High Potency of a Bivalent Human VH Domain in SARS-CoV-2 Animal Models.

Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody VH domain library from which we identified a high-affinity VH binder ab8. Bivalent VH, VH-Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. VH-Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of VH-Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic.

Apolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice.

Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol level measurement in predicting atherosclerotic cardiovascular disease risk, apoB measurement has not become widely adopted into routine clinical practice. One barrier for use of apoB measurement is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. Whereas guidelines have often provided clear low-density lipoprotein cholesterol targets or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we synthesize existing data regarding the epidemiology of apoB by comparing guideline recommendations regarding use of apoB measurement, describing population percentiles of apoB relative to low-density lipoprotein cholesterol levels, summarizing studies of discordance between low-density lipoprotein cholesterol and apoB levels, and evaluating apoB levels in clinical trials of lipid-lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care.

Achieving Equity in Hospital Performance Assessments Using Composite Race-Specific Measures of Risk-Standardized Readmission and Mortality Rates for Heart Failure.

BACKGROUND: The contemporary measures of hospital performance for heart failure hospitalization and 30-day risk-standardized readmission rate (RSRR) and risk-standardized mortality rate (RSMR) are estimated using the same risk adjustment model and overall event rate for all patients. Thus, these measures are mainly driven by the care quality and outcomes for the majority racial and ethnic group, and may not adequately represent the hospital performance for patients of Black and other races. METHODS: Fee-for-service Medicare beneficiaries from January 2014 to December 2019 hospitalized with heart failure were identified. Hospital-level 30-day RSRR and RSMR were estimated using the traditional race-agnostic models and the race-specific approach. The composite race-specific performance metric was calculated as the average of the RSRR/RMSR measures derived separately for each race and ethnicity group. Correlation and concordance in hospital performance for all patients and patients of Black and other races were assessed using the composite race-specific and race-agnostic metrics. RESULTS: The study included 1 903 232 patients (75.7% White [n=1 439 958]; 14.5% Black [n=276 684]; and 9.8% other races [n=186 590]) with heart failure from 1860 hospitals. There was a modest correlation between hospital-level 30-day performance metrics for patients of White versus Black race (Pearson correlation coefficient: RSRR=0.42; RSMR=0.26). Compared with the race-agnostic RSRR and RSMR, composite race-specific metrics for all patients demonstrated stronger correlation with RSRR (correlation coefficient: 0.60 versus 0.74) and RSMR (correlation coefficient: 0.44 versus 0.51) for Black patients. Concordance in hospital performance for all patients and patients of Black race was also higher with race-specific (versus race-agnostic) metrics (RSRR=64% versus 53% concordantly high-performing; 61% versus 51% concordantly low-performing). Race-specific RSRR and RSMR metrics (versus race-agnostic) led to reclassification in performance ranking of 35.8% and 39.2% of hospitals, respectively, with better 30-day and 1-year outcomes for patients of all race groups at hospitals reclassified as high-performing. CONCLUSIONS: Among patients hospitalized with heart failure, race-specific 30-day RSMR and RSRR are more equitable in representing hospital performance for patients of Black and other races.

Achievement of LDL-C <55 mg/dL among US Adults : Findings from the cvMOBIUS2 Registry.

BACKGROUND: Reflecting clinical trial data showing improved outcomes with lower LDL-C levels, guidelines across the globe are increasingly recommending a goal of LDL-C <55 mg/dL in persons with atherosclerotic cardiovascular disease (ASCVD). What proportion of patients with ASCVD are already meeting those goals in the US remains understudied. METHODS: Using electronic health record data from 8 large US health systems, we evaluated lipid-lowering therapy (LLT), LDL-C levels, and factors associated with an LDL-C <55 mg/dL in persons with ASCVD treated between 1/1/2021-12/31/2021. Multivariable modeling was used to evaluate factors associated with achievement of an LDL-C <55 mg/dL. RESULTS: Among 167,899 eligible patients, 22.6% (38,016) had an LDL-C <55 mg/dL. While 76.1% of individuals overall were on a statin, only 38.2% were on a high-intensity statin,;5.9% were on ezetimibe, and 1.7% were on a PCSK9i monoclonal antibody (mAb). Factors associated with lower likelihood of achieving an LDL-C <55 mg/dL included: younger age (odds ratio [OR] 0.91 per 10y), female sex (OR 0.69), Black race (OR 0.76), and non-coronary artery disease forms of ASCVD including peripheral artery disease (OR 0.72) and cerebrovascular disease (OR 0.85), while high-intensity statin use was associated with increased odds of LDL-C <55 mg/dL (OR 1.55). Combination therapy (statin+ezetimibe or statin+PCSK9i mAb) was rare (4.4% and 0.5%, respectively) and was associated with higher odds of an LDL-C <55 mg/dL (OR 1.39 and 3.13, respectively). CONCLUSION: Less than a quarter of US patients with ASCVD in community practice are already achieving an LDL-C <55 mg/dL. Marked increases in utilization of both high intensity statins and combination therapy with non-statin therapy will be needed to achieve LDL-C levels <55 mg/dL at the population level in secondary prevention.

AZGP1 deficiency promotes angiogenesis in prostate cancer.

BACKGROUND: Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive. METHOD: AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples. RESULT: Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1-/- mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues. CONCLUSION: AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

Facilitating Shared Decision Making Among Black Patients at Risk for Sudden Cardiac Arrest : A Randomized Clinical Trial.

BACKGROUND: Racial disparities in implantable cardioverter-defibrillator (ICD) implantation are multifactorial and are partly explained by higher refusal rates. OBJECTIVE: To assess the effectiveness of a video decision support tool for Black patients eligible for an ICD. DESIGN: Multicenter, randomized clinical trial conducted between September 2016 and April 2020. (ClinicalTrials.gov: NCT02819973). SETTING: Fourteen academic and community-based electrophysiology clinics in the United States. PARTICIPANTS: Black adults with heart failure who were eligible for a primary prevention ICD. INTERVENTION: An encounter-based video decision support tool or usual care. MEASUREMENTS: The primary outcome was the decision regarding ICD implantation. Additional outcomes included patient knowledge, decisional conflict, ICD implantation within 90 days, the effect of racial concordance on outcomes, and the time patients spent with clinicians. RESULTS: Of the 330 randomly assigned patients, 311 contributed data for the primary outcome. Among those randomly assigned to the video group, assent to ICD implantation was 58.6% compared with 59.4% in the usual care group (difference, -0.8 percentage point [95% CI, -13.2 to 11.1 percentage points]). Compared with usual care, participants in the video group had a higher mean knowledge score (difference, 0.7 [CI, 0.2 to 1.1]) and a similar decisional conflict score (difference, -2.6 [CI, -5.7 to 0.4]). The ICD implantation rate within 90 days was 65.7%, with no differences by intervention. Participants randomly assigned to the video group spent less time with their clinician than those in the usual care group (mean, 22.1 vs. 27.0 minutes; difference, -4.9 minutes [CI, -9.4 to -0.3 minutes]). Racial concordance between video and study participants did not affect study outcomes. LIMITATION: The Centers for Medicare & Medicaid Services implemented a requirement for shared decision making for ICD implantation during the study. CONCLUSION: A video-based decision support tool increased patient knowledge but did not increase assent to ICD implantation. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute.

Partnership in Cancer Research (PCAR) Program Increases Medical Student Knowledge and Confidence to Perform Cancer Research.

Arkansas has a high cancer burden, and a pressing need exists for more medical students to pursue oncology as a career. The Partnership in Cancer Research (PCAR) program provides a summer research experience at the University of Arkansas for Medical Sciences for 12 medical students who have completed their first year of medical training. A majority of participants spend time pursuing cancer research in basic science, clinical, or community-based research. Students report on their research progress in an interactive "Live from the Lab!" series and assemble a final poster presentation describing their findings. Other activities include participation in a moderated, cancer-patient support group online, lecture series on cancer topics, medical simulations, palliative care clinic visit, "Death Over Dinner" event, and an entrepreneurship competition. Students completed surveys over PCAR's first 2 years in operation to evaluate all aspects of the program. Surveys reveal that students enthusiastically embraced the program in its entirety. This was especially true of the medical simulations which received the highest evaluations. Most significantly, surveys revealed that the program increased cancer knowledge and participant confidence to perform cancer research.

Ninety-Day Risk-Standardized Home Time as a Performance Metric for Cardiac Surgery Hospitals in the United States.

BACKGROUND: Assessing hospital performance for cardiac surgery necessitates consistent and valid care quality metrics. The association of hospital-level risk-standardized home time for cardiac surgeries with other performance metrics such as mortality rate, readmission rate, and annual surgical volume has not been evaluated previously. METHODS: The study included Medicare beneficiaries who underwent isolated or concomitant coronary artery bypass graft, aortic valve, or mitral valve surgery from January 1, 2013, to October 1, 2019. Hospital-level performance metrics of annual surgical volume, 90-day risk-standardized mortality rate, 90-day risk-standardized readmission rate, and 90-day risk-standardized home time were estimated starting from the day of surgery using generalized linear mixed models with a random intercept for the hospital. Correlations between the performance metrics were assessed using the Pearson correlation coefficient. Patient-level clinical outcomes were also compared across hospital quartiles by 90-day risk-standardized home time. Last, the temporal stability of performance metrics for each hospital during the study years was also assessed. RESULTS: Overall, 919 698 patients (age 74.2±5.8 years, 32% women) were included from 1179 hospitals. Median 90-day risk-standardized home time was 71.2 days (25th-75th percentile, 66.5-75.6), 90-day risk-standardized readmission rate was 26.0% (19.5%-35.7%), and 90-day risk-standardized mortality rate was 6.0% (4.0%-8.8%). Across 90-day home time quartiles, a graded decline was observed in the rates of in-hospital, 90-day, and 1-year mortality, and 90-day and 1-year readmission. Ninety-day home time had a significant positive correlation with annual surgical volume (r=0.31; P<0.001) and inverse correlation with 90-day risk-standardized readmission rate (r=-0.40; P <0.001) and 90-day risk-standardized mortality rate (r=-0.60; P <0.001). Use of 90-day home time as a performance metric resulted in a meaningful reclassification in performance ranking of 22.8% hospitals compared with annual surgical volume, 11.6% compared with 90-day risk-standardized mortality rate, and 19.9% compared with 90-day risk-standardized readmission rate. Across the 7 years of the study period, 90-day home time demonstrated the most temporal stability of the hospital performance metrics. CONCLUSIONS: Ninety-day risk-standardized home time is a feasible, comprehensive, patient-centered metric to assess hospital-level performance in cardiac surgery with greater temporal stability than mortality and readmission measures.

Generalizability of an EHR-network dataset to the United States for cardiovascular disease conditions: Comparison of Cerner real world data with the national inpatient sample.

BACKGROUND: Electronic Health Record (EHR) data from health systems are increasingly being combined for clinical research purposes. Yet, it remains unclear whether these large EHR data sources provide a representative assessment of national disease prevalence and treatment. To evaluate this, we compared Cerner RealWorldData (CRWD), a large EHR data source, to those seen in the National Inpatient Sample (NIS) for 3 cardiovascular conditions (myocardial infarction (MI), congestive heart failure (CHF), and stroke. METHODS: Adult patients (age ≥18 years) hospitalized with MI, CHF, and stroke were identified in both CRWD (86 health systems) and the NIS (4,782 hospitals). Patient demographics, comorbidities, procedures, outcomes (length of stay and in-hospital mortality) and hospital type (teaching or nonteaching) were compared between NIS and CRWD patients. RESULTS: Of 86 health systems participating in CRWD, 33 were excluded for potential data quality issues which accounted for about 11% of hospitalizations in the dataset, leaving 53 for inclusion in analysis which accounted for about 89% of hospitalizations in the dataset. Between January 1, 2017 and December 31, 2018, 116,956 MI, 188,107 CHF, and 93,968 stroke hospitalizations were identified in CRWD vs 2,245,300 MI, 4,310,745 CHF, and 1,333,480 stroke hospitalizations in the NIS. Patient demographics were similar among patients in CWRD and the NIS for all 3 cardiovascular groups except for ethnicity, with underrepresentation of Hispanic individuals in CRWD vs the NIS. Patients hospitalized in CRWD had a slightly higher proportion of coded co-morbidities compared with NIS hospitalizations due to a longer potential look-back period. For patients with MI, hospital mortality, length of stay, coronary artery bypass graft (CABG) rates, and percutaneous coronary intervention (PCI) rates were similar between CRWD and NIS. Additionally, there was similar in hospital mortality and length of stay for those with CHF and stroke hospitalizations between CRWD and NIS. CONCLUSIONS: On aggregate, characteristics of hospitalizations for MI, CHF, and stroke using EHR data from one nationwide EHR-derived database, CRWD, appears similar to characteristics of hospitalizations in the nationally representative NIS. Important limitations of CRWD include lack of geographic representativeness, under-representation of Hispanic adults, and the need to exclude health systems for missing data.

Does early detection of atrial fibrillation reduce the risk of thromboembolic events? Rationale and design of the Heartline study.

BACKGROUND: The impact of using direct-to-consumer wearable devices as a means to timely detect atrial fibrillation (AF) and to improve clinical outcomes is unknown. METHODS: Heartline is a pragmatic, randomized, and decentralized application-based trial of US participants aged ≥65 years. Two randomized cohorts include adults with possession of an iPhone and without a history of AF and those with a diagnosis of AF taking a direct oral anticoagulant (DOAC) for ≥30 days. Participants within each cohort are randomized (3:1) to either a core digital engagement program (CDEP) via iPhone application (Heartline application) and an Apple Watch (Apple Watch Group) or CDEP alone (iPhone-only Group). The Apple Watch Group has the watch irregular rhythm notification (IRN) feature enabled and access to the ECG application on the Apple Watch. If an IRN notification is issued for suspected AF then the study application instructs participants in the Apple Watch Group to seek medical care. All participants were "watch-naïve" at time of enrollment and have an option to either buy or loan an Apple Watch as part of this study. The primary end point is time from randomization to clinical diagnosis of AF, with confirmation by health care claims. Key secondary endpoint are claims-based incidence of a 6-component composite cardiovascular/systemic embolism/mortality event, DOAC medication use and adherence, costs/health resource utilization, and frequency of hospitalizations for bleeding. All study assessments, including patient-reported outcomes, are conducted through the study application. The target study enrollment is approximately 28,000 participants in total; at time of manuscript submission, a total of 26,485 participants have been enrolled into the study. CONCLUSION: The Heartline Study will assess if an Apple Watch with the IRN and ECG application, along with application-facilitated digital health engagement modules, improves time to AF diagnosis and cardiovascular outcomes in a real-world environment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04276441.

Time-dependent event accumulation in a cardiovascular outcome trial of patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

BACKGROUND: Estimating cardiovascular (CV) event accrual is important for outcome trial planning. Limited data exist describing event accrual patterns in patients with type 2 diabetes (T2D). We compared apparent CV event accrual patterns with true event rates in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). METHODS: Centrally adjudicated event dates and accrual rates for a 4-point major adverse CV event composite (MACE-4; includes CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina hospitalization), MACE-4 components, all-cause mortality (ACM), and heart failure hospitalization were compiled. We used three graphical methods (Weibull probability plot, plot of negative log of the Kaplan-Meier survival distribution estimate, and the Epanechnikov kernel-smoothed estimate of the hazard rate) to examine hazard rate morphology over time for the 7 outcomes. RESULTS: Plots for all outcomes showed real-time constant event hazard rates for the duration of the follow-up, confirmed by Weibull shape parameters. The Weibull shape parameters for ACM (1.14, 95% CI 1.08-1.21) and CV death (1.08, 95% CI 1.01-1.16) were not sufficiently > 1 as to require non-constant hazard rate models to accurately depict the data. The time lag between event occurrence and event adjudication being completed, the adjudication gap, improved over the course of the trial. CONCLUSIONS: In TECOS, the nonfatal event hazard rates were constant over time. Small increases over time in the hazard rate for fatal events would not require complex modelling to predict event accrual, providing confidence in traditional modelling methods for predicting CV outcome trial event rates in this population. The adjudication gap provides a useful metric to monitor within-trial event accrual patterns. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00790205.

Evaluation of weight change and cardiometabolic risk factors in a real-world population of US adults with overweight or obesity.

Whether individuals in real-world settings are able to lose weight and improve cardiometabolic risk factors over time is unclear. We aimed to determine the management of and degree of body weight change over 2 years among individuals with overweight or obesity, and to assess associated changes in cardiometabolic risk factors and clinical outcomes. Using data from 11 large health systems within the Patient-Centered Outcomes Research Network in the U.S., we collected the following data on adults with a recorded BMI ≥25 kg/m2 between January 1, 2016 and December 31, 2016: body-mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), triglycerides and glycated hemoglobin (HbA1c). We found that among 882,712 individuals with BMI ≥25 kg/m2 (median age 59 years; 56% female), 52% maintained stable weight over 2 years and 1.3% utilized weight loss pharmacotherapy. Weight loss of 10% was associated with small but significant lowering of mean SBP (-2.69 mmHg [95% CI -2.88, -2.50]), DBP (-1.26 mmHg [95% CI -1.35, -1.18]), LDL-C (-2.60 mg/dL [95% CI -3.14, -2.05]), and HbA1c (-0.27% [95% CI -0.35, -0.19]) in the same 12 months. However, these changes were not sustained over the following year. In this study of adults with BMI ≥25 kg/m2, the majority had stable weight over 2 years, pharmacotherapies for weight loss were under-used, and small changes in cardiometabolic risk factors with weight loss were not sustained, possibly due to failure to maintain weight loss.

Control of Pre-formed Halogenated Disinfection Byproducts with Reuse Biofiltration.

Disinfection byproduct (DBP) pre-formation is a major issue when prechlorination is used before or during advanced treatment of impacted drinking water sources. Control strategies for pre-formed DBPs before final disinfection, especially for currently nonregulated although highly toxic DBP species, are not yet established. This study evaluated the biodegradation potential of pre-formed DBPs, including haloacetonitriles (HANs), haloacetamides (HAMs), and haloacetaldehydes (HALs), during biofiltration with sand, anthracite, and biological activated carbon of three wastewater effluents under potable reuse conditions. Up to 90%+ removal of di- and trihalogenated HANs, HAMs, and HALs was observed, and removal was associated with active heterotrophic biomass and removal of biodegradable organic carbon. Unlike the microbial dehalogenation pathway of haloacetic acids (HAAs), removal of HANs and HAMs appeared to result from a biologically mediated hydrolysis pathway (i.e., HANs to HAMs and HAAs) that may be prone to inhibition. After prechlorination, biofiltration effectively controlled pre-formed DBP concentrations (e.g., from 271 µg/L to as low as 22 µg/L in total) and DBP-associated calculated toxicity (e.g., 96%+ reduction). Abiotic residual adsorption capacity in biological activated carbon media was important for controlling trihalomethanes. Overall, the toxicity-driving DBP species exhibited high biodegradation potential and biofiltration showed significant promise as a pre-formed DBP control technology.

Bee Pollinator Mortality Due to Pesticide-Laden Particulate Matter from Beef Cattle Feedyards.

Wild and managed bees are critical for the stability of trophic webs, angiosperm reproduction, and agricultural productivity. Unfortunately, as many as 40% of crop pollinators are in a steep decline due to habitat loss and exposure to agrochemicals. Pyrethroids, neonicotinoids, and macrocyclic lactones are among the many agrochemicals toxic to pollinating insects that are used extensively in industrial beef cattle feeding operations throughout the world. Fugitive feedyard particulate matter (PM) transports agrochemicals into the surrounding environs. To determine the impact of agrochemical-laden feedyard particulate matter on bee pollinators, we conducted in situ experiments wherein honeybees and mason bees were placed downwind and upwind of feedyards (N = 40). Concurrent, colocated total suspended particulate matter samples contained multiple insecticides and parasiticides including pyrethroids, neonicotinoids, and macrocyclic lactones, in significantly higher concentrations downwind of feedyards (bifenthrin, 8.45 ± 4.92; permethrin, 1032.34 ± 740.76; clothianidin, 3.61 ± 1.48; imidacloprid, 73.32 ± 47.52; thiamethoxam, 5.81 ± 3.16; abamectin, 0.45 ± 0.29; ivermectin, 8.88 ± 5.06 ng/g). Honeybees and mason bees sited downwind of feedyards always experienced higher mortality than those correspondingly sited upwind, and male mason bees experienced significantly higher mortality compared to females when both were sited downwind. Bees occurring downwind of beef cattle feedyards for 1 h are 232-260% more likely to die than those occurring upwind. Thus, agrochemicals used on and emitted from beef cattle feedyards are significant threats to bee pollinators.

Removal of Aqueous Uranyl and Arsenate Mixtures after Reaction with Limestone, PO43-, and Ca2.

The co-occurrence of uranyl and arsenate in contaminated water caused by natural processes and mining is a concern for impacted communities, including in Native American lands in the U.S. Southwest. We investigated the simultaneous removal of aqueous uranyl and arsenate after the reaction with limestone and precipitated hydroxyapatite (HAp, Ca10(PO4)6(OH)2). In benchtop experiments with an initial pH of 3.0 and initial concentrations of 1 mM U and As, uranyl and arsenate coprecipitated in the presence of 1 g L-1 limestone. However, related experiments initiated under circumneutral pH conditions showed that uranyl and arsenate remained soluble. Upon addition of 1 mM PO43- and 3 mM Ca2+ in solution (initial concentration of 0.05 mM U and As) resulted in the rapid removal of over 97% of U via Ca-U-P precipitation. In experiments with 2 mM PO43- and 10 mM Ca2+ at pH rising from 7.0 to 11.0, aqueous concentrations of As decreased (between 30 and 98%) circa pH 9. HAp precipitation in solids was confirmed by powder X-ray diffraction and scanning electron microscopy/energy dispersive X-ray. Electron microprobe analysis indicated U was coprecipitated with Ca and P, while As was mainly immobilized through HAp adsorption. The results indicate that natural materials, such as HAp and limestone, can effectively remove uranyl and arsenate mixtures.

Clinical characteristics and treatment of patients with central pulmonary embolism and right heart thrombus.

INTRODUCTION: Right heart thrombus (RHT), also known as clot in transit, is an uncommon finding in pulmonary embolism (PE) that is associated with increased inpatient mortality. To date, there is no consensus on the management of RHT. Therefore, we aim to describe the clinical features, treatments, and outcomes of patients with simultaneous RHT and PE. METHODS: This is a retrospective, cross-sectional, and single-center study of hospitalized patients with central PE who had RHT visualized on transthoracic echocardiography (TTE) from January 2012 to May 2022. We use descriptive statistics to describe their clinical features, treatments, and outcomes, including mechanical ventilation, major bleeding, inpatient mortality, length of hospital stay, and recurrent PE on follow-up. RESULTS: Of 433 patients with central PE who underwent TTE, nine patients (2%) had RHT. The median age was 63 years (range 29-87), most were African American (6/9), and females (5/9). All patients had evidence of RV dysfunction and received therapeutic anticoagulation. Eight patients received RHT-directed interventions, including systemic thrombolysis (2/9), catheter-directed suction embolectomy (4/9), and surgical embolectomy (2/9). Regarding outcomes, 4/9 patients were hemodynamically unstable, 8/9 were hypoxemic, and 2/9 were mechanically ventilated. The median length of hospital stay was six days (range 1-16). One patient died during hospital admission, and two patients had recurrent PE. CONCLUSION: We described the different therapeutic approaches and outcomes of patients with RHT treated in our institution. Our study adds valuable information to the literature, as there is no consensus on the treatment of RHT. HIGHLIGHTS: Right heart thrombus (RHT) was a rare finding in central pulmonary embolism. Most patients with RHT had evidence of RV dysfunction and pulmonary hypertension. Most patients received RHT-directed therapies in addition to therapeutic anticoagulation.

Rapid identification of a human antibody with high prophylactic and therapeutic efficacy in three animal models of SARS-CoV-2 infection.

Effective therapies are urgently needed for the SARS-CoV-2/COVID-19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from large phage-displayed Fab, scFv, and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. A high-affinity Fab was selected from one of the libraries and converted to a full-size antibody, IgG1 ab1, which competed with human ACE2 for binding to RBD. It potently neutralized replication-competent SARS-CoV-2 but not SARS-CoV, as measured by two different tissue culture assays, as well as a replication-competent mouse ACE2-adapted SARS-CoV-2 in BALB/c mice and native virus in hACE2-expressing transgenic mice showing activity at the lowest tested dose of 2 mg/kg. IgG1 ab1 also exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection. The mechanism of neutralization is by competition with ACE2 but could involve antibody-dependent cellular cytotoxicity (ADCC) as IgG1 ab1 had ADCC activity in vitro. The ab1 sequence has a relatively low number of somatic mutations, indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 did not aggregate, did not exhibit other developability liabilities, and did not bind to any of the 5,300 human membrane-associated proteins tested. These results suggest that IgG1 ab1 has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 d of availability of antigen for panning) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.

A novel laboratory method for simulating pollinator exposure to agrochemical-laden particulate matter.

Environmental transport and deposition of particulate matter (PM) associated with toxic chemicals has begun to receive attention as a source of risk to pollinators. For example, dust arising from manipulations of insecticide-treated seed has potential to exert toxic effects among non-target insects. Similarly, synthetic steroid growth promoters, antibiotics and multiple insecticides and parasiticides detected in fugitive beef cattle feedyard PM may also negatively impact pollinators since many of these chemicals have been detected on wildflowers and pollinators collected near beef cattle feedyards. Therefore, there is a need to assess risk to pollinators posed by deposition of agrochemical-laden PM, both in the field and the laboratory. Unfortunately, established laboratory methods for simulating PM exposure or toxicity associated with contaminated PM are few and highly situation-specific. Herein we describe development and use of a PM circulation system that can be employed to evaluate toxicity of agrochemical-contaminated PM in the laboratory under controlled conditions. Two model organisms (honeybees (Apis mellifera) and mason bees (Osmia lignaria)) were exposed to agrochemical-free PM in the circulator system, and post-exposure mortality was compared with controls. No significant differences in mortality between exposed and control bees were observed. Next, honeybees and mason bees were exposed to PM spiked with an insecticide known to exert toxic effects to pollinators (thiamethoxam). Bees experienced significantly higher mortality when exposed to thiamethoxam-laden PM at environmentally relevant concentrations as compared to bees exposed to agrochemical-free PM. These results confirm the validity of these methods for use in controlled laboratory PM toxicity tests and offer a source of positive and negative control groups for laboratory and field experiments examining exposure of pollinators to potentially toxic agrochemical-laden PM. This method facilitates generation of more realistic toxicity data than standard contact toxicity tests when pollinator exposure scenarios involve particulate-based agrochemicals or other toxic chemicals.

Diffusion-Weighted Imaging of the Orbit: A Case Series and Systematic Review.

PURPOSE: To describe the findings of diffusion-weighted imaging (DWI) for a series of orbital lesions and provide a systematic review of relevant literature. METHODS: A retrospective review of 20 patients with orbital lesions who underwent MRI with DWI at two academic institutions between 2015 and 2020 was performed. Lesion diagnosis was histopathologically confirmed except a presumed cavernous hemangioma. Echoplanar diffusion-weighted images had been acquired using 2 or 3 b values (b=0 and 1000 or b=0, 500, and 1000) at 1.5T or 3T. Lesions with significant artifacts were excluded. DWI sequences were analyzed by neuro-radiologists blinded to the diagnosis. Mean ADC values of lesions were calculated from a single region of interest. An independent two-tailed t test was used to compare categories of lesions with p < 0.05 considered significant. A systematic review of the literature was performed. RESULTS: Our study included 21 lesions. ADC values were significantly lower for malignant lesions (0.628 ± 0.125 × 10 -3 mm 2 /s) than inflammatory lesions (1.167 ± 0.381 × 10 -3 mm 2 /s) ( p < 0.001). ADC values were significantly lower for orbital lymphoma (mean 0.621 ± 0.147 × 10 -3 mm 2 /s) than idiopathic orbital inflammation (mean 1.188 ± 0.269 × 10 -3 mm 2 /s) with no overlap ( p < 0.001). CONCLUSIONS: Orbital malignancies demonstrated lower ADC values, while inflammatory processes demonstrated higher ADC values, except IgG4-related disease. DWI and ADC values differentiated idiopathic orbital inflammation from orbital lymphoma. This study highlights the role of DWI in evaluating orbital pathology.

Postintubation Sedation Practices Within Multiple Emergency Departments Across a Large Pediatric Health Care Organization.

OBJECTIVE: Children requiring rapid or standard sequence intubation are at risk of experiencing paralysis without adequate sedation when the duration of neuromuscular blockade exceeds the duration of sedation provided by the induction agent. The objective of this study was to evaluate the rate of appropriately timed postintubation sedation (PIS; defined as the administration of PIS before the clinical effects of the induction agent have dissipated) in patients requiring intubation across multiple emergency department/urgent care sites within a large pediatric health care organization. METHODS: This retrospective cohort study included patients admitted to 1 of 6 affiliated pediatric emergency department or urgent care sites who were intubated with an induction agent and neuromuscular blocker between January 2016 and December 2021. Patients were excluded if they were intubated in the setting of status epilepticus or cardiac arrest. Stepwise logistic regression identified factors associated with appropriately timed PIS. RESULTS: A total of 283 patients met the inclusion criteria (mean age, 8 ± 7.6 years; 56% male). Two hundred thirty-eight patients (83%) received some form of PIS (105 [37%] received appropriately timed PIS and 133 [47%] received delayed PIS), and 45 patients (16%) received no PIS. The median time to receive PIS following administration of the induction agent was 21 minutes (interquartile range, 11-40 minutes). Patients induced with fentanyl were the least likely to receive PIS, whereas patients induced with etomidate were the most likely. However, because of the short duration of etomidate, most patients induced with etomidate failed to receive PIS in a timely manner. CONCLUSIONS: Delayed PIS is common and may result in periods of ongoing paralysis without adequate sedation. Emergency department providers and pharmacists must recognize the brevity of some induction agents and provide more timely PIS.