Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.

Declining labor force participation of older men throughout the 20th century and recent increases in participation have generated substantial interest in understanding the effect of public pensions on retirement. The National Bureau of Economic Research's International Social Security (ISS) Project, a long-term collaboration among researchers in a dozen developed countries, has explored this and related questions. The project employs a harmonized approach to conduct within-country analyses that are combined for meaningful cross-country comparisons. The key lesson is that the choices of policy makers affect the incentive to work at older ages and these incentives have important effects on retirement behavior.

OBJECTIVES/SPECIFIC AIMS: This study investigates the process configuration parameters involved in targeted drug delivery to the avian respiratory system. Previously, direct intratracheal aerosol delivery in an avian model using a commercial atomizer was found to result in delivery of a high portion of the total dose into one lung lobe. We hypothesize that controlling process configuration will decrease the asymmetric distribution. METHODS/STUDY POPULATION: A 3D printed model of an avian trachea and mainstream bronchi was constructed to create a representative model for direct instillation of aerosols. Construction of the model respiratory tract included the trachea and the first mainstream bronchi bifurcation to measure left/right (L/R) distribution of aerosol delivered. Both liquid aerosol delivery (LAD) using a commercial atomizer and dry aerosol delivery (DAD) using a custom-built dry powder insufflator device were tested. Two experimental variables were controlled: (1) retraction distance from the carina and (2) centering of device shaft in the lumen of the trachea. Measurement of device efficiency (dose delivered to the 3D model at as fraction of total dose), aerosol delivery efficiency (dose captured at L/R bifurcations as a fraction of total dose), and aerosol lateralization (L/R) was conducted. RESULTS/ANTICIPATED RESULTS: The aerosol delivery efficiency for both LAD and DAD devices [73.9% (95% CI: 68.2–79.2) and 73.4% (95% CI: 55.5–91.3), respectively] did not have an appreciable difference. However, the LAD device had a higher efficiency as compared with the DAD device. The L/R distribution for the DAD device was found to be highly dependent on both retraction distance and shaft centering. Appreciable improvement in the L/R distribution was seen using the DAD device by increasing the retraction distance distal to the carina. DISCUSSION/SIGNIFICANCE OF IMPACT: The use of targeted drug delivery to treat pulmonary pathogens requires a careful design, manufacture, and therapeutic positioning of devices. In particular, clinically relevant animal models and treatment regimes requires a sound understanding of the physical processes controlling aerosol distribution in the respiratory system. By using a simulated respiratory model, many of the physical parameters of drug delivery can be tested before using a live animal model. This is especially important from an animal welfare perspective as well as an animal subject availability aspect.

Accurate weed emergence models are valuable tools for scheduling planting, cultivation, and herbicide applications. Multiple models predicting giant ragweed emergence have been developed, but none have been validated in diverse crop rotation and tillage systems, which have the potential to influence weed emergence patterns. This study evaluated the performance of published giant ragweed emergence models across various crop rotations and spring tillage dates in southern Minnesota. Across experiments, the most robust model was a mixed-effects Weibull (flexible sigmoidal function) model predicting emergence in relation to hydrothermal time accumulation with a base temperature of 4.4 C, a base soil matric potential of −2.5 MPa, and two random effects determined by overwinter growing degree days (GDD) (10 C) and precipitation accumulated during seedling recruitment. The deviations in emergence between individual plots and the fixed-effects model were distinguished by the positive association between the lower horizontal asymptote (Drop) and maximum daily soil temperature during seedling recruitment. This finding indicates that crops and management practices that increase soil temperature will have a shorter lag phase at the start of giant ragweed emergence compared with practices promoting cool soil temperatures. Thus, crops with early-season crop canopies such as perennial crops and crops planted in early spring and in narrow rows will likely have a slower progression of giant ragweed emergence. This research provides a valuable assessment of published giant ragweed emergence models and illustrates that accurate emergence models can be used to time field operations and improve giant ragweed control across diverse cropping systems.

As herbicide-resistant weed populations become increasingly problematic in crop production, alternative strategies of weed control are necessary. Giant ragweed, one of the most competitive agricultural weeds in row crops, has evolved resistance to multiple herbicide biochemical sites of action within the plant, necessitating the development of new and integrated methods of weed control. This study assessed the quantity and duration of seed retention of giant ragweed grown in soybean fields and adjacent field margins. Seed retention of giant ragweed was monitored weekly during the 2012 to 2014 harvest seasons using seed collection traps. Giant ragweed plants produced an average of 1,818 seeds per plant, with 66% being potentially viable. Giant ragweed on average began shattering hard (potentially viable) and soft (nonviable) seeds September 12 and continued through October at an average rate of 0.75 and 0.44% of total seeds per day during September and October, respectively. Giant ragweed seeds remained on the plants well into the Minnesota soybean harvest season, with an average of 80% of the total seeds being retained on October 11, when Minnesota soybean harvest was approximately 75% completed in the years of the study. These results suggest that there is a sufficient amount of time to remove escaped giant ragweed from production fields and field margins before the seeds shatter by managing weed seed dispersal before or at crop harvest. Controlling weed seed dispersal has potential to manage herbicide-resistant giant ragweed by limiting replenishment of the weed seed bank.

In the midwestern United States, biotypes of giant ragweed resistant to multiple herbicide biochemical sites of action have been identified. Weeds with resistance to multiple herbicides reduce the utility of existing herbicides and necessitate the development of alternative weed control strategies. In two experiments in southeastern Minnesota, we determined the effect of six 3 yr crop-rotation systems containing corn, soybean, wheat, and alfalfa on giant ragweed seedbank depletion and emergence patterns. The six crop-rotation systems included continuous corn, soybean–corn–corn, corn–soybean–corn, soybean–wheat–corn, soybean–alfalfa–corn, and alfalfa–alfalfa–corn. The crop-rotation system had no effect on the amount of seedbank depletion when a zero-weed threshold was maintained, with an average of 96% of the giant ragweed seedbank being depleted within 2 yr. Seedbank depletion occurred primarily through seedling emergence in all crop-rotation systems. However, seedling emergence tended to account for more of the seedbank depletion in rotations containing only corn or soybean compared with rotations with wheat or alfalfa. Giant ragweed emerged early across all treatments, with on average 90% emergence occurring by June 4. Duration of emergence was slightly longer in established alfalfa compared with other cropping systems. These results indicate that corn and soybean rotations are more conducive to giant ragweed emergence than rotations including wheat and alfalfa, and that adopting a zero-weed threshold is a viable approach to depleting the weed seedbank in all crop-rotation systems.

Contemporary neuroimaging methods have been used to gather initial data regarding the neural substrates of posttraumatic stress disorder (PTSD). Morphometric magnetic resonance imaging (MRI) studies have reliably shown reduced hippocampal volume in subjects with PTSD vs control cohorts. Functional imaging studies have implicated a network of brain regions in PTSD, comprising the amygdala, hippocampus, and anterior paralimbic territories (including anterior cingulate cortex), as well as Broca's area and visual cortex. Extant relevant neuroimaging data are reviewed, and a tentative heuristic neuroanatomical model of PTSD is provided. In conclusion, emerging strategies for advancement in this field are outlined.