COVID19, 32 of which developed MIS-C, 16 with HLH, 14 with severe sepsis, 25 with Kawasaki disease, 21 with febrile viral illness, and 20 health controls. The results were tested for significant proteins with a p<=0.05 and those that pasted with an FDR cut off of 0.1 and 80% confidence. Semi-supervised learning using protein analyte profiles of inflammatory disease were used to predict COVID19 similarities and clinical outcomes were compared Results: Analyte comparison COVID19 patients revealed increase in CXCL9 in patients with MIS-C. Semi-supervised predictions revealed HLH as the most common predictor and showed that an HLH plasma signature in pediatric patients with COVID19 was associated with higher instances of MIS-C, longer hospital stay, and higher instances of respiratory failure Conclusion(s): This evaluation of plasma proteins demonstrated that pediatric patients with SARS-Cov2 infection with inflammatory plasma profile similar to an HLH signature experienced more severe disease These results reflect complex range of immune responses in children with COVID19, and they support potential for prospective risk stratification using plasma biomarkers.

Circulating effector γδ T cell populations are associated with acute coronavirus disease 19 in unvaccinated individuals.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe coronavirus disease 2019 (COVID-19) in a small proportion of infected individuals. The immune system plays an important role in the defense against SARS-CoV-2, but our understanding of the cellular immune parameters that contribute to severe COVID-19 disease is incomplete. Here, we show that populations of effector γδ T cells are associated with COVID-19 in unvaccinated patients with acute disease. We found that circulating CD27neg CD45RA+ CX3CR1+ Vδ1effector cells expressing Granzymes (Gzms) were enriched in COVID-19 patients with acute disease. Moreover, higher frequencies of GzmB+ Vδ2+ T cells were observed in acute COVID-19 patients. SARS-CoV-2 infection did not alter the γδ T cell receptor repertoire of either Vδ1+ or Vδ2+ subsets. Our work demonstrates an association between effector populations of γδ T cells and acute COVID-19 in unvaccinated individuals.

Is There Utility of Fetal Echocardiogram for Isolated in vitro Fertilization Pregnancies?

Introduction: Risk of congenital heart disease (CHD) for in vitro fertilization (IVF) pregnancies is higher than the general population, though other factors may be involved. IVF is an indication for fetal echocardiogram (FE), however there is center variation to perform FE without a secondary indication if the anatomy ultrasound (AU) is normal. We aim to assess the number of new CHD diagnoses following normal AU in IVF-only pregnancies. Hypothesis: We hypothesize that there is minimal benefit to a FE in IVF-only pregnancies with a normal AU and may result in overutilization of resources. Method(s): Retrospective chart review from 2016-2021 of all IVF pregnancies with and without a secondary indication for FE at our center. Those without FE during the COVID-19 pandemic were included to assess postnatal CHD detection. Patients were classified as IVF-only if they had a normal AU and no secondary indication for FE;all others classified as IVF+other. Maternal and fetal demographics, AU, FE, and postnatal echo (post-echo) data was obtained. Result(s): A total of 556 maternal and 628 fetal patients from IVF pregnancies were included;401 fetuses were IVF-only with a FE, 116 were IVF-only with no FE, the remaining were IVF+other. There was no complex CHD (CCHD) in either IVF-only groups, the FE group detected several minor findings, and the no FE group detected three small septal defects on post-echo (Table 1). The probability of a normal postnatal evaluation in IVF-only with a normal FE was 94% and with no FE was 96%. Minor variations found on FE triggered additional testing (71 total FE in 43 fetuses) and detected a few minor CHD, none requiring intervention. Conclusion(s): Given low-risk for CCHD in IVF-only pregnancies, there is minimal benefit to a FE in the setting of a normal comprehensive AU and raises questions of cost vs. benefit of FE. This may impact future recommendations for indications for FE in the setting of IVF-only without added risk factors for CHD.

The Path to a Bifurcated Tangible Asset Depreciation Regime in Australia

More than two decades after their adoption, the rationale the generous depreciation concessions for small business remains unclear. Several after-the-fact explanations have been suggested, with the most common being a form of compensation for the proportionally high tax compliance burden borne by small businesses. It is, however, difficult to see how accelerated depreciation can provide appropriate offsets for compliance costs, particularly when the benefit is limited to profitable small businesses acquiring tangible property. Moreover, the emphasis on subsidising the acquisition of tangible assets seems misdirected given the 21st century trend towards deriving value from intangible assets and human capital. The small business depreciation system ultimately remains a concession in search for a plausible tax policy basis. This article provides a brief history of the Australian depreciation system to document how the small business depreciation concessions were adopted and how they have evolved to date, beginning with the legislative amendments that consolidated fragmented depreciation rules away from industry-specific tax expenditures in the 1990s. The article explains that the policy of concessions without logical policy objectives continues with more recent ad-hoc concessions, including the temporary COVID-19 measures.

The effect of COVID-19 on training in cardiology: a survey of UK cardiology trainees

Background: The COVID-19 pandemic has had an unprecedented impact on delivering cardiology services. In the UK and many other countries, cardiologists in training were redeployed to other services. To date, the impact of COVID-19 and the requisite NHS response on cardiology training has been unclear. Purpose: To assess the impact of the COVID-19 pandemic on cardiology training in the UK. Methods: An annual survey of UK cardiology trainees was conducted through the national trainee organisation. In 2021, trainees were asked questions regarding their training experience, procedural exposure, and how they had been impacted by COVID-19. Reported procedural numbers were compared with those reported in 2017–2019. Chi squared analyses were used to compare categorical variables with Mann-Whitney U tests used for continuous variables. Results: A total of 576 trainees completed the survey (70% male, mean age 33±3 years). Of 545 respondents who detailed the impact of COVID-19 on training opportunities, 70.5% (n=384) reported a negative or very negative impact. A similar picture was seen when asked about procedure, diagnostic, and outpatient training opportunities (Figure 1). Those completing core cardiology training in 2021 reported performing significantly fewer coronary angiograms (median 170, IQR 85–315) compared with those completing core cardiology training 2017–2019 (median 285, IQR 165–460, p<0.001).Fifty percent of trainees (n=285) reported being redeployed for a median duration of 4 months (IQR 3–5 months). There was substantial regional variation in both the proportion of trainees redeployed (Figure 2, p<0.001) and the median length of redeployment (p=0.008). Those redeployed were more likely to report negative training experiences as a result of COVID-19 (p<0.001). Redeployed trainees completing core cardiology training in 2021 reported undertaking significantly fewer echocardiograms (median 205, IQR 100–300) compared with those not redeployed (median 280, IQR 200–300, p=0.01). Thirty-five percent of all trainees reported being close to burnout, with redeployed trainees being more likely to feel this way (p<0.001). When asked about methods to redress lost training opportunities, 37% of trainees wanted to prolong their training time with a median of 6 months felt to be required (IQR 6–8 months). Discussion: This large survey of the UK experience illustrates the substantial negative impact of COVID-19 on the quality of cardiology training. Redeployment alone resulted in an estimated 95 person-years of lost training time. Coordinated national and regional strategies are required to avoid the creation of a generation of under-trained consultant cardiologists. Funding Acknowledgement: Type of funding sources: None.Figure 1. COVID-19 and training opportunitiesFigure 2. UK map of rates of redeployment

Adjustment to the COVID-19 pandemic: associations with global and situational meaning.

COVID-19 has created pervasive upheaval and uncertainty in communities around the world. This investigation evaluated associations between discrete dimensions of personal meaning and psychological adjustment to the pandemic among community residents in a southern US state. In this cross-sectional study, 544 respondents were assessed during a period of reopening but accelerating infection rates. Validated measures were used to evaluate theoretically distinct dimensions of perceived global meaning (Meaning-in-Life Questionnaire) and pandemic-specific meaning (Meaning in Illness Scale). Adjustment outcomes included perceived stress, pandemic-related helplessness, and acceptance of the pandemic. In multivariate models that controlled for demographic and pandemic-related factors, stronger attained global meaning (i.e., perceptions that life is generally meaningful) and attained situational meaning (i.e., perceptions that the pandemic experience was comprehensible) were related to better adjustment on all three outcomes (all p's < .001). In contrast, seeking situational meaning (i.e., ongoing efforts to find coherence in the situation) was associated with poorer adjustment on all indices (all p's < .001). Results offer novel information regarding theoretically salient dimensions of meaning, which may have direct relevance for understanding how community residents adapt to the challenges of a major public health crisis.