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A microwave plasma disk reactor oxygen source is employed to yield YBa2Cu3O7-x thin films on single crystal substrates of polished (100) yttria stabilized zirconia, and shows that the best film has a measured JC of 2.9 times 10 to the 5th power A/square centimeter at 4 mTorr and 77 kelvin. The film also has an as-deposited Tc of 79.5 kelvin. Molecular oxygen, when used under the same conditions, yields films that are nonsuperconducting as-deposited.

Background: Standing frames are commonly used by healthcare professionals in their practice with children with cerebral palsy (CP) who do not have an independent standing function. A better understanding of healthcare professionals' attitudes and experiences with standing frames may impact practice and rehabilitation. Therefore, this study aimed to investigate the standing frame practice among healthcare professionals and expand their attitude and experience with the use of standing frames for children with CP., Methods: This is an explanatory sequential mixed methods study. A cross-sectional survey was conducted, providing quantitative data on 210 healthcare professionals' use of standing frames. The quantitative data were descriptively analysed. Subsequently, the results from the survey were followed up with five focus group interviews of healthcare professionals (n = 14). The qualitative data were analysed using thematic analysis, enabling integration between the quantitative and qualitative data., Results: When quantitative and qualitative data are integrated, expansion between the two datasets occurred. The quantitative dataset emphasised the use of GMFCS levels as a guideline for recommending standing frames, whereas the qualitative data showed that the healthcare professionals' recommendations were based on individual needs. Furthermore, the healthcare professionals expanded the quantitative data, showing that the healthcare professionals' considerations regarding age and dosage were based on clinical experience, and saw the standing frame as having many benefits., Conclusion: The healthcare professionals had a child-centred approach, where the child's need for using a standing frame was assessed based on the functional level, stage of development, cognitive level and clinical assessment. All of these considerations showed that the use of standing frames for children with CP was individualised, thereby making it difficult to make unified descriptions., (© 2024 The Author(s). Child: Care, Health and Development published by John Wiley & Sons Ltd.)

Post-COVID-19 conditions (long COVID) has impacted many individuals, yet risk factors for this condition are poorly understood. This retrospective analysis of 88,943 COVID-19 patients at a multi-state US health system compares phenotypes, laboratory tests, medication orders, and outcomes for 1,086 long-COVID patients and their matched controls. We found that history of chronic pulmonary disease (CPD) (odds ratio: 1.9, 95% CI: [1.5, 2.6]), migraine (OR: 2.2, [1.6, 3.1]), and fibromyalgia (OR: 2.3, [1.3, 3.8]) were more common for long-COVID patients. During the acute infection phase long COVID patients exhibited high triglycerides, low HDL cholesterol, and a high neutrophil-lymphocyte ratio; and were more likely hospitalized (5% vs. 1%). Our findings suggest severity of acute infection and history of CPD, migraine, chronic fatigue syndrome (CFS), or fibromyalgia as risk factors for long COVID. These results suggest that suppressing acute disease severity proactively, especially in patients at high risk, can reduce incidence of long COVID., Competing Interests: P.G. was an employee of nference and is a current employee of ConcertAI and has financial interests in these companies and the successful application of this research. M.N., C.P., H.B., U.Y., P.L., P.K., M.N., J.R., S.A., and A.V. are employees of nference and have financial interests in the company and in the successful application of this research. V.S. is an employee of nference and Anumana and has financial interests in these companies and in the successful application of this research. J.O. has received small grants from nference, Inc., and personal consulting fees from Bates College and Elsevier Inc. All of these activities are outside of the present work. R.H. has received a small grant from nference, Inc. and Zealand Pharmaceuticals, and consulting fees from Nestle Nutrition. C.R. acknowledges funding from the National Institutes of Health (1OT2HL162096-01). A.T. is an employee and shareholder of Vir Biotechnology Inc., (© 2024 The Author(s).)

The lack of innovation in von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by patients with VWD. Recently, a few research initiatives aiming to move past replacement therapies using plasma-derived or recombinant von Willebrand factor (VWF) concentrates have started to emerge. Here, we report an original approach using synthetic platelet (SP) nanoparticles for the treatment of VWD type 2B (VWD-2B) and severe VWD (type 3 VWD). SP are liposomal nanoparticles decorated with peptides enabling them to concomitantly bind to collagen, VWF, and activated platelets. In vitro, using various microfluidic assays, we show the efficacy of SPs to improve thrombus formation in VWF-deficient condition (with human platelets) or using blood from mice with VWD-2B and deficient VWF (VWF-KO, ie, type 3 VWD). In vivo, using a tail-clip assay, SP treatment reduced blood loss by 35% in mice with VWD-2B and 68% in mice with VWF-KO. Additional studies using nanoparticles decorated with various combinations of peptides demonstrated that the collagen-binding peptide, although not sufficient by itself, was crucial for SP efficacy in VWD-2B; whereas all 3 peptides appeared necessary for mice with VWF-KO. Clot imaging by immunofluorescence and scanning electron microscopy revealed that SP treatment of mice with VWF-KO led to a strong clot, similar to those obtained in wild-type mice. Altogether, our results show that SP could represent an attractive therapeutic alternative for VWD, especially considering their long half-life and stability., (© 2023 by The American Society of Hematology.)

The emergence of highly transmissible SARS-CoV-2 variants and vaccine breakthrough infections globally mandated the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 2.13 million SARS-CoV-2 genomes from 188 countries/territories (up to June 2021) and performed whole-genome viral sequencing from 102 COVID-19 patients, including 43 vaccine breakthrough infections. We identified 92 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a 3-month window. Deletions in the Spike protein N-terminal domain were highly enriched for these 'surge-associated mutations' (Odds Ratio = 14.19, 95% CI 6.15-32.75, p value = 3.41 × 10 -10 ). Based on a longitudinal analysis of mutational prevalence globally, we found an expanding repertoire of Spike protein deletions proximal to an antigenic supersite in the N-terminal domain that may be one of the key contributors to the evolution of highly transmissible variants. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences from 102 patients and identified 107 unique mutations, including 78 substitutions and 29 deletions. In five patients, we identified distinct deletions between residues 85-90, which reside within a linear B cell epitope. Deletions in this region arose contemporaneously on a diverse background of variants across the globe since December 2020. Overall, our findings based on genomic-epidemiology and clinical surveillance suggest that the genomic deletion of dispensable antigenic regions in SARS-CoV-2 may contribute to the evasion of immune responses and the evolution of highly transmissible variants., (© 2023. The Author(s).)

Purpose: Physical activity (PA) is an important factor contributing to general health. PA declines rapidly during tween years (9-12 years) when children's social world changes. School playgrounds can contribute substantially to children's PA, but little is known about how to motivate tweens to use school playgrounds. Using the three basic psychological needs (autonomy, competence, and relatedness) proposed by the Self-Determination Theory, this qualitative study aimed to investigate how school playgrounds can support tweens' needs., Methods: Tweens (n = 56) participated in focus group go-along interviews in their school playground., Results: We found that tweens needed a variety of play possibilities (autonomy) that challenged their skills (competence) as well as areas to retract and be with friends (relatedness)., Conclusion: This research highlights the importance of incorporating tweens' perspectives in playground design to attract and retain them in play and PA in school playgrounds.

Case reports of patients infected with COVID-19 and influenza virus ("flurona") have raised questions around the prevalence and severity of coinfection. Using data from HHS Protect Public Data Hub, NCBI Virus , and CDC FluView , we analyzed trends in SARS-CoV-2 and influenza hospitalized coinfection cases and strain prevalences. We also characterized coinfection cases across the Mayo Clinic Enterp rise from January 2020 to April 2022. We compared expected and observed coinfection case counts across different waves of the pandemic and assessed symptoms and outcomes of coinfection and COVID-19 monoinfection cases after propensity score matching on clinically relevant baseline characteristics. From both the Mayo Clinic and nationwide datasets, the observed coinfection rate for SARS-CoV-2 and influenza has been higher during the Omicron era (2021 December 14 to 2022 April 2) compared to previous waves, but no higher than expected assuming infection rates are independent. At the Mayo Clinic, only 120 coinfection cases were observed among 197,364 SARS-CoV-2 cases. Coinfected patients were relatively young (mean age: 26.7 years) and had fewer serious comorbidities compared to monoinfected patients. While there were no significant differences in 30-day hospitalization, ICU admission, or mortality rates between coinfected and matched COVID-19 monoinfection cases, coinfection cases reported higher rates of symptoms including congestion, cough, fever/chills, headache, myalgia/arthralgia, pharyngitis, and rhinitis. While most coinfection cases observed at the Mayo Clinic occurred among relatively healthy individuals, further observation is needed to assess outcomes among subpopulations with risk factors for severe COVID-19 such as older age, obesity, and immunocompromised status., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection after full vaccination with BNT162b2 against polymerase chain reaction (PCR)-confirmed symptomatic SARS-CoV-2 infection, in a national medical practice from January 2021 through January 2022. We fit conditional logistic regression (CLR) models stratified on residential county and calendar time of testing to assess the association between time elapsed since vaccination and the odds of symptomatic infection or non-COVID-19 hospitalization (negative control), adjusted for several covariates. There were 5,985 symptomatic individuals with a positive test after full vaccination with BNT162b2 (cases) and 32,728 negative tests contributed by 27,753 symptomatic individuals after full vaccination (controls). The adjusted odds of symptomatic infection were higher 250 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.62, 95% CI: 2.52 to 5.20). The odds of infection were still lower 285 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.50, 95% CI: 0.37 to 0.67), when immune protection approximates the unvaccinated status. Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. The odds of non-COVID-19 associated hospitalization (negative control) decreased with time since vaccination, suggesting a possible underestimation of waning protection by this approach due to confounding factors. In summary, BNT162b2 strongly protected against symptomatic SARS-CoV-2 infection for at least 8 months after full vaccination, but the degree of protection waned significantly over this period., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection against symptomatic infection after vaccination with mRNA-1273. We fit conditional logistic regression (CLR) models stratified on residential county and calendar date of SARS-CoV-2 PCR testing to assess the association between the time elapsed since vaccination and the odds of symptomatic infection, adjusted for several covariates. There were 2,364 symptomatic individuals who had a positive SARS-CoV-2 PCR test after full vaccination with mRNA-1273 ("cases") and 12,949 symptomatic individuals who contributed 15,087 negative tests after full vaccination ("controls"). The odds of symptomatic infection were significantly higher 250 days after full vaccination compared to the date of full vaccination (Odds Ratio [OR]: 2.47, 95% confidence interval [CI]: 1.19-5.13). The odds of non-COVID-19 associated hospitalization and non-COVID-19 pneumonia (negative control outcomes) remained relatively stable over the same time interval (Day 250 OR Non-COVID Hospitalization : 0.68, 95% CI: 0.47-1.0; Day 250 OR Non-COVID Pneumonia : 1.11, 95% CI: 0.24-5.2). The odds of symptomatic infection remained significantly lower almost 300 days after the first mRNA-1273 dose as compared to 4 days after the first dose, when immune protection approximates the unvaccinated state (OR: 0.26, 95% CI: 0.17-0.39). Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. In summary, mRNA-1273 robustly protected against symptomatic SARS-CoV-2 infection at least 8 months after full vaccination, but the degree of protection waned over this time period., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

As of 2021 November 29, booster vaccination against SARS-CoV-2 infection has been recommended for all individuals aged 18 years and older in the United States. A key reason for this recommendation is the expectation that a booster vaccine dose can alleviate observed waning of vaccine effectiveness (VE). Although initial reports of booster effectiveness have been positive, the level of protection from booster vaccination is unclear. We conducted two studies to assess the impact of booster vaccination, with BNT162b2 or mRNA-1273, on the incidence of SARS-CoV-2 infection between August and December 2021. We first compared SARS-CoV-2 infection incidence in cohorts of 3-dose vaccine recipients to incidence in matched cohorts of 2-dose vaccine recipients (cohort size = 24,539 for BNT162b2 and 14,004 for mRNA-1273). Additionally, we applied a test-negative study design to compare the level of protection against symptomatic infection in 3-dose recipients to that observed in recent 2-dose primary vaccine series recipients. The 3-dose recipients experienced a significantly lower incidence rate of SARS-CoV-2 infection than the matched 2-dose cohorts (BNT162b2 Incidence Rate Ratio: 0.11, 95% CI: 0.09 to 0.13 and mRNA-1273 IRR: 0.11, 95% CI: 0.08 to 0.15). Results from the test-negative study showed the third vaccine dose mitigated waning of VE, with the risk of symptomatic infection in 3-dose recipients being comparable to that observed 7 to 73 days after the primary vaccine series. These results show that 3-dose vaccine regimens with BNT162b2 or mRNA-1273 are effective at reducing SARS-CoV-2 infection and support the widespread administration of booster vaccine doses., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

Importance: Recent reports on waning of COVID-19 vaccine-induced immunity have led to the approval and rollout of additional doses and booster vaccinations. Individuals at increased risk of SARS-CoV-2 infection are receiving additional vaccine doses in addition to the regimen that was tested in clinical trials. Risks and adverse event profiles associated with additional vaccine doses are currently not well understood., Objective: To evaluate the safety of third-dose vaccination with US Food and Drug Administration (FDA)-approved COVID-19 mRNA vaccines., Design, Setting, and Participants: This cohort study was conducted using electronic health record (EHR) data from December 2020 to October 2021 from the multistate Mayo Clinic Enterprise. Participants included all 47 999 individuals receiving 3-dose COVID-19 mRNA vaccines within the study setting who met study inclusion criteria. Participants were divided into 2 cohorts by vaccine brand administered and served as their own control groups, with no comparison made between cohorts. Data were analyzed from September through November 2021., Exposures: Three doses of an FDA-authorized COVID-19 mRNA vaccine, BNT162b2 or mRNA-1273., Main Outcomes and Measures: Vaccine-associated adverse events were assessed via EHR report. Adverse event risk was quantified using the percentage of study participants who reported the adverse event within 14 days after each vaccine dose and during a 14-day control period, immediately preceding the first vaccine dose., Results: Among 47 999 individuals who received 3-dose COVID-19 mRNA vaccines, 38 094 individuals (21 835 [57.3%] women; median [IQR] age, 67.4 [52.5-76.5] years) received BNT162b2 (79.4%) and 9905 individuals (5099 [51.5%] women; median [IQR] age, 67.7 [59.5-73.9] years) received mRNA-1273 (20.6%). Reporting of severe adverse events remained low after the third vaccine dose, with rates of pericarditis (0.01%; 95% CI, 0%-0.02%), anaphylaxis (0%; 95% CI, 0%-0.01%), myocarditis (0%; 95% CI, 0%-0.01%), and cerebral venous sinus thrombosis (no individuals) consistent with results from earlier studies. Significantly more individuals reported low-severity adverse events after the third dose compared with after the second dose, including fatigue (2360 individuals [4.92%] vs 1665 individuals [3.47%]; P < .001), lymphadenopathy (1387 individuals [2.89%] vs 995 individuals [2.07%]; P < .001), nausea (1259 individuals [2.62%] vs 979 individuals [2.04%]; P < .001), headache (1185 individuals [2.47%] vs 992 individuals [2.07%]; P < .001), arthralgia (1019 individuals [2.12%] vs 816 individuals [1.70%]; P < .001), myalgia (956 individuals [1.99%] vs 784 individuals [1.63%]; P < .001), diarrhea (817 individuals [1.70%] vs 595 individuals [1.24%]; P < .001), fever (533 individuals [1.11%] vs 391 individuals [0.81%]; P < .001), vomiting (528 individuals [1.10%] vs 385 individuals [0.80%]; P < .001), and chills (224 individuals [0.47%] vs 175 individuals [0.36%]; P = .01)., Conclusions and Relevance: This study found that although third-dose vaccination against SARS-CoV-2 infection was associated with increased reporting of low-severity adverse events, risk of severe adverse events remained comparable with risk associated with the standard 2-dose regime. These findings suggest the safety of third vaccination doses in individuals who were eligible for booster vaccination at the time of this study.

Importance: Continuous assessment of the effectiveness and safety of the US Food and Drug Administration-authorized SARS-CoV-2 vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes., Objective: To evaluate the effectiveness of the Johnson & Johnson Ad26.COV2.S vaccine for preventing SARS-CoV-2 infection., Design, Setting, and Participants: This comparative effectiveness research study used large-scale longitudinal curation of electronic health records from the multistate Mayo Clinic Health System (Minnesota, Arizona, Florida, Wisconsin, and Iowa) to identify vaccinated and unvaccinated adults between February 27 and July 22, 2021. The unvaccinated cohort was matched on a propensity score derived from age, sex, zip code, race, ethnicity, and previous number of SARS-CoV-2 polymerase chain reaction tests. The final study cohort consisted of 8889 patients in the vaccinated group and 88 898 unvaccinated matched patients., Exposure: Single dose of the Ad26.COV2.S vaccine., Main Outcomes and Measures: The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts, measured by SARS-CoV-2 polymerase chain reaction testing., Results: The study was composed of 8889 vaccinated patients (4491 men [50.5%]; mean [SD] age, 52.4 [16.9] years) and 88 898 unvaccinated patients (44 748 men [50.3%]; mean [SD] age, 51.7 [16.7] years). The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts was 0.26 (95% CI, 0.20-0.34) (60 of 8889 vaccinated patients vs 2236 of 88 898 unvaccinated individuals), which corresponds to an effectiveness of 73.6% (95% CI, 65.9%-79.9%) and a 3.73-fold reduction in SARS-CoV-2 infections., Conclusions and Relevance: This study's findings are consistent with the clinical trial-reported efficacy of Ad26.COV2.S and the first retrospective analysis, suggesting that the vaccine is effective at reducing SARS-CoV-2 infection, even with the spread of variants such as Alpha or Delta that were not present in the original studies, and reaffirm the urgent need to continue mass vaccination efforts globally.

Objective: To assess the association of COVID-19 vaccines and non-COVID-19 vaccines with cerebral venous sinus thrombosis (CVST)., Materials and Method: We retrospectively analyzed a cohort of 771,805 vaccination events across 266,094 patients in the Mayo Clinic Health System between 01/01/2017 and 03/15/2021. The primary outcome was a positive diagnosis of CVST, identified either by the presence of a corresponding ICD code or by an NLP algorithm which detected positive diagnosis of CVST within free-text clinical notes. For each vaccine we calculated the relative risk by dividing the incidence of CVST in the 30 days following vaccination to that in the 30 days preceding vaccination., Results: We identified vaccination events for all FDA-approved COVID-19 vaccines including Pfizer-BioNTech (n = 94,818 doses), Moderna (n = 36,350 doses) and Johnson & Johnson - J&J (n = 1,745 doses). We also identified vaccinations events for 10 common FDA-approved non-COVID-19 vaccines (n = 771,805 doses). There was no statistically significant difference in the incidence rate of CVST in 30-days before and after vaccination for any vaccine in this population. We further found the baseline CVST incidence in the study population between 2017 and 2021 to be 45 to 98 per million patient years., Conclusions: This real-world evidence-based study finds that CVST is rare and is not significantly associated with COVID-19 vaccination in our patient cohort. Limitations include the rarity of CVST in our dataset, a relatively small number of J&J COVID-19 vaccination events, and the use of a population drawn from recipients of a SARS-CoV-2 PCR test in a single health system., Competing Interests: Declaration of Competing Interest JCO receives personal fees from Elsevier and Bates College, and receives small grants from nference, Inc, outside the submitted work. ADB is a consultant for Abbvie, is on scientific advisory boards for nference and Zentalis, and is founder and President of Splissen therapeutics. nference collaborates with Janssen and other bio-pharmaceutical companies on data science initiatives unrelated to this study. These collaborations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JRH, JCO, GJG, AWW, AV, MDS, and ADB are employees of the Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Real-world clinical data to support the use of casirivimab-imdevimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. This study aimed to assess the outcomes of casirivimab-imdevimab treatment of mild to moderate COVID-19., Methods: A retrospective cohort of 696 patients who received casirivimab-imdevimab between December 4, 2020 and April 9, 2021 was compared to a propensity-matched control of 696 untreated patients with mild to moderate COVID-19 at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Primary outcome was rate of hospitalization at days 14, 21 and 28 after infusion., Findings: The median age of the antibody-treated cohort was 63 years (interquartile range, 52-71); 45·5% were ≥65 years old; 51.4% were female. High-risk characteristics were hypertension (52.4%), body mass index ≥35 (31.0%), diabetes mellitus (24.6%), chronic lung disease (22.1%), chronic renal disease (11.4%), congestive heart failure (6.6%), and compromised immune function (6.7%). Compared to the propensity-matched untreated control, patients who received casirivimab-imdevimab had significantly lower all-cause hospitalization rates at day 14 (1.3% vs 3.3%; Absolute Difference: 2.0%; 95% confidence interval (CI): 0.5-3.7%), day 21 (1.3% vs 4.2%; Absolute Difference: 2.9%; 95% CI: 1.2-4.7%), and day 28 (1.6% vs 4.8%; Absolute Difference: 3.2%; 95% CI: 1.4-5.1%). Rates of intensive care unit admission and mortality at days 14, 21 and 28 were similarly low for antibody-treated and untreated groups., Interpretation: Among high-risk patients with mild to moderate COVID-19, casirivimab-imdevimab treatment was associated with a significantly lower rate of hospitalization., Funding: Mayo Clinic., Competing Interests: Dr. Arndt has nothing to disclose. Dr. Arndt has nothing to disclose. Dr. Badley reports personal fees from Abbvie, personal fees from Gilead, personal fees from Freedom Tunnel, personal fees from Pinetree Therapeutics, personal fees from Primmune, personal fees from Immunome, personal fees from Flambeau Diagnostics, personal fees from Corvus, personal fees from Equilium, personal fees from Excision Biotherapeutics, personal fees from Zentilis, personal fees from Nference, outside the submitted work Dr. Bierle has nothing to disclose. Ms. Destro Borgen has nothing to disclose. Dr. Ganesh has nothing to disclose. Dr. Hanson has nothing to disclose. Michelle Hedin has nothing to disclose. Dr. Lenehan reports other from Janssen, outside the submitted work. Dr. O'Horo reports personal fees from Bates College, personal fees from Elsevier, Inc, grants from Nference, Inc, outside the submitted work. Dr. Pawlowski reports personal fees from nference, outside the submitted work. Dr. Puranik reports personal fees from nference, outside the submitted work. Dr. Razonable reports grants from Regeneron, grants from Roche, grants from Gilead, personal fees from Novartis, outside the submitted work. Dr. Seville has nothing to disclose. Dr. Speicher has nothing to disclose. Dr. Tulledge-Scheitel has nothing to disclose. Dr. Venkatakrishnan reports personal fees from nference, outside the submitted work. Dr. Wilker has nothing to disclose., (© 2021 The Authors.)

Equitable vaccination distribution is a priority for outcompeting the transmission of COVID-19. Here, the impact of demographic, socioeconomic, and environmental factors on county-level vaccination rates and COVID-19 incidence changes is assessed. In particular, using data from 3142 US counties with over 328 million individuals, correlations were computed between cumulative vaccination rate and change in COVID-19 incidence from 1 December 2020 to 6 June 2021, with 44 different demographic, environmental, and socioeconomic factors. This correlation analysis was also performed using multivariate linear regression to adjust for age as a potential confounding variable. These correlation analyses demonstrated that counties with high levels of uninsured individuals have significantly lower COVID-19 vaccination rates (Spearman correlation: -0.460, p -value: <0.001). In addition, severe housing problems and high housing costs were strongly correlated with increased COVID-19 incidence (Spearman correlations: 0.335, 0.314, p -values: <0.001, <0.001). This study shows that socioeconomic factors are strongly correlated to both COVID-19 vaccination rates and incidence rates, underscoring the need to improve COVID-19 vaccination campaigns in marginalized communities.

Background: Two US Food and Drug Administration (FDA)-authorized coronavirus disease 2019 (COVID-19) mRNA vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), have demonstrated high efficacy in large phase 3 randomized clinical trials. It is important to assess their effectiveness in a real-world setting., Methods: This is a retrospective analysis of 136,532 individuals in the Mayo Clinic health system (Arizona, Florida, Iowa, Minnesota, and Wisconsin) with PCR testing data between December 1, 2020 and April 20, 2021. We compared clinical outcomes for a vaccinated cohort of 68,266 individuals who received at least one dose of either vaccine (n BNT162b2  = 51,795; n mRNA-1273  = 16,471) and an unvaccinated control cohort of 68,266 individuals propensity matched based on relevant demographic, clinical, and geographic features. We estimated real-world vaccine effectiveness by comparing incidence rates of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR testing and COVID-19-associated hospitalization and intensive care unit (ICU) admission starting 7 days after the second vaccine dose., Findings: The real-world vaccine effectiveness of preventing SARS-CoV-2 infection was 86.1% (95% confidence interval [CI]: 82.4%-89.1%) for BNT162b2 and 93.3% (95% CI: 85.7%-97.4%) for mRNA-1273. BNT162b2 and mRNA-1273 were 88.8% (95% CI: 75.5%-95.7%) and 86.0% (95% CI: 71.6%-93.9%) effective in preventing COVID-19-associated hospitalization. Both vaccines were 100% effective (95% CI BNT162b2 : 51.4%-100%; 95% CI mRNA-1273 : 43.3%-100%) in preventing COVID-19-associated ICU admission., Conclusions: BNT162b2 and mRNA-1273 are effective in a real-world setting and are associated with reduced rates of SARS-CoV-2 infection and decreased burden of COVID-19 on the healthcare system., Funding: This study was funded by nference., Competing Interests: C.P., P.L., A.P., V.A., A.V., M.J.M.N., and V.S. are employees of nference and have financial interests in the company and in the successful application of this research. J.C.O. receives personal fees from Elsevier and Bates College and small grants from nference, Inc., outside of the submitted work. A.D.B. is a consultant for Abbvie, is on scientific advisory boards for nference and Zentalis, and is founder and President of Splissen Therapeutics. J.H., J.C.O., M.D.S., A.V., and A.D.B. are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. nference collaborates with Janssen and other bio-pharmaceutical companies on data science initiatives unrelated to this study. These collaborations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies., (© 2021 Elsevier Inc.)

Background: As the coronavirus disease 2019 (COVID-19) vaccination campaign unfolds, it is important to continuously assess the real-world safety of Food and Drug Administration (FDA)-authorized vaccines. Curation of large-scale electronic health records (EHRs) enables near-real-time safety evaluations that were not previously possible., Methods: In this retrospective study, we deployed deep neural networks over a large EHR system to automatically curate the adverse effects mentioned by physicians in over 1.2 million clinical notes between December 1, 2020 and April 20, 2021. We compared notes from 68,266 individuals who received at least one dose of BNT162b2 (n = 51,795) or mRNA-1273 (n = 16,471) to notes from 68,266 unvaccinated individuals who were matched by demographic, geographic, and clinical features., Findings: Individuals vaccinated with BNT162b2 or mRNA-1273 had a higher rate of return to the clinic, but not the emergency department, after both doses compared to unvaccinated controls. The most frequently documented adverse effects within 7 days of each vaccine dose included myalgia, headache, and fatigue, but the rates of EHR documentation for each side effect were remarkably low compared to those derived from active solicitation during clinical trials. Severe events, including anaphylaxis, facial paralysis, and cerebral venous sinus thrombosis, were rare and occurred at similar frequencies in vaccinated and unvaccinated individuals., Conclusions: This analysis of vaccine-related adverse effects from over 1.2 million EHR notes of more than 130,000 individuals reaffirms the safety and tolerability of the FDA-authorized mRNA COVID-19 vaccines in practice., Funding: This study was funded by nference., Competing Interests: R.M., P.L., E.S., A.P., S.A., C.P., V.A., A.J.V., P.A., A.R., C.C., K.C., D.D., N.K., E.R., G.B., A.M., T.W., and V.S. are employees of nference and have financial interests in the company and in the successful application of this research. R.M. is a student at Boston University School of Medicine. P.L. is a student at Harvard Medical School. J.C.O. receives personal fees from Elsevier and Bates College and small grants from nference outside the submitted work. A.D.B. is a consultant for AbbVie, is on scientific advisory boards for nference and Zentalis, and is founder and president of Splissen Therapeutics. J.H., J.C.O., G.J.G., A.W.W., A.V., M.D.S., and A.D.B. are employees of the Mayo Clinic. The Mayo Clinic may stand to gain financially from the successful outcome of the research. nference collaborates with Janssen and other bio-pharmaceutical companies on data science initiatives unrelated to this study. These collaborations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic conflict-of-interest policies., (© 2021 Elsevier Inc.)

Understanding the relationships between pre-existing conditions and complications of COVID-19 infection is critical to identifying which patients will develop severe disease. Here, we leverage ~1.1 million clinical notes from 1803 hospitalized COVID-19 patients and deep neural network models to characterize associations between 21 pre-existing conditions and the development of 20 complications (e.g. respiratory, cardiovascular, renal, and hematologic) of COVID-19 infection throughout the course of infection (i.e. 0-30 days, 31-60 days, and 61-90 days). Pleural effusion was the most frequent complication of early COVID-19 infection (89/1803 patients, 4.9%) followed by cardiac arrhythmia (45/1803 patients, 2.5%). Notably, hypertension was the most significant risk factor associated with 10 different complications including acute respiratory distress syndrome, cardiac arrhythmia, and anemia. The onset of new complications after 30 days is rare and most commonly involves pleural effusion (31-60 days: 11 patients, 61-90 days: 9 patients). Lastly, comparing the rates of complications with a propensity-matched COVID-negative hospitalized population confirmed the importance of hypertension as a risk factor for early-onset complications. Overall, the associations between pre-COVID conditions and COVID-associated complications presented here may form the basis for the development of risk assessment scores to guide clinical care pathways., (© 2021. The Author(s).)

Here we analyze hospitalized andintensive care unit coronavirus disease 2019 (COVID-19) patient outcomes from the international VIRUS registry (https://clinicaltrials.gov/ct2/show/NCT04323787). We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have a higher mortality-rate (390 of 1012 = 39%) compared to patients administered enoxaparin but not unfractionated heparin (270 of 1939 = 14%), presenting a risk ratio of 2.79 (95% confidence interval [CI]: [2.42, 3.16]; p = 4.45e-52). This difference persists even after balancing on a number of covariates including demographics, comorbidities, admission diagnoses, and method of oxygenation, with an increased mortality rate on discharge from the hospital of 37% (268 of 733) for unfractionated heparin versus 22% (154 of 711) for enoxaparin, presenting a risk ratio of 1.69 (95% CI: [1.42, 2.00]; p = 1.5e-8). In these balanced cohorts, a number of complications occurred at an elevated rate for patients administered unfractionated heparin compared to patients administered enoxaparin, including acute kidney injury, acute cardiac injury, septic shock, and anemia. Furthermore, a higher percentage of Black/African American COVID patients (414 of 1294 [32%]) were noted to receive unfractionated heparin compared to White/Caucasian COVID patients (671 of 2644 [25%]), risk ratio 1.26 (95% CI: [1.14, 1.40]; p = 7.5e-5). After balancing upon available clinical covariates, this difference in anticoagulant use remained statistically significant (311 of 1047 [30%] for Black/African American vs. 263 of 1047 [25%] for White/Caucasian, p = .02, risk ratio 1.18; 95% CI: [1.03, 1.36]). While retrospective studies cannot suggest any causality, these findings motivate the need for follow-up prospective research into the observed racial disparity in anticoagulant use and outcomes for severe COVID-19 patients., (© 2021 The Authors. Journal of Medical Virology Published by Wiley Periodicals LLC.)

Background: Consecutive negative SARS-CoV-2 PCR test results are being considered to estimate viral clearance in COVID-19 patients. However, there are anecdotal reports of hospitalization from protracted COVID-19 complications despite such confirmed viral clearance, presenting a clinical conundrum., Methods: We conducted a retrospective analysis of 222 hospitalized COVID-19 patients to compare those that were readmitted post-viral clearance ( hospitalized post-clearance cohort, n  = 49) with those that were not re-admitted post-viral clearance ( non-hospitalized post-clearance cohort, n  = 173) between February and October 2020. In order to differentiate these two cohorts, we used neural network models for the 'augmented curation' of comorbidities and complications with positive sentiment in the Electronic Hosptial Records physician notes., Findings: In the year preceding COVID-19 onset, anemia ( n  = 13 [26.5%], p-value: 0.007), cardiac arrhythmias ( n  = 14 [28.6%], p-value: 0.015), and acute kidney injury ( n  = 7 [14.3%], p-value: 0.030) were significantly enriched in the physician notes of the hospitalized post-clearance cohort ., Interpretation: Overall, this retrospective study highlights specific pre-existing conditions that are associated with higher hospitalization rates in COVID-19 patients despite viral clearance and motivates follow-up prospective research into the associated risk factors., Funding: This work was supported by Nference, inc., Competing Interests: CP, AJV, ER, CK, GB, AP, NK, AA, RB, ADB, and VS have financial interests in nference, Inc. ADB is a consultant for Abbvie and Flambeau Diagnostics and is a DSMB member at Corvus and Equilium. ADB is on the scientific advisory boards for nference and Zentalis and is founder and President of Splissen therapeutics. JCO receives personal fees from Elsevier and Bates College, and receives small grants from nference, Inc, outside the submitted work. CP, AJV, ER, CK, GB, AP, NK, AA, RB and VS are nference employees. CP, NK, VS, CK, AA, AP, AJV, ER, GB and RB received personal fees from nference. The Mayo Clinic has a Financial Conflict of Interest in technology used in the research and may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies., (© 2021 The Authors.)

Background: Coagulopathies are a major class among COVID-19 associated complications. Although anticoagulants such as unfractionated Heparin and Enoxaparin are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated., Methods: We analyzed records of 1,113 patients in the Mayo Clinic Electronic Health Record (EHR) database who were admitted to the hospital for COVID-19 between April 4, 2020 and August 31, 2020, including 19 different Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Among this patient population, we compared cohorts of patients who received different types of anticoagulants, including 441 patients who received unfractionated Heparin and 166 patients who received Enoxaparin. Clinical outcomes at 28 days were compared, and propensity score matching was used to control for potential confounding variables including: demographics, comorbidities, ICU status, chronic kidney disease stage, and oxygenation status. Patients with a history of acute kidney injury and patients who received multiple types of anticoagulants were excluded from the study., Findings: We find that COVID-19 patients administered unfractionated Heparin but not Enoxaparin have higher rates of 28-day mortality (risk ratio: 4.3; 95% Confidence Interval [C.I.].: [1.8, 10.2]; p -value: 8.5e-4, Benjamini Hochberg [BH] adjusted p -value: 2.1e-3), after controlling for potential confounding factors., Interpretation: This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by Enoxaparin versus unfractionated Heparin., Funding: This work was supported by Nference, inc., Competing Interests: CP, AJV, CK, GB, AP, and VS have financial interests in Nference, Inc. ADB is supported by grants from NIAID (grants AI110173 and AI120698) Amfar (#109593) and Mayo Clinic (HH Shieck Khalifa Bib Zayed Al-Nahyan Named Professorship of Infectious Diseases). ADB is a paid consultant for Abbvie and Flambeau Diagnostics, is a paid member of the DSMB for Corvus Pharmaceuticals and Equilium, owns equity for scientific advisory work in Zentalis and Nference, and is founder and President of Splissen therapeutics. JCO reports personal fees from Elsevier, Inc, personal fees from Bates College, and grants from Nference, Inc, outside the submitted work. CP, AJV, CK, GB, AP, and VS are nference employees. The Mayo Clinic has a Financial Conflict of Interest in technology used in the research and may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies., (© 2021 The Authors.)

Clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection through trained immunity. In this exploratory study, we analyze immunization records from 137,037 individuals who received SARS-CoV-2 PCR tests. We find that polio, Haemophilus influenzae type-B (HIB), measles-mumps-rubella (MMR), Varicella, pneumococcal conjugate (PCV13), Geriatric Flu, and hepatitis A/hepatitis B (HepA-HepB) vaccines administered in the past 1, 2, and 5 years are associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, comorbidities, and number of other vaccinations. Furthermore, age, race/ethnicity, and blood group stratified analyses reveal significantly lower SARS-CoV-2 rate among black individuals who have taken the PCV13 vaccine, with relative risk of 0.45 at the 5 year time horizon (n: 653, 95% CI (0.32, 0.64), p-value: 6.9e-05). Overall, this study identifies existing approved vaccines which can be promising candidates for pre-clinical research and Randomized Clinical Trials towards combating COVID-19.

Background: It remains unclear if schoolyard interventions "just" provide more opportunities for those children who are already active. The authors wanted to investigate schoolyard use and physical activity (PA) among the least-active children during recess following schoolyard renewals., Methods: An intervention study design with preresults and postresults comparison was used. Accelerometer and global positioning system data were collected at 6 Danish schools from 553 children at baseline and 439 after renewals (grades 4-9). Based on mean minutes of recess moderate to vigorous PA per child per school, the least-active children were defined as all children in the lowest activity quartile at baseline and follow-up, respectively., Results: One hundred and thirty-five children (70% girls) at baseline and 108 (76% girls) at follow-up were categorized as the least-active children. At follow-up they accumulated more time (12.1 min/d) and PA (4.4 min/d) in the schoolyard during recess compared with baseline. The difference in schoolyard PA found for the least-active children was relatively small compared with the difference for all children., Conclusions: Solely improving the physical schoolyard environment seemed to have limited impact on the least-active children's PA. Future studies should investigate the complex interrelations between the least-active children and the entire schoolyard environment.

Objectives: Pediatric chronic abdominal pain (CAP) is typically managed in primary care settings, although specialty referrals may help patients access the full range of biopsychosocial treatment options. We investigated patterns of specialty referral (gastroenterology or mental health) among children with CAP seen in an academic pediatric primary care clinic., Methods: We retrospectively identified patients age 4-17 years visiting our primary care clinic in 2016-2017 for abdominal pain, identified using International Classification of Diseases (ICD) codes. We excluded patients whose symptoms did not persist for 3 months or who were referred to a specialist before their symptoms had persisted for 3 months. Referral outcomes were assessed through December 2018., Results: Of 320 patients with qualifying ICD codes, 253 were excluded because their symptoms did not persist for 3 months; 31 had already been referred to a specialist within 3 months of pain onset; and one chart could not be accessed. Of the remaining 34 patients (22/12 girls/boys, median age 10 years) 10 (29%) were referred to a gastroenterologist and none were referred to mental health specialists. No clinical or demographic factors reached statistically significant associations with gastroenterology referral, although pain duration was shorter among patients who were referred., Conclusions: Children with CAP managed in our primary care clinic were seldom referred to specialists after their pain persisted over 3 months. Increasing focus on cognitive-behavioral therapies for chronic pain, and the low specialty referral rate, indicates that primary care practices should be prepared to offer these treatment modalities to children with CAP., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVID pos ) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVID neg ) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVID neg patients at the time of diagnostic testing, COVID pos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVID pos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVID pos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis., Competing Interests: CP, TW, AP, KM, LL, AV This author is an employee of nference with financial interests in the company, RP, DH, JO, AW, GG, JH, AB One or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. Mayo Clinic is an investor in nference. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. WM One or more of the investigators associated with this project and Mayo Clinic have a Financial Conflict of Interest in technology used in the research and that the investigator(s) and Mayo Clinic may stand to gain financially from the successful outcome of the research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. The author is also involved in the Mayo Clinic Laboratories. EB, HM, NK This author is an employee of the Janssen pharmaceutical companies of J&J with financial interests in the company, VS The author is an employee of nference and has financial interests in the company. Outside the submitted work, Venky Soundararajan is listed as inventor of the following patent: "Systems, methods, and computer readable media for visualization of semantic information and inference of temporal signals indicating salient associations between life science entities" (US20180082197A1)., (© 2020, Pawlowski et al.)

Objective . Frequent or severe headaches are associated with school absenteeism and functional limitation in children, but trends in headache prevalence are uncertain. We used nationally representative data to describe trends in pediatric headache prevalence in the United States, and to evaluate whether headache has remained consistently associated with functional limitations among school-age children. Methods . We analyzed data on children age 5 to 17 years in the 2007 to 2015 National Health Interview Surveys. Caregivers reported whether each child experienced frequent or severe headache in the past 12 months. Weighted proportions and multivariable regression were used to estimate headache prevalence over the study period and associations between headache and measures of functional limitation. Results . The analysis included 57 272 children (mean age = 11 years; 52% female). Frequent or severe headache was reported for 6% of children, with no discernable trend over the study period. On multivariable Poisson regression, headache became more strongly associated with school absenteeism over time. In 2007, frequent or severe headache was associated with a 70% increase in the number of missed school days (incidence risk ratio [IRR] = 1.70; 95% confidence interval [CI] = 1.50-1.91; P < .001), whereas by 2015, headache was associated with a 139% increase in the number of missed school days (IRR = 2.39; 95% CI = 2.02-2.83; P < .001). Conclusion . Though the prevalence of frequent or severe headache in school-age children did not change in 2007 to 2015, headache became more strongly associated with school absenteeism, highlighting the need for improved management of patients with headaches to prevent negative impact on school performance and functional status.

Purpose: With rapidly evolving treatment options in cancer, the complexity in the clinical decision-making process for oncologists represents a growing challenge magnified by oncologists' disposition of intuition-based assessment of treatment risks and overall mortality. Given the unmet need for accurate prognostication with meaningful clinical rationale, we developed a highly interpretable prediction tool to identify patients with high mortality risk before the start of treatment regimens., Methods: We obtained electronic health record data between 2004 and 2014 from a large national cancer center and extracted 401 predictors, including demographics, diagnosis, gene mutations, treatment history, comorbidities, resource utilization, vital signs, and laboratory test results. We built an actionable tool using novel developments in modern machine learning to predict 60-, 90- and 180-day mortality from the start of an anticancer regimen. The model was validated in unseen data against benchmark models., Results: We identified 23,983 patients who initiated 46,646 anticancer treatment lines, with a median survival of 514 days. Our proposed prediction models achieved significantly higher estimation quality in unseen data (area under the curve, 0.83 to 0.86) compared with benchmark models. We identified key predictors of mortality, such as change in weight and albumin levels. The results are presented in an interactive and interpretable tool ( www.oncomortality.com )., Conclusion: Our fully transparent prediction model was able to distinguish with high precision between highest- and lowest-risk patients. Given the rich data available in electronic health records and advances in machine learning methods, this tool can have significant implications for value-based shared decision making at the point of care and personalized goals-of-care management to catalyze practice reforms.