Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

The Post Pandemic Future: Nursing in the Region of the Americas and MentalHealth

The transformative and impactful role of nurses has been highlighted throughout the COVID-19 pandemic. The healthworkforce has endured many particularly difficult challenges during this time, both professionally and in their personallives, in the effort to respond to the needs of communities, patients, and families. As a result, many nurses and otherproviders are facing their own mental health challenges due to the prolonged response to address pandemic challenges. Inthe Region of the Americas, several areas have faced inequities and greater challenge, especially in countries that are low-and middle income. There is a tremendous gap between the number of people who need mental healthcare and thosewho receive it, even with the current health workforce. Increasing national investments in nursing in the Region of theAmericas is necessary and has been addressed by the Pan American Health Organization. A strategic regional focus hasbeen placed to empower healthcare professionals to achieve the levels of education necessary to improve workingconditions and to have leadership roles supported and recognized in a model of resilient health systems. Protecting mentalhealth of providers has become an important lesson of the pandemic and an essential and permanent component in themanagement of health systems and services. This article offers a summary of challenges in the Region of the America asleaders consider the best strategies to support a positive relationship that features resilience, adequate working conditions,and investments in the nursing profession for a post-COVID-19 future that protects workers' mental health © 2023,Online Journal of Issues in Nursing. All Rights Reserved.

Exploring postgraduate epidemiology competencies: Preparing our students for a post-COVID world.

OBJECTIVE: This research sought consensus from both experts and graduates on postgraduate epidemiology competencies. METHODS: In 2021, a two-round online survey using a modified Delphi method was undertaken exploring competencies across six domains. Focus groups were conducted with recent postgraduate epidemiology graduates to assess their viewpoints on learning experiences and employability. RESULTS: Forty-one experts participated in the first Delphi round. Nineteen factors reached consensus (>70% agreement) for importance and feasibility after two survey rounds in the following domains: general epidemiologic methods/concepts (n=8/13), advanced analytic/statistical skills (n=2/7), applied epidemiology/specialised fields (n=1/4), professional/transferrable skills (n=5/14), general public health knowledge/skills (n=2/4), independent research and work-integrated learning (n=1/3). Nine graduates participated in focus groups. A main theme was the substantial value gained in undertaking a dissertation, acknowledging its benefit for applying research skills and for networking opportunities. CONCLUSIONS: To ensure that high-quality epidemiological research and practice continues, we need consensus on the set of essential skills required of graduating students. IMPLICATIONS FOR PUBLIC HEALTH: Competencies for postgraduate epidemiology students require periodic review to safeguard a workforce that can meet emerging challenges and work across academia, research, policy, and practice.

An Enduring Disaster Response: COVID-19 and Pediatric Residency Program Educational Experiences

Background: The COVID-19 pandemic has impacted every facet of our medical system, including trainee education. To date, the extent of the pandemic's impact on graduate medical education training has not been well-characterized. Pediatrics education may have been affected uniquely, given the lower burden of COVID-19+ disease, but potentially high impact of infection control measures. The goal of this project is to describe pediatric program directors' experiences adapting their approach to resident education during the COVID-19 pandemic. Methods: Semi-structured interviews were conducted with United States pediatric residency program directors and associate program directors (PDs). Purposive sampling was employed to ensure diversity in program location and size. Transcripts were independently reviewed and analyzed for emergent codes, with a finalized codebook independently applied to each interview by the authors to ensure consistency. The authors met monthly to discuss memos, interview summaries, and data sufficiency. Thematic inductive analysis was used to identify common themes among interviews. Results: Seventeen interviews were transcribed and coded. Emergent themes included (1) Experiential learning changes, (2) Non-experiential learning changes, (3) Evaluation of changes, (4) Perceived resident reactions to changes, and (5) Future plans. (Table 1). All residency PDs described drastic changes to experiential learning, including modification or suspension of some rotations, reorganization of resident schedules, and the integration of telehealth. Additionally, PDs described significant changes in patient volume, disease presentation, and acuity, and they were concerned about the short- and long-term impact on residents' readiness for independent practice. Regarding non-experiential learning changes, conferences were quickly adapted to a virtual environment, open-source resources were utilized, and novel independent learning activities were created. Changes have been assessed using preexisting structures, which have revealed the acceptability of virtual learning but with waning attendance and engagement. PDs perceived the resident experience as sub-par, with many concerned about the impact of isolation on resident wellbeing and work-life balance. Finally, though most PDs plan to revert to their pre-pandemic curricula, they anticipate continuing both telehealth and hybrid virtual/in person non-experiential learning due to enhanced accessibility of these formats. Conclusion: Despite heterogeneity in location and degree of COVID-19 case impact for the pediatric programs interviewed, all PDs detailed similar and extensive changes to both experiential and non-experiential learning opportunities. Most changes included adapting educational experiences to a virtual environment while continuing core experiential activities in a way that maintained social distancing and preserved the resident workforce. PDs perceived initial engagement in distance learning as enthusiastic but have noted a waning engagement and are concerned about the impact distance learning can have on resident wellbeing. Though many changes were perceived as sub-optimal, some new opportunities for learning were created. Further evaluation is needed to understand the impact of the described changes on pediatric residents' educational experiences and preparedness for practice. (Table Presented).

What do You Consider Marijuana Use? Limitations of Current Surveillance Systems to Monitor Adolescent Marijuana Use

Purpose: Adolescent health surveillance systems are critical for understanding patterns of marijuana use and generating data to evaluate changes in use following marijuana legalization and during the COVID-19 pandemic. The wording of survey questions may be misaligned with adolescents’ language about marijuana use and the ways they consume it. Our objectives were to compare terminology and prevalence of marijuana use between data from a local surveillance system and from a participatory research study. Methods: To understand marijuana use trajectories over the course of adolescence/young adulthood, we conducted the “Model Building with Adolescents on Peers, Partners, and Substance Use” (MAPPS) study. MAPPS was IRB-approved and included participatory group model building (GMB) with youth in Baltimore City. MAPPS participants were recruited from a health clinic and through community partners. Participants’ marijuana use was assessed with the eligibility screener, an enrollment survey, and through GMB exercises that were conducted over the course of four two-hour workshops. GMB exercises included structured activities with youth, including behavior over time graphs and documenting their mental models in real time. Two independent reviewers interpreted youths’ graphed estimates of marijuana use. Lifetime and past 30-day marijuana use prevalence estimates from MAPPS were compared to estimates from the Baltimore Youth Risk Behavior Survey (YRBS), which is conducted in partnership with CDC’s National YRBS program. Results: MAPPS participants (n=20) had an average age of 18;7 (35%) were male and 19 (95%) were Black. MAPPS participants almost exclusively used the terms weed and blunts for marijuana, whereas the Baltimore YRBS used the term marijuana, and mentioned that it was also called “pot, weed, or cannabis.” Results from MAPPS revealed several discrepancies between different assessments of marijuana use;100% reported lifetime use during GMB activities, whereas 50% (n=10) reported lifetime use on the eligibility screener and 60% (n=12) reported lifetime use on the enrollment survey. Collectively, MAPPS participants estimated that 86% of Baltimore 16-year-olds use marijuana, whereas data from the Baltimore YRBS indicate that 30.2% of eleventh graders report past 30-day use. MAPPS participants perceived that there was a high frequency of use among youth who use and explained that youth who “hit a blunt” off someone else, but who do not buy marijuana themselves, would be unlikely to self report as having used marijuana. Conclusions: Our participatory research with urban, Black youth suggests that the terminology they use for marijuana (i.e., weed, blunt) differs from terms used in local surveillance (e.g., marijuana, pot). We also found that they would consider prevalence estimates from surveillance studies to be underestimated because youth who consume peers’ blunts would not characterize themselves as having used marijuana. Therefore, surveillance questionnaires may be misestimating marijuana use due to discrepancies in terminology in questions versus in spoken language, and because collective use is not considered. Misestimations of use limit effective prevention programming, and bias studies that quantify changes in marijuana use following policy changes or during the pandemic. A more comprehensive understanding of patterns of marijuana use is an important step for improving surveillance, evaluation, and clinical assessment. Sources of Support: NIH K01DA035387.

Moderating effects of emotion regulation difficulties and resilience on students’ mental health and well-being during the COVID-19 pandemic

This study examined whether emotion regulation difficulties and resilience in college students moderated changes in mental health over the course of the COVID-19 pandemic. Participants (N = 321) completed surveys assessing mental health, in addition to levels of emotion dysregulation, and resilience during the pandemic, then utilized an anchoring prompt to recall mental health experiences before the pandemic. Correlations revealed participants with higher levels of emotion dysregulation also reported lower levels of resilience. Analyses using the SPSS Macro MEMORE (Montoya, 2019) revealed participants with higher levels of emotion regulation difficulties had greater increases in depression and insomnia, and greater decreases in well-being over the course of the COVID-19 pandemic, while participants with lower levels of resilience had greater increases in depression, anxiety, and insomnia over the course of the pandemic. These results highlight the importance of additional support services and mental health training at universities to meet college students’ immediate and long-term emotional needs stemming from the pandemic. © The Author(s) 2022.

Transition care for congenital heart disease in the COVID- 19: Adaptations & improvisations in a supra regional CHD service in the United Kingdom

Introduction: The COVID-19 pandemic resulted in prioritisation of healthcare resources to cope with the surge in infected patients, S18 Cardiology in the Young: Volume 32 Supplement 1 leading tosuspension of routine clinical services, including Transition Care Services (TCS). In these unprecendented times, our TCS decided to adapt and improvise so that we could continue with the transition process. We present our experience of the last few months of COVID-19. Methods: The TCS is well established across the North West, North Wales&Isle of Man Congenital Heart Disease Network with the 2 weekly Transition Clinics in two major Children's Hospitals in Liverpool & Manchester. The team consists of 1 ACHD cardiologist, 3 paediatric cardiologists and 6 clinical specialist nurses. With the sudden shut down there was the expected pressure on the wait lists and with no clear end in sight, our Network Transition Service decided to go “fully” virtual as soon aswe could set up this platform. We improvised 2 different models: 1. Initiallywe established “Fully VirtualClinics” on theNHS virtual platform“AttendAnywhere”,whereby the patient&family, the adult team and the paediatric team could “log-in” and conduct a virtual clinic. Each clinic had an initial 30 minutes of “TeamHuddle” to reviewpatient data. Based on the status and recent investigations, future-plans were made. 2. Once guidelines were eased, we moved to a “Hybrid Clinic” model, whereby the patientwould attend the children's hospital, have investigations and be seen by the paediatric team. The adult team would remotely log in, on “Attend Anywhere”. Results: Over eighteen-week period during the pandemic, 106 patients were booked in for initially full virtual & subsequently hybrid clinics. 81 attended their appointments. 17 did not attend and 8 cancelled their appointments. Conclusions: These models proved a big success, with good feedback from patients/families. Virtual clinics were particularly popular with youngsters. It took away the need to travel, helped maintaining social-distancing and reduced the risk of COVID- 19 in this vulnerable group. To our knowledge, there have been no studies in theUKlooking at the effect of the COVID-19 on the provision of TCS. This experience has been critical for us to provide our TCS in the future.

Optimizing social and economic activity while containing SARS-CoV-2 transmission using DAEDALUS

To study the trade-off between economic, social and health outcomes in the management of a pandemic, DAEDALUS integrates a dynamic epidemiological model of SARS-CoV-2 transmission with a multi-sector economic model, reflecting sectoral heterogeneity in transmission and complex supply chains. The model identifies mitigation strategies that optimize economic production while constraining infections so that hospital capacity is not exceeded but allowing essential services, including much of the education sector, to remain active. The model differentiates closures by economic sector, keeping those sectors open that contribute little to transmission but much to economic output and those that produce essential services as intermediate or final consumption products. In an illustrative application to 63 sectors in the United Kingdom, the model achieves an economic gain of between £161 billion (24%) and £193 billion (29%) compared to a blanket lockdown of non-essential activities over six months. Although it has been designed for SARS-CoV-2, DAEDALUS is sufficiently flexible to be applicable to pandemics with different epidemiological characteristics. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

The Effects of the COVID-19 Pandemic on Penetrating Neurotrauma at a Level 1 Trauma Center

INTRODUCTION: The COVID-19 pandemic forced the implementation of social distancing guidelines to minimize spread of the coronavirus. However, it is not yet understood what effects these precautions had on the rates of penetrating neurotrauma. METHODS: We retrospectively analyzed neurotrauma data from our institutional trauma registry from distinct periods defined as pre-COVID-19 (March 2019-September 2019) and COVID-19 (March 2020-September 2020). Demographics, injury characteristics, mechanisms of trauma, and past medical history (including psychiatric diagnosis) were collected. Data were analyzed for between-group differences and presented as odds ratios. RESULTS: We observed a significant rise in the number of neurotrauma cases in 2020 (558 vs. 630, OR 1.129 [1.0071, 1.2657]). There was a decrease in the proportion of male victims (71.3% vs. 68.6%, p = 0.03). There were significant differences noted in the mechanism of injury between groups. Patients in 2020 were less likely to present with falls (42.3% vs. 34.3%, OR 0.7119 [0.5627, 0.9005]) and more likely to present with GSW (4.48% vs. 7.78%, OR 1.7981 [1.0951, 2.9523]). Of the patients with penetrating cranial injuries, the most common motive was assault (56.7% vs. 60.0%), followed by self-inflicted (13.3% vs. 20.0%) and accidental (20.0% vs. 18.3%) with a significant difference between years (p = 0.0043). The presence of comorbid psychiatric illness or substance abuse did not confer an increased odds of presenting with penetrating injuries. No significant differences were noted in mean arrival or discharge GCS or injury severity as measured by ISS. However we did observe significant increases in patients presenting with bilaterally reactive pupils (48.3% vs 59.3%, p = 0.0025), patients discharged home (27.6% vs 37.3%, p = 0.0002), and survival at 6 months (41.4% vs. 54.2%, p = 0.0188). CONCLUSION: We observed a higher rate of penetrating neurotrauma while social distancing measures were in place. It is unclear if the psychosocial effects of quarantine and social distancing had a causative relationship with the increased rates of assault and self-inflicted penetrating injuries.

The River and The Highway: How an Interceptor Failure Produced Solutions

The objective of emergency repairs for TRA is to put critical infrastructure that has failed back in to service immediately to prevent or reduce environmental impacts and to restore wastewater collection and transmission service for our customers. After significant rainfall event in March 2020, the Collection Systems Group for the Trinity River Authority of Texas inspected the external conditions of all of the major interceptor lines in the Central Regional Wastewater System for possible line breaks. On March 26, CSG staff identified a major pipeline failure on the 102-inch pipeline for the West Fork interceptor. The pipeline failed in a section immediately adjacent to the West Fork of the Trinity River while the river was in flood stage from the latest significant rain event. The interceptor was passing over 150 MGD of wastewater meant for the CRWS treatment facility, but a portion of the wastewater flow was escaping from the collapsed pipeline in to the river. Once CSG notified the Construction Services group, of the on-call construction contractor, Flow Line Construction, was contacted and immediately mobilized to stop wastewater leakage and to begin pipeline repairs on the collapsed portion of the pipeline. The solution for the emergency repair was multi-faceted: 1)Construction a massive sandbag wall between the failed pipe and the Trinity River to stop wastewater leaking in to the river and to keep the river from washing out the pipeline work are;2) Build a working surface for excavators to access the pipeline site and to setup of bypass pumps;3) Remove the failed section of pipe from the flow path of the wastewater;4) Install bypass piping and pumping equipment and divert flow from the failed pipeline section;5) Install new segments of pipe to restore the pipeline to serviceable conditions;6) Restore bypass flow back to the interceptor and remove bypass pumps and piping;and 7) Perform all of the work listed above while adhering to rapidly changing conditions due to COVID-19 pandemic without having losing one member of the work force to COVID-19. The Roles and Responsibilities of the project team were: 1) Inspection Supervisor – The owner representative that provides direction to the contractor and coordinates construction plans with in-house engineers;2) Engineer – Provided flow ranges for bypass pumping design, collaborated with the contractor to size and layout the bypass pumps, and oversaw the re-installation of the collapsed pipeline;3) Contractor – The contractor staff includes a professional engineer who collaborated with TRA staff to rapidly develop and implement a plan for demolition and reconstruction. In conclusion, while the work took place in a difficult to access area during a period of greater than normal rain and a pandemic, the pipeline was put back in to service in less than 3 weeks. This was through communication, cooperation, and coordination from the contractor, engineers, and inspection staff. Additionally, the river bank was stabilized and armored to prevent future erosion of the pipeline alignment. Copyright © 2021 Water Environment Federation

Predicting the number of new cases of COVID-19 in India using Survival Analysis and LSTM

COVID-19 has been the cause of death for thousands of people across the globe. The goal of this paper is to forecast the new COVID-19 cases in India. The other methods used to forecast COVID-19 cases fail to give results with good accuracy when they try to predict the new cases number for a long time period or when the count of daily cases reported is large since the population of a country is large. The proposed study overcomes the challenge by firstly customizing the dataset. Second, the survival analysis has been utilized to choose appropriate factors, and third, the data will be integrated into the Long Short-Term Memory Network (LSTM). With a mean absolute percentage error of 5.79 percent, data from the 30th of January, 2020, to the 16th of June, 2021, was used to determine the new cases number of even day for the next 21 days.

Integrative analyses identify genes and their functional consequences underlying COVID-19 hospitalization

Recent emergence of SARS-Cov-2 has resulted in unprecedented spread of COVID-19 exhibiting wide variability in individuals’ symptoms. Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of the role of host genetic variation and the molecular mechanisms including the knowledge of genes and pathways that contribute to COVID-19. Previous research to understand the mechanisms underlying severe COVID-19 outcomes have focused on lung- and brain-related pathologies. Here, we integrated a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identified 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. These genes converge on cytokine-cytokine and the JAK-STAT signaling pathways. We functionally characterized the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (BioVU;n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicated these findings in the African-American cohort here in BioVU and found concordant results. This study highlights putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.

An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor-binding domain vaccine in aged mice

[Figure: see text].

Prevalence and outcomes associated with hyperuricemia in hospitalized patients with COVID-19

Background: COVID-19 can increase catabolism and result in hyperuricemia. Uric acid (UA) potentially causes kidney damage by alteration of renal autoregulation, inhibition of endothelial cell proliferation, cell apoptosis, activation of the proinflammatory cascade, and crystal deposition. Hyperuricemia in patients with COVID-19 may contribute to acute kidney injury and poor outcomes. Methods: We included 834 patients with COVID-19 who were >18 years old and hospitalized for >24 hours in the Mount Sinai Health System and had at least one measurement of serum UA. We examined the association between the first serum UA level and major adverse kidney events (MAKE, defined by a composite of all-cause in-hospital mortality or RRT or 100% increase in serum creatinine from baseline), as well as markers of inflammation and cardiac injury. Results: Among the 834 patients, the median age was 66 years, 42% were women, and the median first UA was 5.9 mg/dL (IQR 4.5-8.8). Overall, 52% experienced MAKE, and 32% died during hospitalization. After adjusting for demographics, comorbidities, and laboratory values, a doubling in serum UA was associated with increased MAKE (OR 2.5 per doubling, 95% CI 1.7-3.5) and in-hospital mortality (OR 1.7 per doubling, 95% CI 1.3-2.3) (Figure A & B). Serum UA levels were independently associated with a higher level of procalcitonin (β, 0.6;SE 0.2) and troponin (β, 1.2;SE 0.2) but was not associated with the serum ferritin, CRP, or IL-6 (Figure C). Conclusions: In patients admitted to the hospital for COVID-19, higher UA levels were independently associated with MAKE and mortality in a dose-dependent manner. In addition, hyperuricemia was associated with higher procalcitonin and troponin levels.