Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection : A Prospective Cohort Study.

BACKGROUND: The performance of rapid antigen tests (Ag-RDTs) for screening asymptomatic and symptomatic persons for SARS-CoV-2 is not well established. OBJECTIVE: To evaluate the performance of Ag-RDTs for detection of SARS-CoV-2 among symptomatic and asymptomatic participants. DESIGN: This prospective cohort study enrolled participants between October 2021 and January 2022. Participants completed Ag-RDTs and reverse transcriptase polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 every 48 hours for 15 days. SETTING: Participants were enrolled digitally throughout the mainland United States. They self-collected anterior nasal swabs for Ag-RDTs and RT-PCR testing. Nasal swabs for RT-PCR were shipped to a central laboratory, whereas Ag-RDTs were done at home. PARTICIPANTS: Of 7361 participants in the study, 5353 who were asymptomatic and negative for SARS-CoV-2 on study day 1 were eligible. In total, 154 participants had at least 1 positive RT-PCR result. MEASUREMENTS: The sensitivity of Ag-RDTs was measured on the basis of testing once (same-day), twice (after 48 hours), and thrice (after a total of 96 hours). The analysis was repeated for different days past index PCR positivity (DPIPPs) to approximate real-world scenarios where testing initiation may not always coincide with DPIPP 0. Results were stratified by symptom status. RESULTS: Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDTs twice 48 hours apart resulted in an aggregated sensitivity of 93.4% (95% CI, 90.4% to 95.9%) among symptomatic participants on DPIPPs 0 to 6. When singleton positive results were excluded, the aggregated sensitivity on DPIPPs 0 to 6 for 2-time serial testing among asymptomatic participants was lower at 62.7% (CI, 57.0% to 70.5%), but it improved to 79.0% (CI, 70.1% to 87.4%) with testing 3 times at 48-hour intervals. LIMITATION: Participants tested every 48 hours; therefore, these data cannot support conclusions about serial testing intervals shorter than 48 hours. CONCLUSION: The performance of Ag-RDTs was optimized when asymptomatic participants tested 3 times at 48-hour intervals and when symptomatic participants tested 2 times separated by 48 hours. PRIMARY FUNDING SOURCE: National Institutes of Health RADx Tech program.

Design and implementation of a digital site-less clinical study of serial rapid antigen testing to identify asymptomatic SARS-CoV-2 infection.

Background: Rapid antigen detection tests (Ag-RDT) for SARS-CoV-2 with emergency use authorization generally include a condition of authorization to evaluate the test's performance in asymptomatic individuals when used serially. We aim to describe a novel study design that was used to generate regulatory-quality data to evaluate the serial use of Ag-RDT in detecting SARS-CoV-2 virus among asymptomatic individuals. Methods: This prospective cohort study used a siteless, digital approach to assess longitudinal performance of Ag-RDT. Individuals over 2 years old from across the USA with no reported COVID-19 symptoms in the 14 days prior to study enrollment were eligible to enroll in this study. Participants throughout the mainland USA were enrolled through a digital platform between October 18, 2021 and February 15, 2022. Participants were asked to test using Ag-RDT and molecular comparators every 48 hours for 15 days. Enrollment demographics, geographic distribution, and SARS-CoV-2 infection rates are reported. Key Results: A total of 7361 participants enrolled in the study, and 492 participants tested positive for SARS-CoV-2, including 154 who were asymptomatic and tested negative to start the study. This exceeded the initial enrollment goals of 60 positive participants. We enrolled participants from 44 US states, and geographic distribution of participants shifted in accordance with the changing COVID-19 prevalence nationwide. Conclusions: The digital site-less approach employed in the "Test Us At Home" study enabled rapid, efficient, and rigorous evaluation of rapid diagnostics for COVID-19 and can be adapted across research disciplines to optimize study enrollment and accessibility.

Efficacy of a Vibrating Crib Mattress to Reduce Pharmacologic Treatment in Opioid-Exposed Newborns: A Randomized Clinical Trial.

Importance: Pharmacologic agents are often used to treat newborns with prenatal opioid exposure (POE) despite known adverse effects on neurodevelopment. Alternative nonpharmacological interventions are needed. Objective: To examine efficacy of a vibrating crib mattress for treating newborns with POE. Design, Setting, and Participants: In this dual-site randomized clinical trial, 208 term newborns with POE, enrolled from March 9, 2017, to March 10, 2020, were studied at their bedside throughout hospitalization. Interventions: Half the cohort received treatment as usual (TAU) and half received standard care plus low-level stochastic (random) vibrotactile stimulation (SVS) using a uniquely constructed crib mattress with a 3-hour on-off cycle. Study initiated in the newborn unit where newborns were randomized to TAU or SVS within 48 hours of birth. All infants whose symptoms met clinical criteria for pharmacologic treatment received morphine in the neonatal intensive care unit per standard care. Main Outcomes and Measures: The a priori primary outcomes analyzed were pharmacotherapy (administration of morphine treatment [AMT], first-line medication at both study sites [number of infants treated], and cumulative morphine dose) and hospital length of stay. Intention-to-treat analysis was conducted. Results: Analyses were performed on 181 newborns who completed hospitalization at the study sites (mean [SD] gestational age, 39.0 [1.2] weeks; mean [SD] birth weight, 3076 (489) g; 100 [55.2%] were female). Of the 181 analyzed infants, 121 (66.9%) were discharged without medication and 60 (33.1%) were transferred to the NICU for morphine treatment (31 [51.7%] TAU and 29 [48.3%] SVS). Treatment rate was not significantly different in the 2 groups: 35.6% (31 of 87 infants who received TAU) and 30.9% (29 of 94 infants who received SVS) (P = .60). Adjusting for site, sex, birth weight, opioid exposure, and feed type, infant duration on the vibrating mattress in the newborn unit was associated with reduction in AMT (adjusted odds ratio, 0.88 hours per day; 95% CI, 0.81-0.93 hours per day). This translated to a 50% relative reduction in AMT for infants who received SVS on average 6 hours per day. Among 32 infants transferred to the neonatal intensive care unit for morphine treatment who completed treatment within 3 weeks, those assigned to SVS finished treatment nearly twice as fast (hazard ratio, 1.96; 95% CI, 1.01-3.81), resulting in 3.18 fewer treatment days (95% CI, -0.47 to -0.04 days) and receiving a mean 1.76 mg/kg less morphine (95% CI, -3.02 to -0.50 mg/kg) than the TAU cohort. No effects of condition were observed among infants treated for more than 3 weeks (n = 28). Conclusions and Relevance: The findings of this clinical trial suggest that SVS may serve as a complementary nonpharmacologic intervention for newborns with POE. Reducing pharmacotherapy with SVS has implications for reduced hospitalization stays and costs, and possibly improved infant outcomes given the known adverse effects of morphine on neurodevelopment. Trial Registration: ClinicalTrials.gov Identifier: NCT02801331.

Social Determinants, Blood Pressure Control, and Racial Inequities in Childbearing Age Women With Hypertension, 2001 to 2018.

Background Hypertension is an important modifiable risk factor of serious maternal morbidity and mortality. Social determinants of health (SDoH) influence hypertension outcomes and may contribute to racial and ethnic differences in hypertension control. Our objective was to assess SDoH and blood pressure (BP) control by race and ethnicity in US women of childbearing age with hypertension. Methods and Results We studied women (aged 20-50 years) with hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg or use of antihypertensive medication) in the National Health and Nutrition Examination Surveys 2001 to 2018. SDoH and BP control (systolic BP <140 mm Hg and diastolic BP <90 mm Hg) were examined by race and ethnicity (White race, Black race, Hispanic ethnicity, and Asian race). Using multivariable logistic regression, odds of uncontrolled BP by race and ethnicity were modeled, adjusting for SDoH, health factors, and modifiable health behaviors. Responses on hunger and affording food determined food insecurity status. Across women of childbearing age with hypertension (N=1293), 59.2% were White race, 23.4% were Black race, 15.8% were Hispanic ethnicity, and 1.7% were Asian race. More Hispanic and Black women experienced food insecurity than White women (32% and 25% versus 13%; both P<0.001). After SDoH, health factor, and modifiable health behavior adjustment, Black women maintained higher odds of uncontrolled BP than White women (odds ratio, 2.31 [95% CI, 1.08-4.92]), whereas Asian and Hispanic women showed no difference. Conclusions We identified racial inequities in uncontrolled BP and food insecurity among women of childbearing age with hypertension. Further exploration beyond the SDoH measured is needed to understand the inequity in hypertension control in Black women.

Finding a Needle in a Haystack: Design and Implementation of a Digital Site-less Clinical Study of Serial Rapid Antigen Testing to Identify Asymptomatic SARS-CoV-2 Infection.

Background: Rapid antigen tests (Ag-RDT) for SARS-CoV-2 with Emergency Use Authorization generally include a condition of authorization to evaluate the test's performance in asymptomatic individuals when used serially. Objective: To describe a novel study design to generate regulatory-quality data to evaluate serial use of Ag-RDT in detecting SARS-CoV-2 virus among asymptomatic individuals. Design: Prospective cohort study using a decentralized approach. Participants were asked to test using Ag-RDT and molecular comparators every 48 hours for 15 days. Setting: Participants throughout the mainland United States were enrolled through a digital platform between October 18, 2021 and February 15, 2022. Ag-RDTs were completed at home, and molecular comparators were shipped to a central laboratory. Participants: Individuals over 2 years old from across the U.S. with no reported COVID-19 symptoms in the 14 days prior to study enrollment were eligible to enroll in this study. Measurements: Enrollment demographics, geographic distribution, and SARS-CoV-2 infection rates are reported. Key Results: A total of 7,361 participants enrolled in the study, and 492 participants tested positive for SARS-CoV-2, including 154 who were asymptomatic and tested negative to start the study. This exceeded the initial enrollment goals of 60 positive participants. We enrolled participants from 44 U.S. states, and geographic distribution of participants shifted in accordance with the changing COVID-19 prevalence nationwide. Limitations: New, complex workflows required significant operational and data team support. Conclusions: The digital site-less approach employed in the 'Test Us At Home' study enabled rapid, efficient, and rigorous evaluation of rapid diagnostics for COVID-19, and can be adapted across research disciplines to optimize study enrollment and accessibility.

Performance of Rapid Antigen Tests to Detect Symptomatic and Asymptomatic SARS-CoV-2 Infection.

Background: Performance of rapid antigen tests for SARS-CoV-2 (Ag-RDT) varies over the course of an infection, and their performance in screening for SARS-CoV-2 is not well established. We aimed to evaluate performance of Ag-RDT for detection of SARS-CoV-2 for symptomatic and asymptomatic participants. Methods: Participants >2 years old across the United States enrolled in the study between October 2021 and February 2022. Participants completed Ag-RDT and molecular testing (RT-PCR) for SARS-CoV-2 every 48 hours for 15 days. This analysis was limited to participants who were asymptomatic and tested negative on their first day of study participation. Onset of infection was defined as the day of first positive RT-PCR result. Sensitivity of Ag-RDT was measured based on testing once, twice (after 48-hours), and thrice (after 96 hours). Analysis was repeated for different Days Post Index PCR Positivity (DPIPP) and stratified based on symptom-status. Results: In total, 5,609 of 7,361 participants were eligible for this analysis. Among 154 participants who tested positive for SARS-CoV-2, 97 were asymptomatic and 57 had symptoms at infection onset. Serial testing with Ag-RDT twice 48-hours apart resulted in an aggregated sensitivity of 93.4% (95% CI: 89.1-96.1%) among symptomatic participants on DPIPP 0-6. Excluding singleton positives, aggregated sensitivity on DPIPP 0-6 for two-time serial-testing among asymptomatic participants was lower at 62.7% (54.7-70.0%) but improved to 79.0% (71.0-85.3%) with testing three times at 48-hour intervals. Discussion: Performance of Ag-RDT was optimized when asymptomatic participants tested three-times at 48-hour intervals and when symptomatic participants tested two-times separated by 48-hours.

Comparison of Rapid Antigen Tests' Performance Between Delta and Omicron Variants of SARS-CoV-2 : A Secondary Analysis From a Serial Home Self-testing Study.

BACKGROUND: It is important to document the performance of rapid antigen tests (Ag-RDTs) in detecting SARS-CoV-2 variants. OBJECTIVE: To compare the performance of Ag-RDTs in detecting the Delta (B.1.617.2) and Omicron (B.1.1.529) variants of SARS-CoV-2. DESIGN: Secondary analysis of a prospective cohort study that enrolled participants between 18 October 2021 and 24 January 2022. Participants did Ag-RDTs and collected samples for reverse transcriptase polymerase chain reaction (RT-PCR) testing every 48 hours for 15 days. SETTING: The parent study enrolled participants throughout the mainland United States through a digital platform. All participants self-collected anterior nasal swabs for rapid antigen testing and RT-PCR testing. All Ag-RDTs were completed at home, whereas nasal swabs for RT-PCR were shipped to a central laboratory. PARTICIPANTS: Of 7349 participants enrolled in the parent study, 5779 asymptomatic persons who tested negative for SARS-CoV-2 on day 1 of the study were eligible for this substudy. MEASUREMENTS: Sensitivity of Ag-RDTs on the same day as the first positive (index) RT-PCR result and 48 hours after the first positive RT-PCR result. RESULTS: A total of 207 participants were positive on RT-PCR (58 Delta, 149 Omicron). Differences in sensitivity between variants were not statistically significant (same day: Delta, 15.5% [95% CI, 6.2% to 24.8%] vs. Omicron, 22.1% [CI, 15.5% to 28.8%]; at 48 hours: Delta, 44.8% [CI, 32.0% to 57.6%] vs. Omicron, 49.7% [CI, 41.6% to 57.6%]). Among 109 participants who had RT-PCR-positive results for 48 hours, rapid antigen sensitivity did not differ significantly between Delta- and Omicron-infected participants (48-hour sensitivity: Delta, 81.5% [CI, 66.8% to 96.1%] vs. Omicron, 78.0% [CI, 69.1% to 87.0%]). Only 7.2% of the 69 participants with RT-PCR-positive results for shorter than 48 hours tested positive by Ag-RDT within 1 week; those with Delta infections remained consistently negative on Ag-RDTs. LIMITATION: A testing frequency of 48 hours does not allow a finer temporal resolution of the analysis of test performance, and the results of Ag-RDTs are based on self-report. CONCLUSION: The performance of Ag-RDTs in persons infected with the SARS-CoV-2 Omicron variant is not inferior to that in persons with Delta infections. Serial testing improved the sensitivity of Ag-RDTs for both variants. The performance of rapid antigen testing varies on the basis of duration of RT-PCR positivity. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Feasibility of At-Home Serial Testing Using Over-the-Counter SARS-CoV-2 Tests With a Digital Smartphone App for Assistance: Longitudinal Cohort Study.

BACKGROUND: The ongoing SARS-CoV-2 pandemic necessitates the development of accurate, rapid, and affordable diagnostics to help curb disease transmission, morbidity, and mortality. Rapid antigen tests are important tools for scaling up testing for SARS-CoV-2; however, little is known about individuals' use of rapid antigen tests at home and how to facilitate the user experience. OBJECTIVE: This study aimed to describe the feasibility and acceptability of serial self-testing with rapid antigen tests for SARS-CoV-2, including need for assistance and the reliability of self-interpretation. METHODS: A total of 206 adults in the United States with smartphones were enrolled in this single-arm feasibility study in February and March 2021. All participants were asked to self-test for COVID-19 at home using rapid antigen tests daily for 14 days and use a smartphone app for testing assistance and to report their results. The main outcomes were adherence to the testing schedule, the acceptability of testing and smartphone app experiences, and the reliability of participants versus study team's interpretation of test results. Descriptive statistics were used to report the acceptability, adherence, overall rating, and experience of using the at-home test and MyDataHelps app. The usability, acceptability, adherence, and quality of at-home testing were analyzed across different sociodemographic, age, and educational attainment groups. RESULTS: Of the 206 enrolled participants, 189 (91.7%) and 159 (77.2%) completed testing and follow-up surveys, respectively. In total, 51.3% (97/189) of study participants were women, the average age was 40.7 years, 34.4% (65/189) were non-White, and 82% (155/189) had a bachelor's degree or higher. Most (n=133/206, 64.6%) participants showed high testing adherence, meaning they completed over 75% of the assigned tests. Participants' interpretations of test results demonstrated high agreement (2106/2130, 98.9%) with the study verified results, with a κ score of 0.29 (P<.001). Participants reported high satisfaction with self-testing and the smartphone app, with 98.7% (157/159) reporting that they would recommend the self-test and smartphone app to others. These results were consistent across age, race/ethnicity, and gender. CONCLUSIONS: Participants' high adherence to the recommended testing schedule, significant reliability between participants and study staff's test interpretation, and the acceptability of the smartphone app and self-test indicate that self-tests for SARS-CoV-2 with a smartphone app for assistance and reporting is a highly feasible testing modality among a diverse population of adults in the United States.

Comparison of Rapid Antigen Tests' Performance between Delta (B.1.61.7; AY.X) and Omicron (B.1.1.529; BA1) Variants of SARS-CoV-2: Secondary Analysis from a Serial Home Self-Testing Study.

Background: There is a need to understand the performance of rapid antigen tests (Ag-RDT) for detection of the Delta (B.1.61.7; AY.X) and Omicron (B.1.1.529; BA1) SARS-CoV-2 variants. Methods: Participants without any symptoms were enrolled from October 18, 2021 to January 24, 2022 and performed Ag-RDT and RT-PCR tests every 48 hours for 15 days. This study represents a non-pre-specified analysis in which we sought to determine if sensitivity of Ag-RDT differed in participants with Delta compared to Omicron variant. Participants who were positive on RT-PCR on the first day of the testing period were excluded. Delta and Omicron variants were defined based on sequencing and date of first RT-PCR positive result (RT-PCR+). Comparison of Ag-RDT performance between the variants was based on sensitivity, defined as proportion of participants with Ag-RDT+ results in relation to their first RT-PCR+ result, for different duration of testing with rapid Ag-RDT. Subsample analysis was performed based on the result of participants' second RT-PCR test within 48 hours of the first RT-PCR+ test. Results: From the 7,349 participants enrolled in the parent study, 5,506 met the eligibility criteria for this analysis. A total of 153 participants were RT-PCR+ (61 Delta, 92 Omicron); among this group, 36 (23.5%) tested Ag-RDT+ on the same day, and 84 (54.9%) tested Ag-RDT+ within 48 hours as first RT-PCR+. The differences in sensitivity between variants were not statistically significant (same-day: Delta 16.4% [95% CI: 8.2-28.1] vs Omicron 28.2% [95% CI: 19.4-38.6]; and 48-hours: Delta 45.9% [33.1-59.2] vs. Omicron 60.9% [50.1-70.9]). This trend continued among the 86 participants who had consecutive RT-PCR+ result (48-hour sensitivity: Delta 79.3% [60.3-92.1] vs. Omicron: 89.5% [78.5-96.0]). Conversely, the 38 participants who had an isolated RT-PCR+ remained consistently negative on Ag-RDT, regardless of the variant. Conclusions: The performance of Ag-RDT is not inferior among individuals infected with the SARS-CoV-2 Omicron variant as compared to the Delta variant. The improvement in sensitivity of Ag-RDT noted with serial testing is consistent between Delta and Omicron variant. Performance of Ag-RDT varies based on duration of RT-PCR+ results and more studies are needed to understand the clinical and public health significance of individuals who are RT-PCR+ for less than 48 hours.

Mouse Lines with Cre-Mediated Recombination in Retinal Amacrine Cells.

Amacrine cells (ACs) are the most diverse neuronal cell type in the vertebrate retina. Yet little is known about the contribution of ACs to visual processing and retinal disease. A major challenge in evaluating AC function is genetic accessibility. A classic tool of mouse genetics, Cre-mediated recombination, can provide such access. We have screened existing genetically-modified mouse strains and identified multiple candidates that express Cre-recombinase in subsets of retinal ACs. The Cre-expressing mice were crossed to fluorescent-reporter mice to assay Cre expression. In addition, a Cre-dependent fluorescent reporter plasmid was electroporated into the subretinal space of Cre strains. Herein, we report three mouse lines (Tac1::IRES-cre, Camk2a-cre, and Scx-cre) that express Cre recombinase in sub-populations of ACs. In two of these lines, recombination occurred in multiple AC types and a small number of other retinal cell types, while recombination in the Camk2a-cre line appears specific to a morphologically distinct AC. We anticipate that these characterized mouse lines will be valuable tools to the community of researchers who study retinal biology and disease.

Hypertension and contraceptive use among women of child-bearing age in the United States from 2001 to 2018.

BACKGROUND: Hypertension (HTN) in pregnancy is a leading cause of maternal mortality in the United States. Contraception is widely used, and estrogen-based combined hormonal forms are known to increase blood pressure (BP). With nearly half of pregnancies unplanned and many antihypertensive medications teratogenic, appropriate contraception is critical in child-bearing age women with HTN. METHODS: Using the National Health and Nutrition Examination Surveys (NHANES) from 2001 to 2018, we evaluated contraception and antihypertensive medication use in women of child-bearing age (20-50 years). Women who had undergone sterilization or menopause were excluded. HTN was defined based on a self-reported provider diagnosis and BP ≥130/80 mm Hg or antihypertensive medication use. Contraception included non-barrier methods (pills/patch/ring, injections, long-acting reversible contraceptives) or consistent condom use. Multivariable logistic regression was used to model the odds of contraception use. Temporal trends in contraception use were reported. RESULTS: Of the 8726 women, 12.4% had HTN with mean age (standard error) 36.0 (0.3) years. In women with HTN, 9.2% used non-barrier contraception and 10.4% used condoms only. Over half (52.7%) of women with HTN on antihypertensive medications were taking medications contraindicated in pregnancy, with no difference seen by contraceptive status. In logistic regression models, contraceptive use was lower in the older-aged women. In women with HTN on non-barrier contraception, combined hormonal contraceptive use declined, from 100% (2001-2006) to 81.4% (2013-2018, P < 0.001). CONCLUSIONS: Many women with self-reported HTN are not using adequate contraception. Of the small proportion on non-barrier contraceptives, the majority are using estrogen-based, BP-raising methods.

Effect of Screen Time on Recovery From Concussion: A Randomized Clinical Trial.

Importance: There are limited data to guide screen time recommendations after concussion. Objective: To determine whether screen time in the first 48 hours after concussion has an effect on the duration of concussive symptoms. Design, Setting, and Participants: This randomized clinical trial was conducted in the pediatric and adult emergency departments of a tertiary medical center between June 2018 and February 2020. Participants included a convenience sample of patients aged 12 to 25 years presenting to the emergency department within 24 hours of sustaining a concussion. A total of 162 patients were approached, 22 patients met exclusion criteria, and 15 patients declined participation; 125 participants were enrolled and randomized. Interventions: Patients were either permitted to engage in screen time (screen time permitted group) or asked to abstain from screen time (screen time abstinent group) for 48 hours after injury. Main Outcomes and Measures: The primary outcome was days to resolution of symptoms, defined as a total Post-Concussive Symptom Scale (PCSS) score of 3 points or lower. Patients completed the PCSS, a 22-symptom scale that grades each symptom from 0 (not present) to 6 (severe), each day for 10 days. Kaplan-Meier curves and Cox regression modeling were used to compare the 2 groups. A Wilcoxon rank sum test was also performed among participants who completed the PCSS each day through recovery or conclusion of the study period. Results: Among 125 patients with concussion, the mean (SD) age was 17.0 (3.4) years; 64 participants (51.2%) were male. A total of 66 patients were randomized to the screen time permitted group, and 59 patients were randomized to the screen time abstinent group. The Cox regression model including the intervention group and the patient's self-identified sex demonstrated a significant effect of screen time (hazard ratio [HR], 0.51; 95% CI, 0.29-0.90), indicating that participants who engaged in screen time were less likely to recover during the study period. In total, 91 patients were included in the Wilcoxon rank sum test (47 patients from the screen time permitted group, and 44 patients from the screen time abstinent group). The screen time permitted group had a significantly longer median recovery time of 8.0 days (interquartile range [IQR], 3.0 to >10.0 days) compared with 3.5 days (IQR, 2.0 to >10.0 days; P = .03) in the screen time abstinent group. The screen time permitted group reported a median screen time of 630 minutes (IQR, 415-995 minutes) during the intervention period compared with 130 minutes (IQR, 61-275 minutes) in the screen time abstinent group. Conclusions and Relevance: The findings of this study indicated that avoiding screen time during acute concussion recovery may shorten the duration of symptoms. A multicenter study would help to further assess the effect of screen time exposure. Trial Registration: ClinicalTrials.gov Identifier: NCT03564210.

A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia.

Amacrine cells are interneurons composing the most diverse cell class in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, metabolic regulation and neurovascular control. Here, we report that in mouse retina (of either sex), an abundant, though previously unstudied inhibitory amacrine cell is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed chemical synapses with known retinal cell types and extensive associations with Müller glia, the processes of which often completely ensheathe the neurites of this amacrine cell. Microinjecting small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Müller glia, leading us to suggest the name "Müller glia-coupled amacrine cell," or MAC. Our data also indicate that MACs release glycine at conventional chemical synapses, and viral retrograde transsynaptic tracing from the dorsal lateral geniculate nucleus (dLGN) showed selective connections between MACs and a subpopulation of RGC types. Visually-evoked responses revealed a strong preference for light increments; these "ON" responses were primarily mediated by excitatory chemical synaptic input and direct electrical coupling with other cells. This initial characterization of the MAC provides the first evidence for neuron-glia coupling in the mammalian retina and identifies the MAC as a potential link between inhibitory processing and glial function.Significance Statement:Gap junctions between pairs of neurons or glial cells are commonly found throughout the nervous system and play multiple roles, including electrical coupling and metabolic exchange. In contrast, gap junctions between neurons and glia cells have rarely been reported and are poorly understood. Here we report the first evidence for neuron-glia coupling in the mammalian retina, specifically between an abundant (but previously unstudied) inhibitory interneuron and Müller glia. Moreover, viral tracing, optogenetics and serial electron microscopy provide new information about the neuron's synaptic partners and physiological responses.

Dietary Habits and Medications to Control Hypertension Among Women of Child-Bearing Age in the United States from 2001 to 2016.

BACKGROUND: Hypertension (HTN) in pregnancy is a leading cause of maternal morbidity and mortality in the United States. Although the Dietary Approaches to Stop Hypertension (DASH) diet is recommended for all adults with HTN, rates of DASH adherence and antihypertensive medication use in women of child-bearing age are unknown. Our objectives were to determine DASH adherence and antihypertensive medication use in women of child-bearing age. METHODS: In the National Health and Nutrition Examination Surveys from 2001 to 2016, we estimated DASH adherence among women of child-bearing age (20-50 years). We derived a DASH score (0-9) based on 9 nutrients, with DASH adherence defined as DASH score ≥4.5. HTN was defined by blood pressure (BP) ≥130/80 mm Hg or antihypertensive medication use. DASH scores were compared across BP categories and antihypertensive medication use was categorized. RESULTS: Of the 7,782 women, the mean age (SE) was 32.8 (0.2) years, 21.4% were non-Hispanic Black, and 20.3% had HTN. The mean DASH score was 2.11 (0.06) for women with self-reported HTN and 2.40 (0.03) for women with normal BP (P < 0.001). DASH adherence was prevalent in 6.5% of women with self-reported HTN compared with 10.1% of women with normal BP (P < 0.05). Self-reported HTN is predominantly managed with medications (84.8%), while DASH adherence has not improved in these women from 2001 to 2016. Moreover, 39.5% of US women of child-bearing age are taking medications contraindicated in pregnancy. CONCLUSIONS: Given the benefits of optimized BP during pregnancy, this study highlights the critical need to improve DASH adherence and guide prescribing among women of child-bearing age.

Study design and rationale for a randomized controlled trial to assess effectiveness of stochastic vibrotactile mattress stimulation versus standard non-oscillating crib mattress for treating hospitalized opioid-exposed newborns.

The incidence of Neonatal Abstinence Syndrome (NAS) continues to rise and there remains a critical need to develop non-pharmacological interventions for managing opioid withdrawal in newborns. Objective physiologic markers of opioid withdrawal in the newborn remain elusive. Optimal treatment strategies for improving short-term clinical outcomes and promoting healthy neurobehavioral development have yet to be defined. This dual-site randomized controlled trial (NCT02801331) is designed to evaluate the therapeutic efficacy of stochastic vibrotactile stimulation (SVS) for reducing withdrawal symptoms, pharmacological treatment, and length of hospitalization, and for improving developmental outcomes in opioid-exposed neonates. Hospitalized newborns (n = 230) receiving standard clinical care for prenatal opioid exposure will be randomly assigned within 48-hours of birth to a crib with either: 1) Intervention (SVS) mattress: specially-constructed SVS crib mattress that delivers gentle vibrations (30-60 Hz, ~12 µm RMS surface displacement) at 3-hr intervals; or 2) Control mattress (treatment as usual; TAU): non-oscillating hospital-crib mattress. Infants will be studied throughout their hospitalization and post discharge to 14-months of age. The study will compare clinical measures (i.e., withdrawal scores, cumulative dose and duration of medications, velocity of weight gain) and characteristic progression of physiologic activity (i.e., limb movement, cardio-respiratory, temperature, blood-oxygenation) throughout hospitalization between opioid-exposed infants who receive SVS and those who receive TAU. Developmental outcomes (i.e., physical, social, emotional and cognitive) within the first year of life will be evaluated between the two study groups. Findings from this randomized controlled trial will determine whether SVS reduces in-hospital severity of NAS, improves physiologic function, and promotes healthy development.

Tmem100- and Acta2-Lineage Cells Contribute to Implant Osseointegration in a Mouse Model.

Metal implants are commonly used in orthopedic surgery. The mechanical stability and longevity of implants depend on adequate bone deposition along the implant surface. The cellular and molecular mechanisms underlying peri-implant bone formation (ie, osseointegration) are incompletely understood. Herein, our goal was to determine the specific bone marrow stromal cell populations that contribute to bone formation around metal implants. To do this, we utilized a mouse tibial implant model that is clinically representative of human joint replacement procedures. Using a lineage-tracing approach, we found that both Acta2.creERT2 and Tmem100.creERT2 lineage cells are involved in peri-implant bone formation, and Pdgfra- and Ly6a/Sca1-expressing stromal cells (PαS cells) are highly enriched in both lineages. Single-cell RNA-seq analysis indicated that PαS cells are quiescent in uninjured bone tissue; however, they express markers of proliferation and osteogenic differentiation shortly after implantation surgery. Our findings indicate that PαS cells are mobilized to repair bone tissue and participate in implant osseointegration after surgery. Biologic therapies targeting PαS cells might improve osseointegration in patients undergoing orthopedic procedures. © 2021 American Society for Bone and Mineral Research (ASBMR).

Single-Cell RNA Sequencing of Calvarial and Long-Bone Endocortical Cells.

Single-cell RNA sequencing (scRNA-Seq) is emerging as a powerful technology to examine transcriptomes of individual cells. We determined whether scRNA-Seq could be used to detect the effect of environmental and pharmacologic perturbations on osteoblasts. We began with a commonly used in vitro system in which freshly isolated neonatal mouse calvarial cells are expanded and induced to produce a mineralized matrix. We used scRNA-Seq to compare the relative cell type abundances and the transcriptomes of freshly isolated cells to those that had been cultured for 12 days in vitro. We observed that the percentage of macrophage-like cells increased from 6% in freshly isolated calvarial cells to 34% in cultured cells. We also found that Bglap transcripts were abundant in freshly isolated osteoblasts but nearly undetectable in the cultured calvarial cells. Thus, scRNA-Seq revealed significant differences between heterogeneity of cells in vivo and in vitro. We next performed scRNA-Seq on freshly recovered long bone endocortical cells from mice that received either vehicle or sclerostin-neutralizing antibody for 1 week. We were unable to detect significant changes in bone anabolism-associated transcripts in immature and mature osteoblasts recovered from mice treated with sclerostin-neutralizing antibody; this might be a consequence of being underpowered to detect modest changes in gene expression, because only 7% of the sequenced endocortical cells were osteoblasts and a limited portion of their transcriptomes were sampled. We conclude that scRNA-Seq can detect changes in cell abundance, identity, and gene expression in skeletally derived cells. In order to detect modest changes in osteoblast gene expression at the single-cell level in the appendicular skeleton, larger numbers of osteoblasts from endocortical bone are required. © 2020 American Society for Bone and Mineral Research.

The influence of payor status on outcomes associated with surgical repair of upper gastrointestinal perforations due to peptic ulcer disease in the United States.

BACKGROUND: An association between lack of insurance and inferior outcomes has been well described for a number of surgical emergencies, yet little is known about the relationship of payor status and outcomes of patients undergoing emergent surgical repair for upper gastrointestinal (UGI) perforations. We evaluated the association of payor status and in-hospital mortality for patients undergoing emergency surgery for UGI perforations in the United States. METHODS: Nationwide Inpatient Sample (NIS) was queried to identify patients between 18 and 64 years of age who underwent emergent (open or laparoscopic) repair for UGI perforations secondary to peptic ulcer disease (2010-2014). Primary outcome was in-hospital mortality. Secondary outcomes were major and minor postoperative complications. The main predictor outcome was insurance status (Private, Medicaid, Uninsured). Univariate and multivariable regression analyses were performed. Data were weighted to provide national estimates. RESULTS: 21,005 patients underwent surgical repair for UGI perforations. Patients with private insurance represented the largest payor group (47%). After adjustment of other factors, payor status was not a statistically significant predictor of in-hospital mortality (Medicaid vs. Private: [OR] 1.1; 95% [CI] 0.67-1.81; Uninsured vs. Private: OR 0.9, 95% CI 0.52-1.61). However, payor status remained a statistically significant predictor of major postoperative complications (Medicaid vs. Private [OR] 1.4; 95% CI 1.1, 1.8; Uninsured vs. Private [OR]1.2, 95% CI 0.9, 1.5) and minor postoperative complications (Medicaid vs. Private [OR] 1.4; 95% CI 1.1, 1.9; Uninsured vs. Private [OR]1.2, 95% CI 0.9, 1.6). CONCLUSIONS: Emergency surgery for UGI perforations is associated with high mortality and morbidity across all payor classes; however, Medicaid is a predictor for both major and minor postoperative complications. Preventing perforation through preventative measures will be key to reducing the burden of peptic ulcer disease across all populations.

Variations in the Delivery of Emergency General Surgery Care in the Era of Acute Care Surgery.

BACKGROUND: Acute care surgery (ACS) was proposed to improve emergency general surgery (EGS) care; however, the extent of ACS model adoption in the United States is unknown. A national survey was conducted to ascertain factors associated with variations in EGS models of care, with particular focus on ACS use. METHODS: A hybrid mail/electronic survey was sent in 2015 to 2,811 acute care hospitals with an emergency room and an operating room. If a respondent indicated that the approach to EGS was a dedicated clinical team whose scope encompasses EGS (± trauma, ± elective general surgery, ± burns), the hospital was considered an ACS hospital. RESULTS: Survey response was 60.1% (n = 1,690); 272 (16.1%) of these hospitals reported having used an ACS model of care for EGS patients. Teaching status and general hospital practices (for example, interventional radiology available within one hour) were associated with ACS use. In bivariate analyses, ACS use was associated with many EGS-specific practices (40.1% of ACS hospitals freed their surgeons of daytime clinical responsibilities after operating overnight vs. 4.7% of general surgeon on call (GSOC) hospitals; p < 0.0001). CONCLUSION: There are wide variations in EGS practices in the United States, with use of an ACS model of care being relatively low despite reported benefits of ACS models of care on EGS access, quality, and costs. Hospital factors associated with using ACS models are overall size and higher level of existing resources. These findings could be applied to the development of centers of excellence for EGS care.

The current State of the acute care surgery workforce: A boots on the ground perspective.

BACKGROUND: Acute care surgery (ACS) was proposed to address a general surgery workforce crisis; however, the ACS workforce composition is unknown. A national survey was conducted to determine the differences in the emergency general surgery (EGS) workforce between ACS and non-ACS hospitals. METHODS: The American Hospital Association (AHA) Annual Survey of Hospitals database was queried to identify acute care general hospitals. A hybrid mail/electronic survey was sent to 2811 acute care hospitals that met the inclusion criteria of hospitals that care for adult patients (≥18 years old) with an emergency room (ER), ≥ 1 operating room (OR), and 24-h ER access. Hospitals were queried on whether they utilized an ACS model. The workforce composition among ACS and non-ACS hospitals was evaluated using X2 tests, t tests, and Wilcoxon rank-sum tests. RESULTS: Survey response was 60% (N = 1690). ACS hospitals had a higher proportion of emergency surgeons who were female (20% vs. 14%, p < 0.0001), newly-trained (17% vs 10%, p < 0.0001), critical care trained (78% vs. 31%, p < 0.0001), and who had an additional degree (35% vs. 13%, p < 0.0001). More ACS hospitals had 24/7 in-house OR nursing staff (72% vs. 15%, p < 0.0001) and ancillary staff. CONCLUSIONS: ACS and non-ACS hospitals differ in their surgical workforce. It is clear that ACS hospitals have more human capital, which suggests that ACS hospitals may require more dedicated resources compared to non-ACS hospitals.