Developing a membrane-proximal CD33-targeting CAR T cell.

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking. METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice. RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy. CONCLUSIONS: Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.

The silver bullet that wasn't: Rapid agronomic weed adaptations to glyphosate in North America.

The rapid adoption of glyphosate-resistant crops at the end of the 20th century caused a simplification of weed management that relied heavily on glyphosate for weed control. However, the effectiveness of glyphosate has diminished. A greater understanding of trends related to glyphosate use will shed new light on weed adaptation to a product that transformed global agriculture. Objectives were to (1) quantify the change in weed control efficacy from postemergence (POST) glyphosate use on troublesome weeds in corn and soybean and (2) determine the extent to which glyphosate preceded by a preemergence (PRE) improved the efficacy and consistency of weed control compared to glyphosate alone. Herbicide evaluation trials from 24 institutions across the United States of America and Canada from 1996 to 2021 were compiled into a single database. Two subsets were created; one with glyphosate applied POST, and the other with a PRE herbicide followed by glyphosate applied POST. Within each subset, mean and variance of control ratings for seven problem weed species were regressed over time for nine US states and one Canadian province. Mean control with POST glyphosate alone decreased over time while variability in control increased. Glyphosate preceded by a labeled PRE herbicide showed little change in mean control or variability in control over time. These results illustrate the rapid adaptation of agronomically important weed species to the paradigm-shifting product glyphosate. Including more diversity in weed management systems is essential to slowing weed adaptation and prolonging the usefulness of existing and future technologies.

Toward rational use of repeat imaging in children with mild traumatic brain injuries and intracranial injuries.

OBJECTIVE: Limited evidence exists on the utility of repeat neuroimaging in children with mild traumatic brain injuries (mTBIs) and intracranial injuries (ICIs). Here, the authors identified factors associated with repeat neuroimaging and predictors of hemorrhage progression and/or neurosurgical intervention. METHODS: The authors performed a multicenter, retrospective cohort study of children at four centers of the Pediatric TBI Research Consortium. All patients were ≤ 18 years and presented within 24 hours of injury with a Glasgow Coma Scale score of 13-15 and evidence of ICI on neuroimaging. The outcomes of interest were 1) whether patients underwent repeat neuroimaging during index admission, and 2) a composite outcome of progression of previously identified hemorrhage ≥ 25% and/or repeat imaging as an indication for subsequent neurosurgical intervention. The authors performed multivariable logistic regression and report odds ratios and 95% confidence intervals. RESULTS: A total of 1324 patients met inclusion criteria; 41.3% of patients underwent repeat imaging. Repeat imaging was associated with clinical change in 4.8% of patients; the remainder of the imaging tests were for routine surveillance (90.9%) or of unclear prompting (4.4%). In 2.6% of patients, repeat imaging findings were reported as an indication for neurosurgical intervention. While many factors were associated with repeat neuroimaging, only epidural hematoma (OR 3.99, 95% CI 2.22-7.15), posttraumatic seizures (OR 2.95, 95% CI 1.22-7.41), and age ≥ 2 years (OR 2.25, 95% CI 1.16-4.36) were significant predictors of hemorrhage progression and/or neurosurgery. Of patients without any of these risk factors, none underwent neurosurgical intervention. CONCLUSIONS: Repeat neuroimaging was commonly used but uncommonly associated with clinical deterioration. Although several factors were associated with repeat neuroimaging, only posttraumatic seizures, age ≥ 2 years, and epidural hematoma were significant predictors of hemorrhage progression and/or neurosurgery. These results provide the foundation for evidence-based repeat neuroimaging practices in children with mTBI and ICI.

Venous thromboembolic screening in pediatric trauma: A prospective cohort study of risk-stratified ultrasonography.

BACKGROUND: This prospective observational cohort study evaluates risk-stratified venous thromboembolism (VTE) screening in injured children. While the reported incidence of VTE is 6% to 10% among critically injured children, there is no standard for screening. Venous thromboembolism may have long-term sequelae in children, including postthrombotic syndrome. METHODS: Patients admitted to a level 1 pediatric trauma center were risk stratified for VTE using a validated prediction algorithm. Children at high risk (risk scores ≥523; i.e., ≥1% risk) received screening duplex ultrasonography. Children at moderate risk (risk scores 410-522; i.e., 0.3-0.99% risk) were screened as a comparison/control. RESULTS: Three-hundred fifty-five children were consecutively risk stratified from October 2019 to May 2021. Forty-seven children received screening duplex ultrasounds: 21 from a high-risk cohort and 26 from a moderate-risk cohort. Four children were diagnosed with VTE in the high-risk cohort compared with seven in the moderate-risk cohort ( p = 0.53). Total incidence of VTE among screened children was 23.4% (11 of 47). Asymptomatic VTE accounted for 81.8% of all events (9 of 11). Fifty-four percent (6 of 11) of VTE were central venous catheter associated. Venous thromboembolism in surviving children resolved by 3 to 6 months with no symptoms of postthrombotic syndrome after 1 year. No cases of VTE were identified in unscreened children, yielding an institutional VTE incidence of 3.1% (11 of 355). DISCUSSION: Risk-stratified screening demonstrates a significant incidence of asymptomatic VTE in injured children. These results may guide reevaluation of prediction algorithms developed from symptomatic VTE risk and longitudinal study of the sequelae of asymptomatic VTE. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Comparison of Influenza and Coronavirus Disease 2019-Associated Hospitalizations Among Children Younger Than 18 Years Old in the United States: FluSurv-NET (October-April 2017-2021) and COVID-NET (October 2020-September 2021).

BACKGROUND: Influenza virus and SARS-CoV-2 are significant causes of respiratory illness in children. METHODS: Influenza- and COVID-19-associated hospitalizations among children <18 years old were analyzed from FluSurv-NET and COVID-NET, 2 population-based surveillance systems with similar catchment areas and methodology. The annual COVID-19-associated hospitalization rate per 100 000 during the ongoing COVID-19 pandemic (1 October 2020-30 September 2021) was compared with influenza-associated hospitalization rates during the 2017-2018 through 2019-2020 influenza seasons. In-hospital outcomes, including intensive care unit (ICU) admission and death, were compared. RESULTS: Among children <18 years, the COVID-19-associated hospitalization rate (48.2) was higher than influenza-associated hospitalization rates: 2017-2018 (33.5), 2018-2019 (33.8), and 2019-2020 (41.7). The COVID-19-associated hospitalization rate was higher among adolescents 12-17 years old (COVID-19: 59.9; influenza range: 12.2-14.1), but similar or lower among children 5-11 (COVID-19: 25.0; influenza range: 24.3-31.7) and 0-4 (COVID-19: 66.8; influenza range: 70.9-91.5) years old. Among children <18 years, a higher proportion with COVID-19 required ICU admission compared with influenza (26.4% vs 21.6%; P < .01). Pediatric deaths were uncommon during both COVID-19- and influenza-associated hospitalizations (0.7% vs 0.5%; P = .28). CONCLUSIONS: In the setting of extensive mitigation measures during the COVID-19 pandemic, the annual COVID-19-associated hospitalization rate during 2020-2021 was higher among adolescents and similar or lower among children <12 years compared with influenza during the 3 seasons before the COVID-19 pandemic. COVID-19 adds substantially to the existing burden of pediatric hospitalizations and severe outcomes caused by influenza and other respiratory viruses.

Vital Signs: Influenza Hospitalizations and Vaccination Coverage by Race and Ethnicity-United States, 2009-10 Through 2021-22 Influenza Seasons.

Introduction: CDC estimates that influenza resulted in 9-41 million illnesses, 140,000-710,000 hospitalizations, and 12,000-52,000 deaths annually during 2010-2020. Persons from some racial and ethnic minority groups have historically experienced higher rates of severe influenza and had lower influenza vaccination coverage compared with non-Hispanic White (White) persons. This report examines influenza hospitalization and vaccination rates by race and ethnicity during a 12-13-year period (through the 2021-22 influenza season). Methods: Data from population-based surveillance for laboratory-confirmed influenza-associated hospitalizations in selected states participating in the Influenza-Associated Hospitalization Surveillance Network (FluSurv-NET) from the 2009-10 through 2021-22 influenza seasons (excluding 2020-21) and influenza vaccination coverage data from the Behavioral Risk Factor Surveillance System (BRFSS) from the 2010-11 through 2021-22 influenza seasons were analyzed by race and ethnicity. Results: From 2009-10 through 2021-22, age-adjusted influenza hospitalization rates (hospitalizations per 100,000 population) were higher among non-Hispanic Black (Black) (rate ratio [RR] = 1.8), American Indian or Alaska Native (AI/AN; RR = 1.3), and Hispanic (RR = 1.2) adults, compared with the rate among White adults. During the 2021-22 season, influenza vaccination coverage was lower among Hispanic (37.9%), AI/AN (40.9%), Black (42.0%), and other/multiple race (42.6%) adults compared with that among White (53.9%) and non-Hispanic Asian (Asian) (54.2%) adults; coverage has been consistently higher among White and Asian adults compared with that among Black and Hispanic adults since the 2010-11 season. The disparity in vaccination coverage by race and ethnicity was present among those who reported having medical insurance, a personal health care provider, and a routine medical checkup in the past year. Conclusions and Implications for Public Health Practice: Racial and ethnic disparities in influenza disease severity and influenza vaccination coverage persist. Health care providers should assess patient vaccination status at all medical visits and offer (or provide a referral for) all recommended vaccines. Tailored programmatic efforts to provide influenza vaccination through nontraditional settings, along with national and community-level efforts to improve awareness of the importance of influenza vaccination in preventing illness, hospitalization, and death among racial and ethnic minority communities might help address health care access barriers and improve vaccine confidence, leading to decreases in disparities in influenza vaccination coverage and disease severity.

Divergent neural and endocrine responses in wild-caught and laboratory-bred Rattus norvegicus.

Although rodents have represented the most intensely studied animals in neurobiological investigations for more than a century, few studies have systematically compared neural and endocrine differences between wild rodents in their natural habitats and laboratory strains raised in traditional laboratory environments. In the current study, male and female Rattus norvegicus rats were trapped in an urban setting and compared to weight-and sex-matched conspecifics living in standard laboratory housing conditions. Brains were extracted for neural assessments and fecal boli were collected for endocrine [corticosterone and dehydroepiandrosterone (DHEA)] assays. Additionally, given their role in immune and stress functions, spleen and adrenal weights were recorded. A separate set of wild rats was trapped at a dairy farm and held in captivity for one month prior to assessments; in these animals, brains were processed but no hormone data were available. The results indicated that wild-trapped rats exhibited 31% heavier brains, including higher densities of cerebellar neurons and glial cells in the bed nucleus of the stria terminalis. The wild rats also had approximately 300% greater spleen and adrenal weights, and more than a six-fold increase in corticosterone levels than observed in laboratory rats. Further research on neurobiological variables in wild vs. lab animals will inform the extensive neurobiological knowledge base derived from laboratory investigations using selectively bred rodents in laboratory environments, knowledge that will enhance the translational value of preclinical laboratory rodent studies.

Measures of Intracranial Injury Size Do Not Improve Clinical Decision Making for Children With Mild Traumatic Brain Injuries and Intracranial Injuries.

BACKGROUND: When evaluating children with mild traumatic brain injuries (mTBIs) and intracranial injuries (ICIs), neurosurgeons intuitively consider injury size. However, the extent to which such measures (eg, hematoma size) improve risk prediction compared with the kids intracranial injury decision support tool for traumatic brain injury (KIIDS-TBI) model, which only includes the presence/absence of imaging findings, remains unknown. OBJECTIVE: To determine the extent to which measures of injury size improve risk prediction for children with mild traumatic brain injuries and ICIs. METHODS: We included children ≤18 years who presented to 1 of the 5 centers within 24 hours of TBI, had Glasgow Coma Scale scores of 13 to 15, and had ICI on neuroimaging. The data set was split into training (n = 1126) and testing (n = 374) cohorts. We used generalized linear modeling (GLM) and recursive partitioning (RP) to predict the composite of neurosurgery, intubation >24 hours, or death because of TBI. Each model's sensitivity/specificity was compared with the validated KIIDS-TBI model across 3 decision-making risk cutoffs (<1%, <3%, and <5% predicted risk). RESULTS: The GLM and RP models included similar imaging variables (eg, epidural hematoma size) while the GLM model incorporated additional clinical predictors (eg, Glasgow Coma Scale score). The GLM (76%-90%) and RP (79%-87%) models showed similar specificity across all risk cutoffs, but the GLM model had higher sensitivity (89%-96% for GLM; 89% for RP). By comparison, the KIIDS-TBI model had slightly higher sensitivity (93%-100%) but lower specificity (27%-82%). CONCLUSION: Although measures of ICI size have clear intuitive value, the tradeoff between higher specificity and lower sensitivity does not support the addition of such information to the KIIDS-TBI model.

Interim Estimates of 2021-22 Seasonal Influenza Vaccine Effectiveness - United States, February 2022.

In the United States, annual vaccination against seasonal influenza is recommended for all persons aged ≥6 months except when contraindicated (1). Currently available influenza vaccines are designed to protect against four influenza viruses: A(H1N1)pdm09 (the 2009 pandemic virus), A(H3N2), B/Victoria lineage, and B/Yamagata lineage. Most influenza viruses detected this season have been A(H3N2) (2). With the exception of the 2020-21 season, when data were insufficient to generate an estimate, CDC has estimated the effectiveness of seasonal influenza vaccine at preventing laboratory-confirmed, mild/moderate (outpatient) medically attended acute respiratory infection (ARI) each season since 2004-05. This interim report uses data from 3,636 children and adults with ARI enrolled in the U.S. Influenza Vaccine Effectiveness Network during October 4, 2021-February 12, 2022. Overall, vaccine effectiveness (VE) against medically attended outpatient ARI associated with influenza A(H3N2) virus was 16% (95% CI = -16% to 39%), which is considered not statistically significant. This analysis indicates that influenza vaccination did not reduce the risk for outpatient medically attended illness with influenza A(H3N2) viruses that predominated so far this season. Enrollment was insufficient to generate reliable VE estimates by age group or by type of influenza vaccine product (1). CDC recommends influenza antiviral medications as an adjunct to vaccination; the potential public health benefit of antiviral medications is magnified in the context of reduced influenza VE. CDC routinely recommends that health care providers continue to administer influenza vaccine to persons aged ≥6 months as long as influenza viruses are circulating, even when VE against one virus is reduced, because vaccine can prevent serious outcomes (e.g., hospitalization, intensive care unit (ICU) admission, or death) that are associated with influenza A(H3N2) virus infection and might protect against other influenza viruses that could circulate later in the season.

Hospitalizations Associated with COVID-19 Among Children and Adolescents - COVID-NET, 14 States, March 1, 2020-August 14, 2021.

Although COVID-19-associated hospitalizations and deaths have occurred more frequently in adults,† COVID-19 can also lead to severe outcomes in children and adolescents (1,2). Schools are opening for in-person learning, and many prekindergarten children are returning to early care and education programs during a time when the number of COVID-19 cases caused by the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, is increasing.§ Therefore, it is important to monitor indicators of severe COVID-19 among children and adolescents. This analysis uses Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET)¶ data to describe COVID-19-associated hospitalizations among U.S. children and adolescents aged 0-17 years. During March 1, 2020-August 14, 2021, the cumulative incidence of COVID-19-associated hospitalizations was 49.7 per 100,000 children and adolescents. The weekly COVID-19-associated hospitalization rate per 100,000 children and adolescents during the week ending August 14, 2021 (1.4) was nearly five times the rate during the week ending June 26, 2021 (0.3); among children aged 0-4 years, the weekly hospitalization rate during the week ending August 14, 2021, was nearly 10 times that during the week ending June 26, 2021.** During June 20-July 31, 2021, the hospitalization rate among unvaccinated adolescents (aged 12-17 years) was 10.1 times higher than that among fully vaccinated adolescents. Among all hospitalized children and adolescents with COVID-19, the proportions with indicators of severe disease (such as intensive care unit [ICU] admission) after the Delta variant became predominant (June 20-July 31, 2021) were similar to those earlier in the pandemic (March 1, 2020-June 19, 2021). Implementation of preventive measures to reduce transmission and severe outcomes in children is critical, including vaccination of eligible persons, universal mask wearing in schools, recommended mask wearing by persons aged ≥2 years in other indoor public spaces and child care centers,†† and quarantining as recommended after exposure to persons with COVID-19.§§.

Development and external validation of the KIIDS-TBI tool for managing children with mild traumatic brain injury and intracranial injuries.

BACKGROUND: Clinical decision support (CDS) may improve the postneuroimaging management of children with mild traumatic brain injuries (mTBI) and intracranial injuries. While the CHIIDA score has been proposed for this purpose, a more sensitive risk model may have broader use. Consequently, this study's objectives were to: (1) develop a new risk model with improved sensitivity compared to the CHIIDA model and (2) externally validate the new model and CHIIDA model in a multicenter data set. METHODS: We analyzed children ≤18 years old with mTBI and intracranial injuries included in the PECARN head injury data set (2004-2006). We used binary recursive partitioning to predict the composite outcome of neurosurgical intervention, intubation for > 24 h due to TBI, or death due to TBI. The new model was externally validated in a separate data set that included children treated at any one of six centers from 2006 to 2019. RESULTS: Based on 839 patients from the PECARN data set, a new risk model, the KIIDS-TBI model, was developed that incorporated imaging (e.g., midline shift) and clinical (e.g., Glasgow Coma Scale score) findings. Based on the model-predicted probability of the composite outcome, three cutoffs were evaluated to classify patients as "high risk" for level of care decisions. In the external validation data set consisting of 1,630 patients, the most conservative cutoff (i.e., any predictor present) identified 119 of 119 children with the composite outcome (sensitivity = 100%), but had the lowest specificity (26.3%). The other two decision-making cutoffs had worse sensitivity (94.1%-96.6%) but improved specificity (67.4%-81.3%). The CHIIDA model lacked the most conservative cutoff and otherwise showed the same or slightly worse performance compared to the other two cutoffs. CONCLUSIONS: The KIIDS-TBI model has high sensitivity and moderate specificity for risk stratifying children with mTBI and intracranial injuries. Use of this CDS tool may help improve the safe, resource-efficient management of this important patient population.

Changes in Influenza and Other Respiratory Virus Activity During the COVID-19 Pandemic - United States, 2020-2021.

The COVID-19 pandemic and subsequent implementation of nonpharmaceutical interventions (e.g., cessation of global travel, mask use, physical distancing, and staying home) reduced transmission of some viral respiratory pathogens (1). In the United States, influenza activity decreased in March 2020, was historically low through the summer of 2020 (2), and remained low during October 2020-May 2021 (<0.4% of respiratory specimens with positive test results for each week of the season). Circulation of other respiratory pathogens, including respiratory syncytial virus (RSV), common human coronaviruses (HCoVs) types OC43, NL63, 229E, and HKU1, and parainfluenza viruses (PIVs) types 1-4 also decreased in early 2020 and did not increase until spring 2021. Human metapneumovirus (HMPV) circulation decreased in March 2020 and remained low through May 2021. Respiratory adenovirus (RAdV) circulated at lower levels throughout 2020 and as of early May 2021. Rhinovirus and enterovirus (RV/EV) circulation decreased in March 2020, remained low until May 2020, and then increased to near prepandemic seasonal levels. Circulation of respiratory viruses could resume at prepandemic levels after COVID-19 mitigation practices become less stringent. Clinicians should be aware of increases in some respiratory virus activity and remain vigilant for off-season increases. In addition to the use of everyday preventive actions, fall influenza vaccination campaigns are an important component of prevention as COVID-19 mitigation measures are relaxed and schools and workplaces resume in-person activities.

A novel program to enhance pediatric emergency medicine training in Thailand.

BACKGROUND: In Thailand, there are few pediatric emergency medicine (PEM) fellowship-trained providers, and emergency departments (EDs) are staffed by pediatricians and emergency physicians. Our pediatric ED collaborated with Thailand's largest private hospital system to develop a training program designed to improve emergency care for children. OBJECTIVE: The objective was to develop, implement, and assess the efficacy of a curriculum to improve PEM care by emergency providers in a Thai health system. METHODS: We conducted a prospective study from January 2018 to July 2019. After an initial needs assessment, we developed a curriculum with 22 modules, divided into basic and advanced courses. Each course began with baseline testing, consisting of written tests and several simulated cases led by physician-nurse teams. Each course was administered longitudinally through electronic modules over 6 months, with in-person shadowing and skills workshops at the course midpoint, culminating in final summative examinations and repeat simulation testing. RESULTS: On written examination scores for the basic course, physicians (n = 5) improved by 37.6% (95% confidence interval [CI] = 29.8% to 45.4%, p < 0.001), while nurses (n = 5) improved by 55.7% (95% CI = 45.8% to 65.6%, p < 0.001). For simulation testing among physician-nurse dyads, performance improved by 19.5% (95% CI = 3.9% to 35.1%, p = 0.004) for critical action items and by 3.0 points (95% CI = 2.3 to 3.7, p < 0.001) on a 16-point teamwork scale. For the advanced course, physicians improved on the written examination by 36.9% (95% CI = 29.2% to 44.7%, p < 0.001) and nurses by 50.6 (95% CI = 47.3% to 54.0%, p < 0.001). For simulation testing, performance improved from 22.2% (95% CI = 8.2% to 35.6%, p < 0.001) for critical actions and 1.3 points (95% CI = 0.2 to 2.2, p = 0.005) on teamwork measures. CONCLUSIONS: We designed an interdisciplinary curriculum and successfully trained Thai physicians and nurses to improve PEM knowledge and teamwork.

SCRATCH Trial: An Initiative to Reduce Excess Use of High-Flow Nasal Cannula.

OBJECTIVES: We aimed to reduce unnecessary use of high-flow nasal cannula (HFNC) at lower flow rates through the implementation of a standard daily trial off HFNC at a medium-sized academic center. METHODS: We used an interprofessional quality improvement collaboration to develop and implement interventions to reduce HFNC waste in children aged 1 month to 24 months with bronchiolitis who were admitted to the inpatient ward or ICU. Key interventions included development and implementation of the Simple Cannula/Room Air Trial for Children (SCRATCH Trial), a standard trial off HFNC for eligible infants. Process measures were selected as metrics of use of the newly developed trial. The primary outcome measure was hours of treatment with ≤8 L per minute (LPM) of HFNC. Additional outcome measures included total hours of treatment with HFNC and length of stay. RESULTS: A total of 271 patients were included in this study, 131 in the preimplementation group and 140 in the postimplementation group. The mean hours of treatment below our a priori determined waste line (≤8 LPM of HFNC) decreased from 36.3 to 16.8 hours after SCRATCH Trial implementation, and mean length of stay decreased from 4.1 to 3.0 days. CONCLUSIONS: The SCRATCH Trial was successfully implemented across hospital units, with a significant reduction in hours on ≤8 LPM of flow. Rapid discontinuation of HFNC appears feasible and may be associated with a shorter length of stay.

Pediatric trauma venous thromboembolism prediction algorithm outperforms current anticoagulation prophylaxis guidelines: a pilot study.

PURPOSE: Venous thromboembolism (VTE) in injured children is rare, but sequelae can be morbid and life-threatening. Recent trauma society guidelines suggesting that all children over 15 years old should receive thromboprophylaxis may result in overtreatment. We sought to evaluate the efficacy of a previously published VTE prediction algorithm and compare it to current recommendations. METHODS: Two institutional trauma registries were queried for all pediatric (age < 18 years) patients admitted from 2007 to 2018. Clinical data were applied to the algorithm and the area under the receiver operating characteristic (AUROC) curve was calculated to test algorithm efficacy. RESULTS: A retrospective review identified 8271 patients with 30 episodes of VTE (0.36%). The VTE prediction algorithm classified 51 (0.6%) as high risk (> 5% risk), 322 (3.9%) as moderate risk (1-5% risk) and 7898 (95.5%) as low risk (< 1% risk). AUROC was 0.93 (95% CI 0.89-0.97). In our population, prophylaxis of the 'moderate-' and 'high-risk' cohorts would outperform the sensitivity (60% vs. 53%) and specificity (96% vs. 77%) of current guidelines while anticoagulating substantially fewer patients (373 vs. 1935, p < 0.001). CONCLUSION: A VTE prediction algorithm using clinical variables can identify injured children at risk for venous thromboembolic disease with more discrimination than current guidelines. Prospective studies are needed to investigate the validity of this model. LEVEL OF EVIDENCE: III-Clinical decision rule evaluated in a single population.

Update: Influenza Activity - United States and Worldwide, May 19-September 28, 2019, and Composition of the 2020 Southern Hemisphere Influenza Vaccine.

During May 19-September 28, 2019,* low levels of influenza activity were reported in the United States, with cocirculation of influenza A and influenza B viruses. In the Southern Hemisphere seasonal influenza viruses circulated widely, with influenza A(H3) predominating in many regions; however, influenza A(H1N1)pdm09 and influenza B viruses were predominant in some countries. In late September, the World Health Organization (WHO) recommended components for the 2020 Southern Hemisphere influenza vaccine and included an update to the A(H3N2) and B/Victoria-lineage components. Annual influenza vaccination is the best means for preventing influenza illness and its complications, and vaccination before influenza activity increases is optimal. Health care providers should recommend vaccination for all persons aged ≥6 months who do not have contraindications to vaccination (1).

Impact of alpha-tocopherol deficiency and supplementation on sacrocaudalis and gluteal muscle fiber histopathology and morphology in horses.

BACKGROUND: A subset of horses deficient in alpha-tocopherol (α-TP) develop muscle atrophy and vitamin E-responsive myopathy (VEM) characterized by mitochondrial alterations in the sacrocaudalis dorsalis medialis muscle (SC). OBJECTIVES: To quantify muscle histopathologic abnormalities in subclinical α-TP deficient horses before and after α-TP supplementation and compare with retrospective (r)VEM cases. ANIMALS: Prospective study; 16 healthy α-TP-deficient Quarter Horses. Retrospective study; 10 retrospective vitamin E-responsive myopathy (rVEM) cases . METHODS: Blood, SC, and gluteus medius (GM) biopsy specimens were obtained before (day 0) and 56 days after 5000 IU/450 kg horse/day PO water dispersible liquid α-TP (n = 8) or control (n = 8). Muscle fiber morphology and mitochondrial alterations were compared in samples from days 0 and 56 and in rVEM cases. RESULTS: Mitochondrial alterations more common than our reference range (<2.5% affected fibers) were present in 3/8 control and 4/8 treatment horses on day 0 in SC but not in GM (mean, 2.2; range, 0%-10% of fibers). Supplementation with α-TP for 56 days did not change the percentage of fibers with mitochondrial alterations or anguloid atrophy, or fiber size in GM or SC. Clinical rVEM horses had significantly more mitochondrial alterations (rVEM SC, 13% ± 7%; GM, 3% ± 2%) and anguloid atrophy compared to subclinical day 0 horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinically normal α-TP-deficient horses can have mitochondrial alterations in the SC that are less severe than in atrophied VEM cases and do not resolve after 56 days of α-TP supplementation. Preventing α-TP deficiency may be of long-term importance for mitochondrial viability.

Previously Identified Genetic Variants in ADGRL3 Are not Associated with Risk for Equine Degenerative Myeloencephalopathy across Breeds.

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is a neurologic disease that has been reported in young horses from a wide range of breeds. The disease is inherited and associated with vitamin E deficiency during the first two years of life, resulting in bilateral symmetric ataxia. A missense mutation (chr3:71,917,591 C > T) within adhesion G protein-coupled receptor L3 (ADGRL3) was recently associated with risk for EDM in the Caspian breed. In order to confirm these findings, genotyping of this missense mutation, along with the three other associated single nucleotide polymorphisms (SNPs) in the genomic region, was carried out on 31 postmortem-confirmed eNAD/EDM cases and 43 clinically phenotyped controls from various breeds. No significant association was found between eNAD/EDM confirmed cases and genotype at any of the four identified SNPs (P > 0.05), including the nonsynonymous variant (EquCab2.0 chr3:71,917,591; allelic P = 0.85). These findings suggest that the four SNPs, including the missense variant in the ADGRL3 region, are not associated with risk for eNAD/EDM across multiple breeds of horses.