Serological response to vaccination in post-acute sequelae of COVID.

BACKGROUND: Individuals with post-acute sequelae of COVID (PASC) may have a persistence in immune activation that differentiates them from individuals who have recovered from COVID without clinical sequelae. To investigate how humoral immune activation may vary in this regard, we compared patterns of vaccine-provoked serological response in patients with PASC compared to individuals recovered from prior COVID without PASC. METHODS: We prospectively studied 245 adults clinically diagnosed with PASC and 86 adults successfully recovered from prior COVID. All participants had measures of humoral immunity to SARS-CoV-2 assayed before or after receiving their first-ever administration of COVID vaccination (either single-dose or two-dose regimen), including anti-spike (IgG-S and IgM-S) and anti-nucleocapsid (IgG-N) antibodies as well as IgG-S angiotensin-converting enzyme 2 (ACE2) binding levels. We used unadjusted and multivariable-adjusted regression analyses to examine the association of PASC compared to COVID-recovered status with post-vaccination measures of humoral immunity. RESULTS: Individuals with PASC mounted consistently higher post-vaccination IgG-S antibody levels when compared to COVID-recovered (median log IgG-S 3.98 versus 3.74, P < 0.001), with similar results seen for ACE2 binding levels (median 99.1 versus 98.2, P = 0.044). The post-vaccination IgM-S response in PASC was attenuated but persistently unchanged over time (P = 0.33), compared to in COVID recovery wherein the IgM-S response expectedly decreased over time (P = 0.002). Findings remained consistent when accounting for demographic and clinical variables including indices of index infection severity and comorbidity burden. CONCLUSION: We found evidence of aberrant immune response distinguishing PASC from recovered COVID. This aberrancy is marked by excess IgG-S activation and ACE2 binding along with findings consistent with a delayed or dysfunctional immunoglobulin class switching, all of which is unmasked by vaccine provocation. These results suggest that measures of aberrant immune response may offer promise as tools for diagnosing and distinguishing PASC from non-PASC phenotypes, in addition to serving as potential targets for intervention.

Symptomology following mRNA vaccination against SARS-CoV-2.

Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination.

Interaction between the RNA binding domains of Ser-Arg splicing factor 1 and U1-70K snRNP protein determines early spliceosome assembly.

It has been widely accepted that the early spliceosome assembly begins with U1 small nuclear ribonucleoprotein (U1 snRNP) binding to the 5' splice site (5'SS), which is assisted by the Ser/Arg (SR)-rich proteins in mammalian cells. In this process, the RS domain of SR proteins is thought to directly interact with the RS motif of U1-70K, which is subject to regulation by RS domain phosphorylation. Here we report that the early spliceosome assembly event is mediated by the RNA recognition domains (RRM) of serine/arginine-rich splicing factor 1 (SRSF1), which bridges the RRM of U1-70K to pre-mRNA by using the surface opposite to the RNA binding site. Specific mutation in the RRM of SRSF1 that disrupted the RRM-RRM interaction also inhibits the formation of spliceosomal E complex and splicing. We further demonstrate that the hypo-phosphorylated RS domain of SRSF1 interacts with its own RRM, thus competing with U1-70K binding, whereas the hyper-phosphorylated RS domain permits the formation of a ternary complex containing ESE, an SR protein, and U1 snRNP. Therefore, phosphorylation of the RS domain in SRSF1 appears to induce a key molecular switch from intra- to intermolecular interactions, suggesting a plausible mechanism for the documented requirement for the phosphorylation/dephosphorylation cycle during pre-mRNA splicing.

The SRSF1 linker induces semi-conservative ESE binding by cooperating with the RRMs.

SR proteins promote spliceosome formation by recognizing exonic splicing enhancers (ESEs) during pre-mRNA splicing. Each SR protein binds diverse ESEs using strategies that are yet to be elucidated. Here, we show that the RNA-binding domain (RBD) of SRSF1 optimally binds to decameric purine rich ESE sequences although locations of purines are not stringently specified. The presence of uracils either within or outside of the recognition site is detrimental for binding with SRSF1. The entire RBD, comprised of two RRMs and a glycine-rich linker, is essential for ESE binding. Mutation within each segment reduced or nearly abolished binding, suggesting that these segments mediate cooperative binding. The linker plays a decisive role in organizing ESE binding. The flanking basic regions of the linker appear to communicate with each other in bringing the two RRMs close together to form the complex with RNA. Our study thus suggests semi-conservative adaptable interaction between ESE and SRSF1, and such binding mode is not only essential for the recognition of plethora of physiological ESE sequences but may also be essential for the interaction with various factors during the spliceosome assembly.

Examining barriers and facilitators in asthma inhaler technique education and technology-enhanced educational tools in children: A mixed methods evaluation using the theoretical domains framework.

INTRODUCTION: Educational interventions for asthma inhaler technique have been identified as successful in improving technique in children, yet inhaler technique has not improved over time. New approaches should be considered, including the use of technology-based interventions such as smartphone and tablet applications. Adoption and implementation of such technology in healthcare has been historically slow. This mixed-methods study aimed to identify the barriers and facilitators of delivering and receiving asthma inhaler education for children in a hospital setting, including technology-based interventions. METHODS: Children with asthma, their caregivers, and healthcare professionals who regularly provide asthma education, were invited to participate in a qualitative interview and brief questionnaire to describe their experiences, knowledge, beliefs, and recommendations about asthma education delivery. The Theoretical Domains Framework was used to develop questions for the semistructured moderator guide, questionnaire, and provide the rigorous evaluation framework for deductive thematic analysis. RESULTS: Sixteen interviews and questionnaires were conducted with participants. Overall, healthcare professionals perceived more barriers in asthma inhaler education delivery than asthmatic children and their caregivers to receiving the education. Healthcare professionals and caregivers identified time-pressures within a hospital setting as a barrier for providing sufficient education. However, all participants felt they had adequate knowledge in their asthma management skills and inhaler technique. Technology-based innovations were viewed positively by all participant groups to improve asthma education. CONCLUSIONS: Several barriers and facilitators to current hospital-based asthma education delivery were reported by target end-users. Future programs should consider these findings when developing asthma inhaler educational interventions, particularly those using technology-enhanced information delivery.

Co-design of an Augmented Reality Asthma Inhaler Educational Intervention for Children: Development and Usability Study.

BACKGROUND: Smartphone and tablet apps that deliver health care education have been identified as effective in improving patient knowledge and treatment adherence in asthma populations. Despite asthma being the most common chronic disease in pediatrics, there are few apps that are targeted specifically for children. Only half of children with asthma have acceptable control of their symptoms, and 40%-98% do not use their inhalers correctly. With children being increasingly connected to technology, there is an opportunity to improve asthma inhaler technique education by delivery via smartphone or tablet apps. Augmented reality (AR) technology was used in this study to capitalize on growing technological innovations. Digital health interventions that use a co-design process for development have the highest likelihood of successful uptake and effectiveness on their intended outcomes. Perceived usability also has been shown to improve the effectiveness of education as well as the acceptance of the intervention. OBJECTIVE: The aims of this study were to describe the co-design process, development, and design outcomes of a smartphone or tablet app that incorporates AR technology to deliver asthma inhaler technique education to children with asthma. This study also aimed to provide a usability evaluation, using the System Usability Scale to inform our work and future research, and recommendations for others performing similar work. METHODS: The development of the AR asthma inhaler technique education app was based on an iterative co-design process with likely end users (children with asthma, their caregivers, and health care professionals). This involved multiple stages: recruitment of end users for qualitative interviews and usability testing with a previously designed educational intervention, which used an AR-embedded smartphone or tablet app; ideation of content for a specific asthma inhaler technique education intervention with end users; development of the specific asthma inhaler intervention; and 2 further rounds of interviews and usability testing with the redesign of the initial prototype. RESULTS: We included 16 participants aged 9-45 years. Using the co-design process, the AR asthma inhaler technique education app was designed, incorporating the preferences of end users. After iteration 1, animation was included based on the feedback provided. Iteration 2 feedback resulted in increased AR experiences and the removal of the requirement of a paper-based resource to trigger AR in the third iteration. Throughout all rounds, the ease of use of the app and the novel nature of the intervention were frequently described. The usability of the intervention overall was perceived to be excellent, and the mean System Usability Scale score of the intervention was found to be highest in the final round of evaluation (90.14). CONCLUSIONS: The results from this co-design process and usability evaluation will be used to develop a final AR asthma inhaler technique educational intervention, which will be evaluated in the clinical setting. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1177/16094069211042229.

The Acceptability of Using Augmented Reality as a Mechanism to Engage Children in Asthma Inhaler Technique Training: Qualitative Interview Study With Deductive Thematic Analysis.

BACKGROUND: Inhaled medications or inhalers provide first-line pharmacotherapeutic treatment for patients with asthma for both acute symptomatic relief and long-term management to keep symptoms under control. A good technique requires only basic instruction and training; however, a recent study identified that 92% of children do not follow all correct steps when using inhalers. There is a growing interest in technology-enhanced asthma education, with evidence demonstrating improvements in knowledge and treatment adherence. Subsequently, there are calls to explore the role of technology-based solutions in improving asthma management and disease outcomes from public health experts, health professionals, and patients with asthma. Augmented reality (AR) technology is an information delivery mechanism with proven efficacy in educational settings. AR displays digital content in a real-world environment using the camera on a smartphone or tablet device to create an immersive learning experience. OBJECTIVE: The study aimed to evaluate the acceptability of AR as a mechanism for delivering asthma inhaler technique education from the perspective of children with asthma and their parents and health professionals, examined through the theoretical framework of acceptability (TFA). METHODS: An asthma education resource enhanced with AR technology was created to provide inhaler technique education to children. An iterative co-design process was undertaken with target end users for a qualitative evaluation. The participants were 8 to 12 years old with asthma, their caregivers, and health professionals who had experience in managing asthma. Qualitative data were obtained through semistructured one-on-one interviews. Deductive thematic analysis using TFA was undertaken using NVivo software 2020 to assess the acceptability of AR as a delivery modality for asthma inhaler technique education. RESULTS: Overall, 6 health care professionals, 5 asthmatic children, and 5 caregivers of children with asthma totaled a sample of 16. The use of AR in the asthma inhaler resource was found to be acceptable when responses were examined in accordance with TFA. Each of the 7 component constructs of TFA was coded throughout the 16 interviews, with perceived effectiveness (157 times) and affective attitude (63 times) coded most frequently. Positive responses included the intervention being accessible, easy to use, interesting, and fitting within the users' value systems. Negative responses included the need to maintain an interest in children and concerns about the loss of face-to-face interaction with health professionals. CONCLUSIONS: AR appears to be an acceptable modality for delivering asthma education to children when explored using TFA constructs. Although some challenges were identified with the use of AR, the results were predominantly positive. Future designs of asthma education interventions involving AR should consider the results of this study, and further research should focus on the feasibility, usability, and barriers and facilitators of behavior change to ensure the successful implementation and uptake of AR into clinical settings. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1177/16094069211042229.

Cardiac microstructural alterations measured by echocardiography identify sex-specific risk for heart failure.

OBJECTIVE: Established preclinical imaging assessments of heart failure (HF) risk are based on macrostructural cardiac remodelling. Given that microstructural alterations may also influence HF risk, particularly in women, we examined associations between microstructural alterations and incident HF. METHODS: We studied N=2511 adult participants (mean age 65.7±8.8 years, 56% women) of the Framingham Offspring Study who were free of cardiovascular disease at baseline. We employed texture analysis of echocardiography to quantify microstructural alteration, based on the high spectrum signal intensity coefficient (HS-SIC). We examined its relations to incident HF in sex-pooled and sex-specific Cox models accounting for traditional HF risk factors and macrostructural alterations. RESULTS: We observed 94 new HF events over 7.4±1.7 years. Individuals with higher HS-SIC had increased risk for incident HF (HR 1.67 per 1-SD in HS-SIC, 95% CI 1.31 to 2.13; p<0.0001). Adjusting for age and antihypertensive medication use, this association was significant in women (p=0.02) but not men (p=0.78). Adjusting for traditional risk factors (including body mass index, total/high-density lipoprotein cholesterol, blood pressure traits, diabetes and smoking) attenuated the association in women (HR 1.30, p=0.07), with mediation of HF risk by the HS-SIC seen for a majority of these risk factors. However, the HS-SIC association with HF in women remained significant after adjusting for relative wall thickness (representing macrostructure alteration) in addition to these risk factors (HR 1.47, p=0.02). CONCLUSIONS: Cardiac microstructural alterations are associated with elevated risk for HF, particularly in women. Microstructural alteration may identify sex-specific pathways by which individuals progress from risk factors to clinical HF.

Disparities in Geographic Access to Cardiac Rehabilitation in Los Angeles County.

Background Exercise-based cardiac rehabilitation (CR) is known to reduce morbidity and mortality for patients with cardiac conditions. Sociodemographic disparities in accessing CR persist and could be related to the distance between where patients live and where CR facilities are located. Our objective is to determine the association between sociodemographic characteristics and geographic proximity to CR facilities. Methods and Results We identified actively operating CR facilities across Los Angeles County and used multivariable Poisson regression to examine the association between sociodemographic characteristics of residential proximity to the nearest CR facility. We also calculated the proportion of residents per area lacking geographic proximity to CR facilities across sociodemographic characteristics, from which we calculated prevalence ratios. We found that racial and ethnic minorities, compared with non-Hispanic White individuals, more frequently live ≥5 miles from a CR facility. The greatest geographic disparity was seen for non-Hispanic Black individuals, with a 2.73 (95% CI, 2.66-2.79) prevalence ratio of living at least 5 miles from a CR facility. Notably, the municipal region with the largest proportion of census tracts comprising mostly non-White residents (those identifying as Hispanic or a race other than White), with median annual household income <$60 000, contained no CR facilities despite ranking among the county's highest in population density. Conclusions Racial, ethnic, and socioeconomic characteristics are significantly associated with lack of geographic proximity to a CR facility. Interventions targeting geographic as well as nongeographic factors may be needed to reduce disparities in access to exercise-based CR programs. Such interventions could increase the potential of CR to benefit patients at high risk for developing adverse cardiovascular outcomes.

Temporal variations in the severity of COVID-19 illness by race and ethnicity.

INTRODUCTION: Early reports highlighted racial/ethnic disparities in the severity of COVID-19 seen across the USA; the extent to which these disparities have persisted over time remains unclear. Our research objective was to understand temporal trends in racial/ethnic variation in severity of COVID-19 illness presenting over time. METHODS: We conducted a retrospective cohort analysis using longitudinal data from Cedars-Sinai Medical Center, a high-volume health system in Southern California. We studied patients admitted to the hospital with COVID-19 illness from 4 March 2020 through 5 December 2020. Our primary outcome was COVID-19 severity of illness among hospitalised patients, assessed by racial/ethnic group status. We defined overall illness severity as an ordinal outcome: hospitalisation but no intensive care unit (ICU) admission; admission to the ICU but no intubation; and intubation or death. RESULTS: A total of 1584 patients with COVID-19 with available demographic and clinical data were included. Hispanic/Latinx compared with non-Hispanic white patients had higher odds of experiencing more severe illness among hospitalised patients (OR 2.28, 95% CI 1.62 to 3.22) and this disparity persisted over time. During the initial 2 months of the pandemic, non-Hispanic blacks were more likely to suffer severe illness than non-Hispanic whites (OR 2.02, 95% CI 1.07 to 3.78); this disparity improved by May, only to return later in the pandemic. CONCLUSION: In our patient sample, the severity of observed COVID-19 illness declined steadily over time, but these clinical improvements were not seen evenly across racial/ethnic groups; greater illness severity continues to be experienced among Hispanic/Latinx patients.