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Posttraumatic stress symptoms (PTSS) are common following traumatic stress exposure (TSE). Identification of individuals with PTSS risk in the early aftermath of TSE is important to enable targeted administration of preventive interventions. In this study, we used baseline survey data from two prospective cohort studies to identify the most influential predictors of substantial PTSS.
Self-identifying black and white American women and men (n = 1546) presenting to one of 16 emergency departments (EDs) within 24 h of motor vehicle collision (MVC) TSE were enrolled. Individuals with substantial PTSS (⩾33, Impact of Events Scale – Revised) 6 months after MVC were identified via follow-up questionnaire. Sociodemographic, pain, general health, event, and psychological/cognitive characteristics were collected in the ED and used in prediction modeling. Ensemble learning methods and Monte Carlo cross-validation were used for feature selection and to determine prediction accuracy. External validation was performed on a hold-out sample (30% of total sample).
Twenty-five percent (n = 394) of individuals reported PTSS 6 months following MVC. Regularized linear regression was the top performing learning method. The top 30 factors together showed good reliability in predicting PTSS in the external sample (Area under the curve = 0.79 ± 0.002). Top predictors included acute pain severity, recovery expectations, socioeconomic status, self-reported race, and psychological symptoms.
These analyses add to a growing literature indicating that influential predictors of PTSS can be identified and risk for future PTSS estimated from characteristics easily available/assessable at the time of ED presentation following TSE.
The following chapter details factors to consider when evaluating patients with Parkinson’s disease, essential tremor, or dystonia for treatment with deep brain stimulation (DBS) therapy. An understanding of what factors tend to predict a good outcome from DBS is critical in counseling patients, helping the clinician determine which patients are likely to realize meaningful benefit, and gauging when along the course of each patient’s disease process to intervene. These factors are discussed independently for Parkinson’s disease (PD), essential tremor (ET), and dystonia. The risks related to surgical implantation of the system and stimulation itself need to be weighted against the expected benefit.
Veterans’ Affairs (VA) healthcare providers perceive that Veterans expect and base visit satisfaction on receiving antibiotics for upper respiratory tract infections (URIs). No studies have tested this hypothesis. We sought to determine whether receiving and/or expecting antibiotics were associated with Veteran satisfaction with URI visits.
This cross-sectional study included Veterans evaluated for URI January 2018–December 2019 in an 18-clinic ambulatory VA primary-care system. We evaluated Veteran satisfaction via the Patient Satisfaction Questionnaire Short Form (RAND Corporation), an 18-item 5-point Likert scale survey. Additional items assessed Veteran antibiotic expectations. Antibiotic receipt was determined via medical record review. We used multivariable regression to evaluate whether antibiotic receipt and/or Veteran antibiotic expectations were associated with satisfaction. Subgroup analyses focused on Veterans who accurately remembered antibiotic prescribing during their URI visit.
Of 1,329 eligible Veterans, 432 (33%) participated. Antibiotic receipt was not associated with differences in mean total satisfaction (adjusted score difference, 0.6 points; 95% confidence interval [CI], −2.1 to 3.3). However, mean total satisfaction was lower for Veterans expecting an antibiotic (adjusted score difference −4.4 points; 95% CI −7.2 to −1.6). Among Veterans who accurately remembered the visit and did not receive an antibiotic, those who expected an antibiotic had lower mean satisfaction scores than those who did not (unadjusted score difference, −16.6 points; 95% CI, −24.6 to −8.6).
Veteran expectations for antibiotics, not antibiotic receipt, are associated with changes in satisfaction with outpatient URI visits. Future research should further explore patient expectations and development of patient-centered and provider-focused interventions to change patient antibiotic expectations.
One of the most important financial decisions that pension participants make concerns how they access their pension assets when they terminate employment with their plan sponsor. Their choices depend both on own preferences and the options offered by their retirement plan. This paper examines both past and future pension withdrawal choices for those with defined benefit (DB) and defined contribution (DC) pensions, separately. Our data are drawn from a set of pension distribution questions we fielded in the Understanding American Study. Results show significant differences in distribution choices based on the type of retirement plan, with individuals covered by DB plans significantly more likely to select annuities compared to similar employees covered by DC plans. We also find differences in how higher annual income affects annuity choices based on coverage by DB plans. Individuals with lower levels of financial literacy and lower annual income have less knowledge of basic pension characteristics.
A field experiment was conducted in 2019 and 2020 including a total of six site-years and four locations in Arkansas to determine the optimal sequence and timing of dicamba and glufosinate applications when applied alone, sequentially, or in combination to control Palmer amaranth by size: labeled (<10-cm height) and non-labeled (13- to 25-cm height). Single applications of dicamba, glufosinate, and dicamba plus glufosinate (not labeled) resulted in less than 80% Palmer amaranth control, regardless of weed size. The mixture of dicamba plus glufosinate was antagonistic for Palmer amaranth control and percent mortality. Sequential applications, averaged over all time intervals and herbicides, improved the percentage of Palmer amaranth control 11 to 17 percentage points over a single application, regardless of weed size at application 28 d after final application (DAFA). Palmer amaranth control with glufosinate followed by (fb) glufosinate and dicamba fb dicamba, pending weed size, were optimized at 7-, and 14- to 21-day intervals, respectively. Since single site of action (SOA) postemergence systems increase the likelihood of resistant biotypes and are not a best management practice (BMP) in that regard, sequential applications involving both dicamba and glufosinate were more effective. Further the sequence of application mattered with a preference for applying dicamba first. Dicamba fb glufosinate at a 14-day interval was profit-maximizing and the only herbicide treatment that resulted in 100% weed control when size was <10-cm. For larger weed sizes, economic analysis revealed dicamba fb dicamba to perform better than dicamba fb glufosinate when no penalty was assigned for using a single SOA. This resulted in greater yield loss risk and soil weed seed bank in comparison to timelier weed control with the smaller weed size. Hence timely weed control and two SOA to control Palmer amaranth are recommended as BMPs that reduce producer risk.
Palmer amaranth is a common weed on levees in rice fields but has become increasingly problematic with adoption of furrow-irrigated rice and the lack of an established flood. Florpyrauxifen-benzyl has previously been found effective for controlling Palmer amaranth in rice, but the efficacy of low rates of florpyrauxifen-benzyl and the effect of Palmer amaranth size on control is unknown. The objective of this research was to find the level of Palmer amaranth control expected with single and sequential applications of florpyrauxifen-benzyl at varying weed heights. The first study was conducted at the Lon Mann Cotton Research Station near Marianna, AR, in 2019 and 2020 to determine the effect of florpyrauxifen-benzyl rate on control of <10 cm (labeled size) and 28- to 32-cm tall (larger-than-labeled size) Palmer amaranth. The second experiment was conducted in 2020 at Pine Tree Research Station and Lon Mann Cotton Research Station to compare single applications of florpyrauxifen-benzyl at low rates to sequential applications at the same rates with a 14-day interval on 20- and 40-cm tall Palmer amaranth. Results revealed that florpyrauxifen-benzyl at 15 g ae ha−1 was as effective as 30 g ae ha−1 in controlling <10-cm tall Palmer amaranth (92% and 95% mortality in 2019). Sequential applications of florpyrauxifen-benzyl at 8 g ae ha−1 was as effective as single or sequential applications at 30 g ae ha−1. However, no rate of florpyrauxifen-benzyl applied to 20- or 40-cm tall Palmer amaranth was sufficient to provide season-long control of the weed, with the escaping female plants producing as many as 6,120 seed per plant following a single application.
Background: Eye movements reveal neurodegenerative disease processes due to overlap between oculomotor circuitry and disease-affected areas. Characterizing oculomotor behaviour in context of cognitive function may enhance disease diagnosis and monitoring. We therefore aimed to quantify cognitive impairment in neurodegenerative disease using saccade behaviour and neuropsychology. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with neurodegenerative disease: one of Alzheimer’s disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, or cerebrovascular disease. Patients (n=450, age 40-87) and healthy controls (n=149, age 42-87) completed a randomly interleaved pro- and anti-saccade task (IPAST) while their eyes were tracked. We explored the relationships of saccade parameters (e.g. task errors, reaction times) to one another and to cognitive domain-specific neuropsychological test scores (e.g. executive function, memory). Results: Task performance worsened with cognitive impairment across multiple diseases. Subsets of saccade parameters were interrelated and also differentially related to neuropsychology-based cognitive domain scores (e.g. antisaccade errors and reaction time associated with executive function). Conclusions: IPAST detects global cognitive impairment across neurodegenerative diseases. Subsets of parameters associate with one another, suggesting disparate underlying circuitry, and with different cognitive domains. This may have implications for use of IPAST as a cognitive screening tool in neurodegenerative disease.
Early adolescents (ages 10–14) living in low- and middle-income countries have heightened vulnerability to psychosocial risks, but available evidence from these settings is limited. This study used data from the Global Early Adolescent Study to characterize prototypical patterns of emotional and behavioral problems among 10,437 early adolescents (51% female) living in the Democratic Republic of Congo (DRC), Malawi, Indonesia, and China, and explore the extent to which these patterns varied by country and sex. LCA was used to identify and classify patterns of emotional and behavioral problems separately by country. Within each country, measurement invariance by sex was evaluated. LCA supported a four-class solution in DRC, Malawi, and Indonesia, and a three-class solution in China. Across countries, early adolescents fell into the following subgroups: Well-Adjusted (40–62%), Emotional Problems (14–29%), Behavioral Problems (15–22%; not present in China), and Maladjusted (4–15%). Despite the consistency of these patterns, there were notable contextual differences. Further, tests of measurement invariance indicated that the prevalence and nature of these classes differed by sex. Findings can be used to support the tailoring of interventions targeting psychosocial adjustment, and suggest that such programs may have utility across diverse cross-national settings.
The ability of weed populations to evolve resistance to herbicides affects management strategies and the profitability of crop production. The objective of this research was to screen Palmer amaranth accessions from Arkansas for glufosinate resistance. Additional efforts focused on the effectiveness of various herbicides, across multiple sites of action (SOAs), on each putative-resistant accession. The three putative accessions were selected from 60 Palmer amaranth accessions collected in 2019 and 2020 and screened with to 0.5× and 1× rates of glufosinate. A dose-response experiment was conducted for glufosinate on accessions A2019, A2020, and B2020. The effectiveness of various preemergence- and postemergence-applied herbicides were evaluated on each accession. Resistance ratios of A2019, A2020, and B2020 to glufosinate ranged from 5.1 to 27.4 when comparing LD50 values to two susceptible accessions, thus all three accessions were resistant to glufosinate. All three accessions (A2019, A2020, and B2020) were found to have a reduction equal to or greater than 20 percentage points in mortality to at least one herbicide from five different SOAs equal to or greater than five sites of action. Herbicides from nine different SOAs controlled A2019 at least 20 percentage points less than the susceptible accessions, which points to a need for additional research to characterize the response of this accession.
Pre-pandemic psychological distress is associated with increased susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but associations with the coronavirus disease 2019 (COVID-19) severity are not established. The authors examined the associations between distress prior to SARS-CoV-2 infection and subsequent risk of hospitalization.
Between April 2020 (baseline) and April 2021, we followed 54 781 participants from three ongoing cohorts: Nurses' Health Study II (NHSII), Nurses' Health Study 3 (NHS3), and the Growing Up Today Study (GUTS) who reported no current or prior SARS-CoV-2 infection at baseline. Chronic depression was assessed during 2010–2019. Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at baseline. SARS-CoV-2 infection and hospitalization due to COVID-19 was self-reported. Relative risks (RRs) were calculated by Poisson regression.
3663 participants reported a positive SARS-CoV-2 test (mean age = 55.0 years, standard deviation = 13.8) during follow-up. Among these participants, chronic depression prior to the pandemic [RR = 1.72; 95% confidence interval (CI) 1.20–2.46], and probable depression (RR = 1.81, 95% CI 1.08–3.03), being very worried about COVID-19 (RR = 1.79; 95% CI 1.12–2.86), and loneliness (RR = 1.81, 95% CI 1.02–3.20) reported at baseline were each associated with subsequent COVID-19 hospitalization, adjusting for demographic factors and healthcare worker status. Anxiety and perceived stress were not associated with hospitalization. Depression, worry about COVID-19, and loneliness were as strongly associated with hospitalization as were high cholesterol and hypertension, established risk factors for COVID-19 severity.
Psychological distress may be a risk factor for hospitalization in patients with SARS-CoV-2 infection. Assessment of psychological distress may identify patients at greater risk of hospitalization. Future work should examine whether addressing distress improves physical health outcomes.
The late Holocene Bonneville landslide, a 15.5 km2 rockslide-debris avalanche, descended 1000 m from the north side of the Columbia River Gorge and dammed the Columbia River where it bisects the Cascade Range of Oregon and Washington, USA. The landslide, inundation, and overtopping created persistent geomorphic, ecologic, and cultural consequences to the river corridor, reported by Indigenous narratives and explorer accounts, as well as scientists and engineers. From new dendrochronology and radiocarbon dating of three trees killed by the landslide, one entrained and buried by the landslide and two killed by rising water in the impounded Columbia River upstream of the blockage, we find (1) the two drowned trees and the buried tree died the same year, and (2) the age of tree death, and hence the landslide (determined by combined results of nine radiocarbon analyses of samples from the three trees), falls within AD 1421–1455 (3σ confidence interval). This result provides temporal context for the tremendous physical, ecological, and cultural effects of the landslide, as well as possible triggering mechanisms. The age precludes the last Cascadia Subduction Zone earthquake of AD 1700 as a landslide trigger, but not earlier subduction zone or local crustal earthquakes.
Negative emotionality (NE) was evaluated as a candidate mechanism linking prenatal maternal affective symptoms and offspring internalizing problems during the preschool/early school age period. The participants were 335 mother–infant dyads from the Maternal Adversity, Vulnerability and Neurodevelopment project. A Confirmatory Bifactor Analysis (CFA) based on self-report measures of prenatal depression and pregnancy-specific anxiety generated a general factor representing overlapping symptoms of prenatal maternal psychopathology and four distinct symptom factors representing pregnancy-specific anxiety, negative affect, anhedonia and somatization. NE was rated by the mother at 18 and 36 months. CFA based on measures of father, mother, child-rated measures and a semistructured interview generated a general internalizing factor representing overlapping symptoms of child internalizing psychopathology accounting for the unique contribution of each informant. Path analyses revealed significant relationships among the general maternal affective psychopathology, the pregnancy- specific anxiety, and the child internalizing factors. Child NE mediated only the relationship between pregnancy-specific anxiety and the child internalizing factors. We highlighted the conditions in which prenatal maternal affective symptoms predicts child internalizing problems emerging early in development, including consideration of different mechanistic pathways for different maternal prenatal symptom presentations and child temperament.
There is currently a heightened need for transparency in pharmaceutical sectors. The inclusion of real-world (RW) evidence, in addition to clinical trial evidence, in decision-making processes, was an important step forward toward a more inclusive established value proposition. This advance has introduced new transparency challenges. Increasing transparency is a critical step toward accelerating improvement in type, quality, and access to data, regardless of whether these originate from clinical trials or from RW studies. However, so far, advances in transparency have been relatively restricted to clinical trials, and there remains a lack of similar expectations or standards of transparency concerning the generation and reporting of RW data. This perspective paper aims to highlight the need for transparency concerning RW studies, data, and evidence across health care sectors, to identify areas for improvement, and provide concrete recommendations and practices for the future. Specific issues are discussed from different stakeholder perspectives, culminating in recommended actions, from individual stakeholder perspectives, for improved RW study, data, and evidence transparency. Furthermore, a list of potential guidelines for consideration by stakeholders is proposed. While recommendations from different stakeholder perspectives are made, true transparency in the processes involved in the generation, reporting, and use of RW evidence will require a concerted effort from all stakeholders across health care sectors.
OBJECTIVES/GOALS: The SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus-2), which underlies the current COVID-19 pandemic, among other tissues, also targets the central nervous system (CNS). The goal of this study is to investigate mechanisms of neuroinflammation in Lipopolysaccharides (LPS)-treated mouse model and SARS-CoV-2-infected hamsters. METHODS/STUDY POPULATION: In this research I will assay vascular reactivity of cerebral vessels to assess vascular dysfunction within the microcirculation. I will determine expression of proinflammatory cytokines, coagulation factors and AT1 receptors (AT1R) in isolated microvessels from the circle of Willis to assess inflammation, thrombosis and RAS activity in the microvasculature. LPS and SARS-CoV-2, are both associated with coagulopathies and because of that I will measure concentration of PAI-1, von Willebrand Factor, thrombin and D-dimer to assess the thrombotic pathway in the circulation. Histology and immunohistochemistry will assess immune cell type infiltration into the brain parenchyma, microglia activation and severity of neuroinflammation and neural injury. RESULTS/ANTICIPATED RESULTS: We hypothesize that under conditions of reduced ACE2 (e.g., SARS-CoV-2 infection), AT1R activity is upregulated in the microvasculature. In the presence of an inflammatory insult, these AT1Rs promote endothelialitis and immunothrombosis through pro-thrombotic pathways and pro-inflammatory cytokine production leading to endothelial dysfunction in the microvasculature, blood brain barrier (BBB) injury, deficits in cognition and increased anxiety. We will test this hypothesis through 2 aims: Aim 1: Determine the role of the pro-injury arm of the RAS in the pathophysiology of the brain in animal models of neuroinflammation and COVID-19. Aim 1: Determine the role of the protective arm of the RAS in the pathophysiology of the brain in animal models of neuroinflammation and COVID-19. DISCUSSION/SIGNIFICANCE: This study will provide insights that will complement on-going clinical trials on angiotensin type 1 receptor (AT1R) blockers (ARBs) in COVID-19. This research is a necessary first step in understanding mechanisms of brain pathogenesis that can set the groundwork for future studies of more complex models of disease.
OBJECTIVES/GOALS: The goal of this study was to understand the impact of a high sodium diet on gene networks in the kidney that correlate with blood pressure in female primates, and translating findings to women. METHODS/STUDY POPULATION: Sodium-naÃ¯ve female baboons (n=7) were fed a low-sodium (LS) diet for 6 weeks followed by a high sodium (HS) diet for 6 weeks. Sodium intake, serum 17 beta-estradiol, and ultrasound-guided kidney biopsies for RNA-Seq were collected at the end of each diet. Blood pressure was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. Weighted gene coexpression network analysis was performed on RNA-Seq data to identify transcripts correlated with blood pressure on each diet. Network analysis was performed on transcripts highly correlated with BP, and in silico findings were validated by immunohistochemistry of kidney tissues. RESULTS/ANTICIPATED RESULTS: On the LS diet, Na+ intake and serum 17 beta-estradiol concentration correlated with BP. Cell type composition of renal biopsies was consistent among all animals for both diets. Kidney transcriptomes differed by diet; analysis by unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet. Network analysis of module genes showed causal networks linking hormone receptors, proliferation and differentiation, methylation, hypoxia, insulin and lipid regulation, and inflammation as regulators underlying variation in BP on the HS diet. Our results show variation in BP correlated with novel kidney gene networks with master regulators PPARG and MYC in female baboons on a HS diet. DISCUSSION/SIGNIFICANCE: Previous studies in primates to identify molecular networks dysregulated by HS diet focused on males. Current clinical guidelines do not offer sex-specific treatment plans for sodium sensitive hypertension. This study leveraged variation in BP as a first step to identify correlated kidney regulatory gene networks in female primates after a HS diet.
OBJECTIVES/GOALS: A functional precision medicine platform to identify therapeutic targets for a glioblastoma patient with Li Fraumeni syndrome was performed. Comparative transcriptomics identified druggable targets and patient derived organoids and a 3D-PREDICT drug screening assay was used to validate the pipeline and identify further therapeutic targets. METHODS/STUDY POPULATION: A comparative transcriptomics pipeline was used to identify druggable genes that are uniquely overexpressed in our patient of interest relative to a cancer compendium of 12,747 tumor RNA sequencing datasets including 200 GBMs. Mini-ring patient derived organoid-based drug viability assays were performed to validate the comparative transcriptomics data. Additionally, a spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. RESULTS/ANTICIPATED RESULTS: Using comparative transcriptomics STAT1 and STAT2 were found to be significantly overexpressed in our patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitor, as a potential therapy. Druggable pathways predicted using comparative transcriptomics corresponded with ruxolitinib sensitivity in a panel of patient derived organoids screened with this compound. Cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. Additionally, 3D-PREDICT screening identified the mTOR inhibitor everolimus as a potential candidate. These two targeted therapies were selected for our patient and resulted in radiographic disease stability. DISCUSSION/SIGNIFICANCE: This research illustrates the use of comparative transcriptomics to identify druggable pathways irrespective of actionable DNA mutations present. Our results are promising and serve to highlight the importance of functional precision medicine in tailoring treatment regimes to specific patients.
The complexities of chemical composition and crystal structure are fundamental characteristics of minerals that have high relevance to the understanding of their stability, occurrence and evolution. This review summarises recent developments in the field of mineral complexity and outlines possible directions for its future elaboration. The database of structural and chemical complexity parameters of minerals is updated by H-correction of structures with unknown H positions and the inclusion of new data. The revised average complexity values (arithmetic means) for all minerals are 3.54(2) bits/atom and 345(10) bits/cell (based upon 4443 structure reports). The distributions of atomic information amounts, chemIG and strIG, versus the number of mineral species fit the normal modes, whereas the distributions of total complexities, chemIG,total and strIG,total, along with numbers of atoms per formula and per unit cell are log normal. The three most complex mineral species known today are ewingite, morrisonite and ilmajokite, all either discovered or structurally characterised within the last five years. The most important complexity-generating mechanisms in minerals are: (1) the presence of isolated large clusters; (2) the presence of large clusters linked together to form three-dimensional frameworks; (3) formation of complex three-dimensional modular frameworks; (4) formation of complex modular layers; (5) high hydration state in salts with complex heteropolyhedral units; and (6) formation of ordered superstructures of relatively simple structure types. The relations between symmetry and complexity are considered. The analysis of temporal dynamics of mineralogical discoveries since 1875 with the step of 25 years show the increasing chemical and structural complexities of human knowledge of the mineral kingdom in the history of mineralogy. In the Earth's history, both diversity and complexity of minerals experience dramatic increases associated with the formation of Earth's continental crust, initiation of plate tectonics and the Great Oxidation event.
OBJECTIVES/GOALS: Using the covariate-rich Veteran Health Administration data, estimate the association between Proton Pump Inhibitor (PPI) use and severe COVID-19, rigorously adjusting for confounding using propensity score (PS)-weighting. METHODS/STUDY POPULATION: We assembled a national retrospective cohort of United States veterans who tested positive for SARS-CoV-2, with information on 33 covariates including comorbidity diagnoses, lab values, and medications. Current outpatient PPI use was compared to non-use (two or more fills and pills on hand at admission vs no PPI prescription fill in prior year). The primary composite outcome was mechanical ventilation use or death within 60 days; the secondary composite outcome included ICU admission. PS-weighting mimicked a 1:1 matching cohort, allowing inclusion of all patients while achieving good covariate balance. The weighted cohort was analyzed using logistic regression. RESULTS/ANTICIPATED RESULTS: Our analytic cohort included 97,674 veterans with SARS-CoV-2 testing, of whom 14,958 (15.3%) tested positive (6,262 [41.9%] current PPI-users, 8,696 [58.1%] non-users). After weighting, all covariates were well-balanced with standardized mean differences less than a threshold of 0.1. Prior to PS-weighting (no covariate adjustment), we observed higher odds of the primary (9.3% vs 7.5%; OR 1.27, 95% CI 1.13-1.43) and secondary (25.8% vs 21.4%; OR 1.27, 95% CI 1.18-1.37) outcomes among PPI users vs non-users. After PS-weighting, PPI use vs non-use was not associated with the primary (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16) or secondary (23.4% vs 22.9%;OR 1.03, 95% CI 0.95-1.12) outcomes. DISCUSSION/SIGNIFICANCE: The associations between PPI use and severe COVID-19 outcomes that have been previously reported may be due to limitations in the covariates available for adjustment. With respect to COVID-19, our robust PS-weighted analysis provides patients and providers with further evidence for PPI safety.