Initial impact of the COVID-19 pandemic on public health training: participatory action research to understand experiences in the East Midlands.

BACKGROUND: Specialty public health training consists of 48 months of practice across the domains of health protection, healthcare public health and health improvement.With the onset of the COVID-19 pandemic, activity pivoted towards pandemic management and the response became a significant element of registrar practice.This research aimed to understand the impact of this shift in focus on registrars' role and training. METHODS: Participatory action research comprising (i) a reflective survey sent to all specialty registrars in the East Midlands training region and (ii) Delphi rounds with survey respondents to generate consensus and define themes. RESULTS: Sixteen (44%) registrars completed the survey with 12 (75%) participating in the Delphi rounds. The early pandemic response stages both challenged and re-affirmed registrars' role and identity in public health and training while providing unique and diverse learning and development. Underpinning these themes is a variability in experience depending on prior experience, placement and training stage. CONCLUSIONS: The pandemic impacted the practice, training and home-life of registrars who were required to negotiate significant challenge and uncertainty. This original work adds to a growing body of correspondence and opinion pieces articulating the experiences and challenges of medical and public health education during a pandemic.

Covid Sepsis Gene Expression Subphenotypes Manifest Differential Plasma Protein Signatures

INTRODUCTION: Transcriptome-derived sepsis subphenotypes, termed 'adaptive', 'inflammopathic' and 'coagulopathic', have been reliably identified in sepsis cohorts, however plasma proteomics in these groups have not been well characterized. We hypothesized that inflammatory and vascular injury markers would be elevated in the inflammopathic and coagulopathic groups compared to the adaptive group. METHOD(S): We prospectively enrolled and obtained blood from 130 inpatients with COVID19-related sepsis. Severity was classified by NIH ordinal scale. Gene expression analysis was performed by Nanostring nCounter (Inflammatix). Inflammatory proteins interleukin (IL)-6, IL8, IL10, IL1RA, IL1RL1, and IFNg and vascular markers ANGPT2, sICAM, vWF, ADAMTS13, and protein C were measured with OLINK proximity extension assay. Clinical variables were compared by chi-square and protein levels were compared using ANOVA with Bonferroni adjustment. RESULT(S): The transcriptomic classifier identified 32% (41) inflammopathic, 50% (65) adaptive and 18% (24) coagulopathic subjects. The inflammopathic group had more patients requiring mechanical ventilation (39% vs 9% vs 21%;p < 0.001) and higher 90-day mortality (32% vs 8% vs 13%, p = 0.016). Inflammatory cytokines IL8 and IL10 were significantly higher in inflammopathic compared to adaptive (p=0.038 and p=0.017 respectively), but not compared to coagulopathic (p>0.99 and p=0.24, respectively). Both the inflammopathic and coagulopathic groups expressed higher IL1RL1 and interferon-gamma compared to adaptive (IL1RL1;p< 0.001, p=0.002, IFNg;p=0.007, p=0.001). Plasma IL6 and IL1RA did not differ between groups, nor did many vascular proteins. The inflammopathic group expressed higher sICAM (p=0.049 vs adaptive) and lower ADAMTS13 compared to the adaptive group, and the coagulopathic group did not differ in its vascular protein expression. CONCLUSION(S): Transcriptomic subphenotypes are present in COVID-19 sepsis at similar proportions to non-COVID-19 sepsis. Inflammopathic subjects manifested higher severity of illness at admission, higher expression of inflammatory proteins and higher mortality. Markers of vascular injury did not distinguish the coagulopathic group. Integrating RNA and protein expression may offer new insights to host immune dysregulation during COVID sepsis.

A systematic review of GAS implementation practices by caregivers in randomized controlled trials

Aims: Goal attainment scaling (GAS) is an established individualized, patient-centered outcome measure widely used to capture the patient's voice. Although it was first introduced ~ 60 years ago, there are few published guidelines for implementing GAS. This is especially true for its use with caregivers. We conducted a systematic review of randomized controlled trials where GAS was implemented with caregiver input. Method(s): The search protocol was registered in PROSPERO (Oct 2021). We searched Medline, Embase, Cochrane, PsycInfo and CINAHL databases. Variations of these keywords were searched: randomized controlled trials, family caregiver and proxy, goal setting/planning/ attainment/achievement. Three researchers screened and reviewed articles, with one reviewer screening all s and full texts, and the second reviewer screening 25% of s. Covidence software was used to perform screening and data extraction. Result(s): Of 2205 studies imported for screening, 20 studies were included for the final data extraction. Most studies (55%) had GAS as a primary outcome, with over 75% of studies having children as study participants. The most common disorders represented in the review were cerebral palsy (40%), developmental delay disorders (25%) and dementia/Alzheimer's disease (20%). Essential details including the number of goals set, number of attainment levels, baseline level, and training given to GAS facilitators were missing from most studies. Disease-specific semi-standardized goal inventories were not provided. The traditional five-point GAS scale from -2 to + 2 was most commonly implemented, with -1 level being the baseline. Both caregivers and patients were involved in the goalsetting process, with clinicians assessing goal attainment post-intervention. T-tests were often used to analyze most between-group treatment effects, and mean change score was the most common effect size measure reported (median of the mean change score = 5.4, ranging from 0.8 to 45.2). Conclusion(s): GAS with caregivers was feasible in randomized controlled trials across a range of disorders, in diverse patient populations and across disciplines. Many crucial details related to the specifics of GAS implementation were not reported, this limits the potential for reproducibility. A standardized checklist for consistent reporting of GAS details seems useful. In addition, the inclusion of semi-standardized goal inventories may enhance the application of this patient-centered outcome measure.

Comparing impacts of the COVID-19 pandemic on training of public health Specialty Registrars starting before or after its onset.

Objectives: To capture and compare the differences in experiences of public health Specialty Registrars who commenced training prior to the COVID-19 pandemic (pre-pandemic Registrars) and those who commenced training during the pandemic (post-pandemic Registrars). Study design: This is a mixed methods study comprising a cross-sectional survey and participatory action research. Methods: A questionnaire of 10 open and 5 closed questions exploring participants experience of training during the pandemic was sent to East Midlands Specialty Registrars. Thematic analysis and double coding were undertaken, coded based on pre- or post-pandemic Registrar status. Participatory action research was then undertaken in 2 rounds with 2 groups, based on pre/post-pandemic status to consolidate themes. Results: The survey was completed by 17 Registrars (8 pre-pandemic, and 9 post-pandemic) and 19 Registrars took part in participatory action research. The findings showed pre-pandemic Registrars noted the importance of negative impacts on their mental health whilst post-pandemic Registrars were more positive and felt well supported in their training. Conclusions: There is a stark difference in the impact of the pandemic for Registrars who started training before compared to during the pandemic. The training programme was not resilient to the impact of the pandemic. Robustness could be increased by encouraging early leadership experience and providing wellbeing support, particularly for post pandemic Registrars now and in future.

A social media-based campaign to promote COVID-19 vaccine uptake in underrepresented groups in the US

Problem The COVID-19 pandemic highlighted existing healthcare disparities in the US, with people of color dying from COVID-19 at twice the rate of white people. A striking disparity in vaccination rates for racial minorities followed, with vaccination rates among white people over 2.5 times that for Latinx and nearly twice that for Black people (March 2021). It is vital we ensure tailored public health messaging regarding the COVID-19 vaccine is delivered to all communities. Facebook provides an opportunity for large-scale, targeted health promotion. Description of practice Our goal is to increase COVID-19 vaccination uptake across the US, with a specific focus on reaching underrepresented communities most affected by the pandemic. We created a public health campaign centered on a representative group of physicians conveying their own short (<1 minute) video messages that the COVID-19 vaccine is safe and effective. We placed these videos as advertisements on Facebook and directed them using geotargeting to reach zip codes in the US with the highest COVID-19 death rates cross-referenced with zip codes in which >50% of the population is Black or Latinx. We launched the campaign in California on April 9, and nationwide on April 12 2021. The primary outcome measures of the campaign were reach (number of individuals exposed, frequency and duration of views) and engagement (number of likes and shares). Results During our campaign (April 9-April 30), the videos appeared on Facebook newsfeeds 54.4 million times, reaching 9.9 million individuals an average of 5.5 times each. Overall, the videos received 10,053 reactions and 1,161 shares. 1.8 million video plays ran for at least 25% of the video. Lessons We demonstrate the feasibility of rapid, social media-based dissemination of tailored public health messages regarding the COVID-19 vaccine to communities in need. We are now focusing efforts on strategies to assess the impact of such messaging on vaccination uptake. Key messages Geotargeting on social media enabled rapid dissemination of COVID-19 vaccine uptake messages to underrepresented communities. Further work is required to evaluate behavioral change impact.

Utilization of donor-derived cell-free DNA and total cell-free DNA to inform treatment decisions in a pancreas transplant recipient with COVID-19 infection and active rejection

Introduction: Donor derived cell-free DNA (dd-cfDNA) is an established noninvasive biomarker for immunologic rejection of donor tissue in organ transplant recipients. The ProsperaTM test, a SNP-based mmPCR methodology, evaluates ddcfDNA levels as a fraction of total cfDNA. Atypical elevations in total cfDNA, as seen in immunologic responses, could affect the assessment of active rejection (AR). dd-cfDNA has been analyzed in patients undergoing kidney transplants, however, early data suggests that dd-cfDNA behaves similarly following pancreas transplant. Here we present the clinical course of a pancreas transplant recipient with COVID-19 infection for whom, serial dd-cfDNA testing was performed. Case Description: A 51-year-old female received a deceased donor pancreas transplant in August, 2020. The patient was maintained on a triple immunosuppressive (IS) therapy regime, had stable amylase and lipase levels and no episodes of rejection. Six months later, the patient received the first dose of a COVID-19 vaccine, and the second dose three weeks later. The patient's spouse was diagnosed with COVID-19 and soon after, the patient had elevated pancreatic enzymes, 156 and 199 (prior labs 67 and 27) and presented with elevated temperature (100.4 F), cough, fatigue, loss of taste, diarrhea, myalgias and rhinorrhea. The patient was determined to have COVID-19 with a severity score of 2. IS was reduced and monoclonal ab therapy was initiated. dd-cfDNA fraction was 1.38%, indicated high-risk for AR, with corresponding total cfDNA elevated 10.2 multiples of the median (MoM). The patient was treated with Methylprednisolone 500 mg with a PO Prednisone tail. Three weeks later, the patient was negative for COVID-19 and IS was resumed. The dd-cfDNA fraction at this time was 1.59%, and total cfDNA decreased to 1.1 MoM. Subsequent weekly Prospera tests indicated dd-cfDNA fractions of 1.03%, 0.54%, and 0.81% with total cfDNA levels of 1.4 MoM, 1.3 MoM, and 0.94 MoM. Discussion: Measurement of dd-cfDNA can guide IS management in pancreas transplant recipients with COVID-19 undergoing AR. Viral infections and anti-rejection therapies can influence total cfDNA. Thus, continued monitoring of both total and ddcfDNA are needed to identify a true response to therapy.

Early platelet counts distinguish viral and bacterial pulmonary sepsis

Rationale: Respiratory viruses are commonly detected pathogens in pulmonary sepsis. Prior studies have demonstrated that patients with respiratory viral infections may have transient lymphocytopenia and thrombocytopenia. Leukocyte parameters including lymphocyte to monocyte ratio (LMR) and neutrophil to lymphocyte ratio (NLR) have been reported as screening tools for viral infections. Platelet counts and dynamics have been described as quantitative traits for ARDS risk and mortality. Therefore, we hypothesized that early hematologic parameters including lymphocyte count, monocyte count, platelet count, NLR, and LMR may distinguish viral from bacterial pulmonary sepsis. Methods: We enrolled 1,158 critically ill patients with pulmonary sepsis from 2009 to 2020 and measured lymphocyte count, monocyte count, platelet count, NLR, and LMR on ICU admission and at 24-hrs. Respiratory viruses were detected via PCR panel on nasopharyngeal swabs. Pulmonary sepsis was adjudicated by a physician panel. APACHE III scores were collected during the first 24-hrs. Shock was assessed by vasopressor use or mean arterial pressure <65mmHg despite 30cc/kg fluid resuscitation. ARDS was defined per Berlin criteria. We assessed mortality at 30 days. We used multivariable linear regression to test the association between each of the laboratory studies and a positive respiratory pathogen panel (RVP) adjusting for APACHE III score, age, sex, malignancy, and race. We used multivariable logistic regression to assess for associations between a positive RVP and outcomes. Results: The incidence of respiratory virus detection was 33.9%. The incidence of ARDS and mortality were 52.7% and 49.0%, respectively. The most commonly detected pathogens were SARS-CoV-2 and rhinovirus (Table 1). Lower platelet counts at 24-hrs were significantly associated with respiratory virus detection (β-41.59 × 109/L [95%CI-79.03,-4.15], p=0.03), whereas admission platelet counts were not significantly associated (β-22.38 × 109/L [95%CI-63.26, 20.49], p=0.32). The significant association at 24-hrs was also present on sensitivity analyses excluding patients with SARS-CoV-2. There were no statistically significant differences between the populations with respect to lymphocyte count, monocyte count, NLR, LMR, ARDS, shock, and mortality. Conclusion: Lower early platelet counts were identified in patients with viral pulmonary sepsis. Although LMR and NLR have been reported as screening tools for viral infections in non-critically ill populations, we did not detect significant associations between lymphocyte count, monocyte count, NLR or LMR and viral detection in pulmonary sepsis. Our findings suggest that platelet counts in combination with other validated parameters may warrant further investigation for the early discrimination of viral versus bacterial pulmonary sepsis.

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.