• COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur

  Koupenova, Milka; Chung, Mina K; Bristow, Michael R (2023-05-11)

  The world has finally emerged from the great medical, economic, and social calamity of 2020 to 2022, the COVID-19 pandemic. This Compendium of 10 articles describes various aspects of the effects of SARS-CoV-2 on the cardiovascular system, focusing on the heart. The Minotaur from Greek mythology is an apt metaphor, because this half bull/half man spike-adorned gain of function mutant slaughtered the innocent was nearly impossible to eradicate in his labyrinthian environs, inspired mass fear of the unknown, and ultimately was eliminated by resourceful, determined collaborators.1 Although SARS-CoV-2 infection has not been eliminated, it has been contained to the point of acquiring the status of a manageable infectious disease.
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  Barriers and Facilitators to the Implementation of Adolescent Cancer Prevention Interventions in Rural Primary Care Settings: A Scoping Review

  Ryan, Grace W; Whitmire, Paula; Batten, Annabelle J.; Goulding, Melissa; Baltich Nelson, Becky; Lemon, Stephenie C.; Pbert, Lori (2023-03-13)

  Purpose: We conducted a scoping review of studies to examine the implementation of interventions to promote adolescent cancer prevention in rural, primary care settings and identify barriers and facilitators. Methods: We followed the JBI scoping review protocol and used a systematic extraction and coding process. Our search of MEDLINE, PsycInfo, Cochrane, CINAHL, and Scopus identified articles related to implementation of interventions in the following areas: obesity, human papillomavirus (HPV) vaccination, tobacco use, and sun exposure. We used the Consolidated Framework for Implementation Research (CFIR), an implementation framework consisting of 5 domains (outer setting, inner setting, intervention characteristics, individual characteristics, process), each with a sub-set of constructs, to classify barriers and facilitators reported. Results: We identified 3046 references, excluded 2969 during initial screening, assessed 74 for full-text eligibility, and abstracted 24. Of these, 17 addressed obesity, 6 addressed HPV vaccination, 1 addressed skin cancer, and 1 addressed multiple behaviors. 10 studies were either non-randomized experimental designs (n=8) or randomized controlled trials (n=2). The remaining were observational or descriptive research. Barriers in the outer setting (e.g., lack of external funding sources, patients' beliefs) and inner setting (e.g., time available for implementation efforts and clinic infrastructure) were most common, compared to the other CFIR domains. Similarly, facilitators in the outer setting (e.g., partnerships with other organizations and parents' trust in health care providers) and inner setting (e.g., efficiency in practice protocols) were commonly reported. Conclusions: Adolescence is a critical growth window to establish healthy behaviors to prevent future cancers. Rural areas have higher rates of cancer morbidity and mortality than urban ones, putting rural adolescents at heightened risk for cancers. Yet, we found a dearth of studies addressing the implementation of adolescent cancer prevention in rural primary care settings. Further research is needed to understand the implementation challenges and potential strategies to improve implementation efforts to promote cancer prevention among rural adolescents.
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  Provider perceptions of barriers and facilitators to care in eating disorder treatment for transgender and gender diverse patients: a qualitative study

  Ferrucci, Katarina A; McPhillips, Emily; Lapane, Kate L; Jesdale, Bill M; Dubé, Catherine E (2023-03-08)

  Background: The prevalence of eating disorders is higher in transgender and non-binary compared to cisgender people. Gender diverse people who seek eating disorder treatment often report struggling to find affirming and inclusive treatment from healthcare clinicians. We sought to understand eating disorder care clinicians' perceptions of facilitators of and barriers to effective eating disorder treatment for transgender and gender diverse patients. Methods: In 2022, nineteen US-based licensed mental health clinicians who specialized in eating disorder treatment participated in semi-structured interviews. We used inductive thematic analysis to identify themes around perceptions and knowledge of facilitators and barriers to care for transgender and gender diverse patients diagnosed with eating disorders. Results: Two broad themes were identified: (1) factors affecting access to care; and (2) factors affecting care while in treatment. Within the first theme, the following subthemes were found: stigmatization, family support, financial factors, gendered clinics, scarcity of gender-competent care, and religious communities. Within the second theme, prominent subthemes included discrimination and microaggressions, provider lived experience and education, other patients and parents, institutions of higher education, family-centered care, gendered-centered care, and traditional therapeutic techniques. Conclusion: Many barriers and facilitators have potential to be improved upon, especially those caused by clinicians' lack of knowledge or attitudes towards gender minority patients in treatment. Future research is needed to identify how provider-driven barriers manifest and how they can be improved upon to better patient care experiences.
• Performance of Rapid Antigen Tests Based on Symptom Onset and Close Contact Exposure: A secondary analysis from the Test Us At Home prospective cohort study [preprint]

  Herbert, Carly; Wang, Biqi; Lin, Honghuang; Hafer, Nathaniel; Pretz, Caitlin; Stamegna, Pamela; Tarrant, Seanan; Hartin, Paul; Ferranto, Julia; Behar, Stephanie; et al. (2023-02-24)

  Background: The performance of rapid antigen tests for SARS-CoV-2 (Ag-RDT) in temporal relation to symptom onset or exposure is unknown, as is the impact of vaccination on this relationship. Objective: To evaluate the performance of Ag-RDT compared with RT-PCR based on day after symptom onset or exposure in order to decide on 'when to test'. Design setting and participants: The Test Us at Home study was a longitudinal cohort study that enrolled participants over 2 years old across the United States between October 18, 2021 and February 4, 2022. All participants were asked to conduct Ag-RDT and RT-PCR testing every 48 hours over a 15-day period. Participants with one or more symptoms during the study period were included in the Day Post Symptom Onset (DPSO) analyses, while those who reported a COVID-19 exposure were included in the Day Post Exposure (DPE) analysis. Exposure: Participants were asked to self-report any symptoms or known exposures to SARS-CoV-2 every 48-hours, immediately prior to conducting Ag-RDT and RT-PCR testing. The first day a participant reported one or more symptoms was termed DPSO 0, and the day of exposure was DPE 0. Vaccination status was self-reported. Main outcome and measures: Results of Ag-RDT were self-reported (positive, negative, or invalid) and RT-PCR results were analyzed by a central laboratory. Percent positivity of SARS-CoV-2 and sensitivity of Ag-RDT and RT-PCR by DPSO and DPE were stratified by vaccination status and calculated with 95% confidence intervals. Results: A total of 7,361 participants enrolled in the study. Among them, 2,086 (28.3%) and 546 (7.4%) participants were eligible for the DPSO and DPE analyses, respectively. Unvaccinated participants were nearly twice as likely to test positive for SARS-CoV-2 than vaccinated participants in event of symptoms (PCR+: 27.6% vs 10.1%) or exposure (PCR+: 43.8% vs. 22.2%). The highest proportion of vaccinated and unvaccinated individuals tested positive on DPSO 2 and DPE 5-8. Performance of RT-PCR and Ag-RDT did not differ by vaccination status. Ag-RDT detected 78.0% (95% Confidence Interval: 72.56-82.61) of PCR-confirmed infections by DPSO 4. For exposed participants, Ag-RDT detected 84.9% (95% CI: 75.0-91.4) of PCR-confirmed infections by day five post-exposure (DPE 5). Conclusions and relevance: Performance of Ag-RDT and RT-PCR was highest on DPSO 0-2 and DPE 5 and did not differ by vaccination status. These data suggests that serial testing remains integral to enhancing the performance of Ag-RDT.
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  Data quality considerations for evaluating COVID-19 treatments using real world data: learnings from the National COVID Cohort Collaborative (N3C)

  Sidky, Hythem; Young, Jessica C; Girvin, Andrew T; Lee, Eileen; Shao, Yu Raymond; Hotaling, Nathan; Michael, Sam; Wilkins, Kenneth J; Setoguchi, Soko; Funk, Michele Jonsson (2023-02-17)

  Background: Multi-institution electronic health records (EHR) are a rich source of real world data (RWD) for generating real world evidence (RWE) regarding the utilization, benefits and harms of medical interventions. They provide access to clinical data from large pooled patient populations in addition to laboratory measurements unavailable in insurance claims-based data. However, secondary use of these data for research requires specialized knowledge and careful evaluation of data quality and completeness. We discuss data quality assessments undertaken during the conduct of prep-to-research, focusing on the investigation of treatment safety and effectiveness. Methods: Using the National COVID Cohort Collaborative (N3C) enclave, we defined a patient population using criteria typical in non-interventional inpatient drug effectiveness studies. We present the challenges encountered when constructing this dataset, beginning with an examination of data quality across data partners. We then discuss the methods and best practices used to operationalize several important study elements: exposure to treatment, baseline health comorbidities, and key outcomes of interest. Results: We share our experiences and lessons learned when working with heterogeneous EHR data from over 65 healthcare institutions and 4 common data models. We discuss six key areas of data variability and quality. (1) The specific EHR data elements captured from a site can vary depending on source data model and practice. (2) Data missingness remains a significant issue. (3) Drug exposures can be recorded at different levels and may not contain route of administration or dosage information. (4) Reconstruction of continuous drug exposure intervals may not always be possible. (5) EHR discontinuity is a major concern for capturing history of prior treatment and comorbidities. Lastly, (6) access to EHR data alone limits the potential outcomes which can be used in studies. Conclusions: The creation of large scale centralized multi-site EHR databases such as N3C enables a wide range of research aimed at better understanding treatments and health impacts of many conditions including COVID-19. As with all observational research, it is important that research teams engage with appropriate domain experts to understand the data in order to define research questions that are both clinically important and feasible to address using these real world data.
• Breakthrough SARS-CoV-2 infection outcomes in vaccinated patients with chronic liver disease and cirrhosis: A National COVID Cohort Collaborative study

  Ge, Jin; Digitale, Jean C; Pletcher, Mark J; Lai, Jennifer C (2023-02-17)

  Background and aims: Outcomes of breakthrough SARS-CoV-2 infections have not been well characterized in non-veteran vaccinated patients with chronic liver diseases (CLD). We used the National COVID Cohort Collaborative (N3C) to describe these outcomes. Approach and results: We identified all CLD patients with or without cirrhosis who had SARS-CoV-2 testing in the N3C Data Enclave as of January 15, 2022. We used Poisson regression to estimate incidence rates of breakthrough infections and Cox survival analyses to associate vaccination status with all-cause mortality at 30 days among infected CLD patients. We isolated 278,457 total CLD patients: 43,079 (15%) vaccinated and 235,378 (85%) unvaccinated. Of 43,079 vaccinated patients, 32,838 (76%) were without cirrhosis and 10,441 (24%) with cirrhosis. Breakthrough infection incidences were 5.4 and 4.9 per 1000 person-months for fully vaccinated CLD patients without cirrhosis and with cirrhosis, respectively. Of the 68,048 unvaccinated and 10,441 vaccinated CLD patients with cirrhosis, 15% and 3.7%, respectively, developed SARS-CoV-2 infection. The 30-day outcome of mechanical ventilation or death after SARS-CoV-2 infection for unvaccinated and vaccinated CLD patients with cirrhosis were 15.2% and 7.7%, respectively. Compared to unvaccinated patients with cirrhosis, full vaccination was associated with a 0.34-times adjusted hazard of death at 30 days. Conclusions: In this N3C study, breakthrough infection rates were similar among CLD patients with and without cirrhosis. Full vaccination was associated with a 66% reduction in risk of all-cause mortality for breakthrough infection among CLD patients with cirrhosis. These results provide an additional impetus for increasing vaccination uptake in CLD populations.
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  Coding long COVID: characterizing a new disease through an ICD-10 lens

  Pfaff, Emily R; Madlock-Brown, Charisse; Baratta, John M; Bhatia, Abhishek; Davis, Hannah; Girvin, Andrew; Hill, Elaine; Kelly, Elizabeth; Kostka, Kristin; Loomba, Johanna; et al. (2023-02-16)

  Background: Naming a newly discovered disease is a difficult process; in the context of the COVID-19 pandemic and the existence of post-acute sequelae of SARS-CoV-2 infection (PASC), which includes long COVID, it has proven especially challenging. Disease definitions and assignment of a diagnosis code are often asynchronous and iterative. The clinical definition and our understanding of the underlying mechanisms of long COVID are still in flux, and the deployment of an ICD-10-CM code for long COVID in the USA took nearly 2 years after patients had begun to describe their condition. Here, we leverage the largest publicly available HIPAA-limited dataset about patients with COVID-19 in the US to examine the heterogeneity of adoption and use of U09.9, the ICD-10-CM code for "Post COVID-19 condition, unspecified." Methods: We undertook a number of analyses to characterize the N3C population with a U09.9 diagnosis code (n = 33,782), including assessing person-level demographics and a number of area-level social determinants of health; diagnoses commonly co-occurring with U09.9, clustered using the Louvain algorithm; and quantifying medications and procedures recorded within 60 days of U09.9 diagnosis. We stratified all analyses by age group in order to discern differing patterns of care across the lifespan. Results: We established the diagnoses most commonly co-occurring with U09.9 and algorithmically clustered them into four major categories: cardiopulmonary, neurological, gastrointestinal, and comorbid conditions. Importantly, we discovered that the population of patients diagnosed with U09.9 is demographically skewed toward female, White, non-Hispanic individuals, as well as individuals living in areas with low poverty and low unemployment. Our results also include a characterization of common procedures and medications associated with U09.9-coded patients. Conclusions: This work offers insight into potential subtypes and current practice patterns around long COVID and speaks to the existence of disparities in the diagnosis of patients with long COVID. This latter finding in particular requires further research and urgent remediation.
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  CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer

  Mou, Haiwei; Eskiocak, Onur; Özler, Kadir A; Gorman, Megan; Yue, Junjiayu; Jin, Ying; Wang, Zhikai; Gao, Ya; Janowitz, Tobias; Meyer, Hannah V; et al. (2023-02-08)

  CRISPR/Cas9-driven cancer modeling studies are based on the disruption of tumor suppressor genes by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of Ctnnb1 (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms in vivo. CRISPR/Cas9-mediated exon skipping of Ctnnb1 induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar CTNNB1 exon-skipping events in patients with hepatocellular carcinoma. Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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  A method for comparing multiple imputation techniques: A case study on the U.S. national COVID cohort collaborative

  Casiraghi, Elena; Wong, Rachel; Hall, Margaret; Coleman, Ben; Notaro, Marco; Evans, Michael D; Tronieri, Jena S; Blau, Hannah; Laraway, Bryan; Callahan, Tiffany J; et al. (2023-01-27)

  Healthcare datasets obtained from Electronic Health Records have proven to be extremely useful for assessing associations between patients' predictors and outcomes of interest. However, these datasets often suffer from missing values in a high proportion of cases, whose removal may introduce severe bias. Several multiple imputation algorithms have been proposed to attempt to recover the missing information under an assumed missingness mechanism. Each algorithm presents strengths and weaknesses, and there is currently no consensus on which multiple imputation algorithm works best in a given scenario. Furthermore, the selection of each algorithm's parameters and data-related modeling choices are also both crucial and challenging. In this paper we propose a novel framework to numerically evaluate strategies for handling missing data in the context of statistical analysis, with a particular focus on multiple imputation techniques. We demonstrate the feasibility of our approach on a large cohort of type-2 diabetes patients provided by the National COVID Cohort Collaborative (N3C) Enclave, where we explored the influence of various patient characteristics on outcomes related to COVID-19. Our analysis included classic multiple imputation techniques as well as simple complete-case Inverse Probability Weighted models. Extensive experiments show that our approach can effectively highlight the most promising and performant missing-data handling strategy for our case study. Moreover, our methodology allowed a better understanding of the behavior of the different models and of how it changed as we modified their parameters. Our method is general and can be applied to different research fields and on datasets containing heterogeneous types.
• Association Between Patient and Facility Characteristics and Rehabilitation Outcomes After Joint Replacement Surgery in Different Rehabilitation Settings for Older Adults: A Systematic Review

  Osundolire, Seun; Mbrah, Attah; Liu, Shao-Hsien; Lapane, Kate L (2023-01-04)

  Background and purpose: In the United States, an exponential increase in total hip arthroplasty (THA) and total knee arthroplasty (TKA) demand has occurred over the last 2 decades. Evidence suggesting patients receiving inpatient rehabilitation following a TKA or THA experience similar outcomes as those with rehabilitation in other settings led to dramatic shifts in postsurgical care settings owing to Centers for Medicare & Medicaid Services (CMS) payment reforms. A contemporary synthesis of evidence about the association between patient and facility factors and outcomes from older adults undergoing THA or TKA in the United States is needed. Methods: To identify eligible studies, we searched PubMed, Scopus, and CINAHL. We followed PRISMA guidelines to identify articles evaluating either patient or facility factors associated with outcomes after THA or TKA for older adults who may have been cared for in inpatient settings (ie, inpatient rehabilitation or skilled nursing facility [SNF]). Eligible articles were conducted in the United States and were published between January 1, 2000, and December 31, 2021. Results: We included 8 articles focused on patient factors and 9 focused on facility factors. Most included older adults and the majority were White (in those reporting race/ethnicity). Most studies evaluated outcomes at discharge and showed that patients admitted to inpatient rehabilitation facilities had either similar or better functional outcomes (mobility, self-care, and functional independence measure (FIM) score) and lower length of stay compared with those in SNFs. Few studies focused on home health care. Conclusions: The systematic review focused on older adults showed that findings in these patients are consistent with previous research. Older adults undergoing THA/TKA had acceptable outcomes regardless of postsurgical, inpatient setting of care. Research conducted after CMS payment reforms, in home health care settings, and in more diverse samples is needed. Given the known racial/ethnic disparities in THA/TKA and the shifts to postsurgical home health care with little regulatory oversight of care quality, contemporary research on outcomes of postsurgical THA/TKA outcomes is warranted.
• Pediatrician and Child Adolescent Psychiatrist Perspectives of Coordinated Care for Emerging Adults

  Hugunin, Julie; Khan, Sara; McPhillips, Emily; Davis, Maryann; Larkin, Celine; Skehan, Brian; Lapane, Kate L (2023-01-03)

  Purpose: To explore pediatrician and child/adolescent psychiatrists' perspectives of the role of coordinated care for emerging adults with serious mental health conditions, particularly as they transition to adult care. Methods: Semi-structured individual interviews of a purposive sample of 10 pediatricians and 11 child/adolescent psychiatrists in Massachusetts were used to explore coordinated care for emerging adults. Following verbatim transcription and double coding, we conducted a thematic analysis to identify key themes. Care coordination concepts explored included a case discussion, teamwork, communication methods, medication management, transition to adult care, the healthcare home, and youth and family role. Organizational and societal barriers were also discussed. Results: Providers described key barriers to continuous, coordinated care for youth with serious mental health conditions, including poor communication systems between providers, no organized process for the transition from pediatric to adult care, state licensing laws (particularly impacting college-age youth), inadequate connection to community supports, and poor reimbursement rates for psychiatric care. Termination of primary care in young adults and inadequate medication side effect monitoring were described as key gaps in care. Discussion: The current system of coordinated care for emerging adults with serious mental health conditions is a perfect storm of challenges that creates a vicious cycle of interconnected barriers which lead to fragmented, discontinuous, and sub-par care for this population.
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  Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons

  Kumar, Meenakshi Sundaram; Fowler-Magaw, Megan E; Kulick, Daniel; Boopathy, Sivakumar; Gadd, Del Hayden; Rotunno, Melissa; Douthwright, Catherine; Golebiowski, Diane; Yusuf, Issa; Xu, Zuoshang; et al. (2022-12-16)

  ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.
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  Profiling genome-wide recombination in Epstein Barr virus reveals type-specific patterns and associations with endemic-Burkitt lymphoma

  Agwati, Eddy O; Oduor, Cliff I; Ayieko, Cyrus; Ong'echa, John Michael; Moormann, Ann M; Bailey, Jeffrey A (2022-12-08)

  Background: Endemic Burkitt lymphoma (eBL) is potentiated through the interplay of Epstein Barr virus (EBV) and holoendemic Plasmodium falciparum malaria. To better understand EBV's biology and role in eBL, we characterized genome-wide recombination sites and patterns as a source of genetic diversity in EBV genomes in our well-defined population of eBL cases and controls from Western Kenya. Methods: EBV genomes representing 54 eBL cases and 32 healthy children from the same geographic region in Western Kenya that we previously sequenced were analyzed. Whole-genome multiple sequence alignment, recombination analyses, and phylogenetic inference were made using multiple alignment with fast Fourier transform, recombination detection program 4, and molecular evolutionary genetics analysis. Results: We identified 28 different recombination events and 71 (82.6%) of the 86 EBV genomes analyzed contained evidence of one or more recombinant segments. Associated recombination breakpoints were found to occur in a total of 42 different genes, with only 7 (16.67%) being latent genes. Recombination events were major drivers of clustering within genome-wide phylogenetic trees. The occurrence of recombination segments was comparable between genomes from male and female participants and across age groups. More recombinant segments were found in EBV type 1 genomes (p = 6.4e - 06) and the genomes from the eBLs (p = 0.037). Two recombination events were enriched in the eBLs; event 47 (OR = 4.07, p = 0.038) and event 50 (OR = 14.24, p = 0.012). Conclusions: EBV genomes have extensive evidence of recombination likely acquired progressively and cumulatively over time. Recombination patterns display a heterogeneous occurrence rate across the genome with enrichment in lytic genes. Overall, recombination appears to be a major evolutionary force impacting EBV diversity and genome structure with evidence of the association of specific recombinants with eBL.
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  Vaccination Against SARS-CoV-2 Decreases Risk of Adverse Events in Patients who Develop COVID-19 Following Cancer Surgery

  Verhagen, Nathaniel B; Koerber, Nicolas K; Szabo, Aniko; Taylor, Bradley; Wainaina, J Njeri; Evans, Douglas B; Kothari, Anai N (2022-12-07)

  Early in the COVID-19 pandemic, mortality rates were observed to exceed 25% in patients who developed postoperative SARS-CoV-2 infections.1 This prompted numerous perioperative structural and process changes to mitigate this risk.2,3 As the pandemic has progressed, the emergence of novel therapeutic and preventative measures have proven effective in decreasing the overall burden of SARS-CoV-2 infection. These advances likely reduce the risk in surgical patients; however, this has not been reexamined at a population level. This study reports 30-day adverse postoperative event rates in patients who develop postoperative COVID-19 and measures the impact of vaccination on these outcomes.
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  Development and Beta-Testing of the CONFIDENCE Intervention to Increase Pediatric COVID-19 Vaccination

  Ryan, Grace W; Goulding, Melissa; Borg, Amy; Minkah, Princilla; Beeler, Angela; Rosal, Milagros C; Lemon, Stephenie C (2022-11-17)

  Introduction: Innovative strategies are needed to improve pediatric COVID-19 vaccination rates. We describe the process for developing a clinic-based intervention, CONFIDENCE, to improve pediatric COVID-19 vaccine uptake and present results of our beta-test for feasibility and acceptability. Method: CONFIDENCE included communication training with providers, a poster campaign, and parent-facing educational materials. We assessed feasibility and acceptability through interviews and measured preliminary vaccine intention outcomes with a pre-post parent survey. Interviews were analyzed using rapid qualitative methods. We generated descriptive statistics for variables on the parent survey and used Fisher's exact test to assess pre-post differences. Results: Participating providers (n = 4) reported high levels of feasibility and acceptability. We observed positive trends in parents' (n = 69) reports of discussing vaccination with their provider and the parental decision to accept COVID-19 vaccination. Discussion: Our next steps will be to use more rigorous methods to establish the efficacy and effectiveness of the CONFIDENCE intervention.
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  Youth Empowerment Modeling in building COVID-19 Vaccine Confidence in Local Communities

  Minkah, Princilla; Borg, Amy; Ryan, Grace W.; Goulding, Melissa; Perrone, Domenica; Castiel, Matilde; Rosal, Milagros C.; Lemon, Stephenie C. (2022-11-07)

  Background: Rates of COVID-19 vaccinations among youth remain sub-optimal, particularly among racial and ethnic minority populations. The Centers for Disease Control and Prevention-funded UMass Worcester Prevention Research Center partnered with the vaccination equity initiative of Worcester, Massachusetts and youth-serving organizations to develop, implement, and evaluate a youth led public health campaign to promote COVID-19 vaccine confidence and uptake. Methods: Guided by the youth empowerment model to promote behavior change by helping youth reflect, identify, and take action on what is meaningful to them, we created a youth vaccine ambassador public health campaign to promote COVID-19 vaccination. Ambassadors were guided through self-reflection of questions, answers and motivations for COVID-19 vaccination. Youth motivations and narratives became the campaign messaging. Youth collaborated to create and disseminate social media, video, and print content to display in local neighborhoods, using social norming approaches to foster youth and family vaccine confidence and vaccination. Results: We trained nine youth (aged 18- 22 years) as vaccine ambassadors. English/Spanish vaccine messages developed by youth ambassadors were disseminated through social media platforms (n=3), radio (n=2), local TV (n=2), flyers (n=2,086), posters (n=362), billboards (n=7), and local bus ads (n=18). Qualitative youth feedback indicated participation in the campaign was a positive and empowering experience which reinforces the importance of engaging youth in public health messaging. Discussion: Amplifying youth voices by engaging them to develop and share their personal vaccine stories and motivations facilitated youths’ role as public health messengers. Youth empowerment through storytelling and personal narratives holds promise for future public health campaigns.
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  Association of prenatal modifiable risk factors with attention-deficit hyperactivity disorder outcomes at age 10 and 15 in an extremely low gestational age cohort

  Cochran, David M; Jensen, Elizabeth T; Frazier, Jean A; Jalnapurkar, Isha; Kim, Sohye; Roell, Kyle R; Joseph, Robert M; Hooper, Stephen R; Santos, Hudson P; Kuban, Karl C K; et al. (2022-10-20)

  Background: The increased risk of developing attention-deficit hyperactivity disorder (ADHD) in extremely preterm infants is well-documented. Better understanding of perinatal risk factors, particularly those that are modifiable, can inform prevention efforts. Methods: We examined data from the Extremely Low Gestational Age Newborns (ELGAN) Study. Participants were screened for ADHD at age 10 with the Child Symptom Inventory-4 (N = 734) and assessed at age 15 with a structured diagnostic interview (MINI-KID) to evaluate for the diagnosis of ADHD (N = 575). We studied associations of pre-pregnancy maternal body mass index (BMI), pregestational and/or gestational diabetes, maternal smoking during pregnancy (MSDP), and hypertensive disorders of pregnancy (HDP) with 10-year and 15-year ADHD outcomes. Relative risks were calculated using Poisson regression models with robust error variance, adjusted for maternal age, maternal educational status, use of food stamps, public insurance status, marital status at birth, and family history of ADHD. We defined ADHD as a positive screen on the CSI-4 at age 10 and/or meeting DSM-5 criteria at age 15 on the MINI-KID. We evaluated the robustness of the associations to broadening or restricting the definition of ADHD. We limited the analysis to individuals with IQ ≥ 70 to decrease confounding by cognitive functioning. We evaluated interactions between maternal BMI and diabetes status. We assessed for mediation of risk increase by alterations in inflammatory or neurotrophic protein levels in the first week of life. Results: Elevated maternal BMI and maternal diabetes were each associated with a 55-65% increase in risk of ADHD, with evidence of both additive and multiplicative interactions between the two exposures. MSDP and HDP were not associated with the risk of ADHD outcomes. There was some evidence for association of ADHD outcomes with high levels of inflammatory proteins or moderate levels of neurotrophic proteins, but there was no evidence that these mediated the risk associated with maternal BMI or diabetes. Conclusion: Contrary to previous population-based studies, MSDP and HDP did not predict ADHD outcomes in this extremely preterm cohort, but elevated maternal pre-pregnancy BMI, maternal diabetes, and perinatal inflammatory markers were associated with increased risk of ADHD at age 10 and/or 15, with positive interaction between pre-pregnancy BMI and maternal diabetes.
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  Evaluation of mRNA-1273 Vaccine in Children 6 Months to 5 Years of Age

  Anderson, Evan J; Creech, C Buddy; Berthaud, Vladimir; Piramzadian, Arin; Johnson, Kimball A; Zervos, Marcus; Garner, Fredric; Griffin, Carl; Palanpurwala, Khozema; Turner, Mark; et al. (2022-10-19)

  Background: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown. Methods: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-μg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo. Results: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-μg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-μg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-μg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant. Conclusions: Two 25-μg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).
• COVID-19 in people with neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis

  Banerjee, Jineta; Friedman, Jan M; Klesse, Laura J; Yohay, Kaleb H; Jordan, Justin T; Plotkin, Scott R; Allaway, Robert J; Blakeley, Jaishri O (2022-10-19)

  Purpose: People with pre-existing conditions may be more susceptible to severe COVID-19 when infected by SARS-CoV-2. The relative risk and severity of SARS-CoV-2 infection in people with rare diseases such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN) is unknown. Methods: We investigated the proportions of people with NF1, NF2, or SWN in the National COVID Cohort Collaborative (N3C) electronic health record data set who had a positive test result for SARS-CoV-2 or COVID-19. Results: The cohort sizes in N3C were 2501 (NF1), 665 (NF2), and 762 (SWN). We compared these with N3C cohorts of patients with other rare diseases (98-9844 individuals) and the general non-NF population of 5.6 million. The site- and age-adjusted proportion of people with NF1, NF2, or SWN who had a positive test result for SARS-CoV-2 or COVID-19 (collectively termed positive cases) was not significantly higher than in individuals without NF or other selected rare diseases. There were no severe outcomes reported in the NF2 or SWN cohorts. The proportion of patients experiencing severe outcomes was no greater for people with NF1 than in cohorts with other rare diseases or the general population. Conclusion: Having NF1, NF2, or SWN does not appear to increase the risk of being SARS-CoV-2 positive or of being a patient with COVID-19 or of developing severe complications from SARS-CoV-2.
• A prospective analysis of red blood cell membrane polyunsaturated fatty acid levels and risk of non-Hodgkin lymphoma

  Ardisson Korat, Andres V; Chiu, Yu-Han; Bertrand, Kimberly A; Zhang, Shumin; Epstein, Mara M; Rosner, Bernard A; Chiuve, Stephanie; Campos, Hannia; Giovannucci, Edward L; Chavarro, Jorge E; et al. (2022-10-18)

  Published studies report inconsistent associations of polyunsaturated fatty acid (PUFA) intake with non-Hodgkin lymphoma (NHL) risk. We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants to evaluate a hypothesis of inverse association of pre-diagnosis red blood cell (RBC) membrane PUFA levels with risk of NHL endpoints. We confirmed 583 NHL cases and matched 583 controls by cohort/sex, age, race and blood draw date/time. We estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL endpoints using logistic regression. RBC PUFA levels were not associated with all NHL risk; cis 20:2n-6 was associated with follicular lymphoma risk (OR [95% CI] per one standard deviation increase: 1.35 [1.03-1.77]), and the omega-6/omega-3 PUFA ratio was associated with diffuse large B-cell lymphoma risk (2.33 [1.23-4.43]). Overall, PUFA did not demonstrate a role in NHL etiology; the two unexpected positive associations lack clear biologic explanations.

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