Bank distress was a defining feature of the Great Depression in the United States. Most banks, however, weathered the storm and remained in operation throughout the contraction. We show that surviving banks cut lending when depositors withdrew funds en masse during panics. This panic-induced decline in lending explains about one-third of the reduction in aggregate commercial bank lending between 1929 and 1932, more than twice as much as attributed to the failure of banks.

Turbidity currents, which are stratified, sediment-laden bottom flows in the ocean or lakes, can run out for hundreds or thousands of kilometres in submarine channels without losing their stratified structure. Here, we derive a layer-averaged, two-layer model for turbidity currents, specifically designed to capture long-runout. A number of previous models have captured runout of only tens of kilometres, beyond which thickening of the flows becomes excessive, and the models without a lateral overspill mechanism fail. In our framework, a lower layer containing nearly all the sediment is a faster, gravity-driven flow that propels an upper layer, where sediment concentration is nearly zero. The thickness of the lower layer is controlled by competition between interfacial water entrainment due to turbulent mixing and water detrainment due to sediment settling at the interface. The detrainment mechanism, first identified in experiments, is the key feature that prevents excessive thickening of the lower layer and allows long-runout. Under normal flow conditions, we obtain an exact solution to the two-layer formulation, revealing a constant velocity and a constant thickening rate in each of the two layers. Numerical simulations applied

to gradually varied flows on both constant and exponentially declining bed slopes, with boundary conditions mimicking field observations, show that the predicted lower layer thickness after 200 km flow propagation compares with observed submarine channel depths, whereas previous models overestimate this thickness three- to fourfold. This formulation opens new avenues for modelling the fluid mechanics and morphodynamics of long-runout turbidity currents in the submarine setting.

Objectives/Goals: To develop and deploy an academic learning health system (aLHS) Bridge Program to capitalize on our unique organizational strengths in Implementation Science (IS) and to overcome the gap between science and practice that threatens the success of an aLHS. The aLHS Bridges includes an IS Shared Resource, intended to advance IS to practice. Methods/Study Population: The new IS Shared Resource is built on our expertise in dissemination and implementation science, pragmatic, and adaptive trials and the CTSI’s prior success in integrating academic and clinical missions. We also leveraged our existing experts to co-lead the aLHS Bridge including Kristie Foley, PhD, inaugural Chair of the Department of Implementation Science, and Gary Rosenthal, MD, Chair of the Department of Internal Medicine. Specifically, the new IS Shared Resource builds on the capacity of the Department of IS, comprised of 36 faculty members (19 primary and 17 secondary/adjunct appointments) with expertise in qualitative and mixed-methods research, stakeholder engagement, participatory research, digital health, and organizational theory. Results/Anticipated Results: The IS Shared Resource is primed to aid faculty with dissemination and implementation needs, including shortening the time of intervention adoption and using implementation science to inform sustainable and effective implementation practice. The IS Shared Resource is equipped to provide consultation services to faculty members to understand their specific request and match IS faculty members who are expertly trained in specific strategies or contexts. Discussion/Significance of Impact: Leveraging current resources and our first-of-its-kind Department of Implementation Science, our CTSI was able to stand up the IS Shared Resource to support the goals of the CTSA and our greater institution mission. Using a multidisciplinary approach was essential to the success of the IS Shared Resource.

Objectives/Goals: The Fanconi anemia (FA) pathway is responsible for faithful DNA damage repair. FA mutations are common in multiple types of cancer, including HPV-negative head and neck cancers. We sought to identify synthetic lethal genes within this pathway to target treatment of FA-mutant tumors through siRNA- and chemical-compound-based screens. Methods/Study Population: First, we completed siRNA-based and chemical compound-based screening assays to identify gene targets that reduce patient derived Fanconi pathway mutant cell (FA-D2) viability compared to Fanconi pathway proficient cells (FA-D2 + FANCD2). Five aurora kinase (AURK) inhibitors from the compound screen were chosen for further evaluation. Cell lines were treated with AURK inhibitors or siRNA-based AURK knockdown to assess viability, proliferation, DNA repair, and cell cycle progression differences. Patient mutational, mRNA expression, and outcome data were accessed through The Cancer Genome Atlas (TCGA) portal and the Caris CODEai portal. We stratified patients by tumor AURKA and AURKB mRNA levels and assessed differences in patient survival, tumor grade, and DNA repair proficiency. Results/Anticipated Results: In both screens, AURKA came up as a target to selectively reduce the growth of FA-D2 cells compared to FA-D2 + FANCD2 cells. All five AURK inhibitors identified showed selective growth inhibition (~50–75%) in FA-D2 cells at low nanomolar doses. We narrowed our selection to hesperadin, an AURKB-specific inhibitor, which showed the highest selectivity. siRNA knockdown of AURKA and AURKB decreased cell viability by 50% and 20%, respectively. Patients with FA-mutated tumors from the TCGA pan-cancer dataset had high AURKA (twofold) and AURKB (threefold) mRNA expression. AURKA and AURKB tumor mRNA expression was significantly associated with poor patient survival. Homologous recombination deficiency scores were increased ~5-fold (p Discussion/Significance of Impact: We hypothesize that in FA-deficient backgrounds, loss of AURKA or AURKB leads to heightened genomic instability due to cell cycle dysregulation and accumulated DNA damage. Our findings warrant investigation of the therapeutic potential for AURK inhibitors, specifically hesperadin, in FA-mutant head and neck cancers.

Objectives/Goals: Understand the impact of sarcopenia on the main respiratory muscle, the diaphragm (DIAm). We hypothesize that in the DIAm of older (i.e., 24 months) compared to younger (i.e., 6 months) rats, maximum specific force (P0) is reduced, maximum shortening velocity (Vmax) is slower, maximum power output is reduced, and endurance is improved. Methods/Study Population: Mid-costal DIAm strips were excised from 6-month (n = 8; 4 female and 4 male) and 24-month (n = 8; 4 female and 4 male) rats. The DIAm was stimulated using platinum plate electrodes, and mechanical and endurance properties were measured (at 26oC). Results/Anticipated Results: In the DIAm, maximum tetanic formce (P0) decreased by ~35%, maximum velocity of shortening (Vmax) slowed by ~20%, and peak power output was reduced by ~35% in 24-month compared to 6-month rats. During repetitive isovelocity (30% Vmax; approximating peak power output) contractions, endurance (the period during which power output was sustained) of the DIAm was unaffected by aging. Corresponding with previous findings, Discussion/Significance of Impact: The changes in DIAm mechanical performance corresponded to an age-related atrophy of type IIx/IIb muscle fibers. We conclude that force generation and endurance of the DIAm required for breathing motor function is preserved in old age, while DIAm sarcopenia does impair more forceful expulsive airway clearance and voiding behaviors.

Objectives/Goals: Knowledge about predictive factors for immune-related endocrinopathies can help identify appropriate populations for specific screening approaches, provide recommendations for ICI therapy selection, guide clinical monitoring strategies to improve patient outcomes, and guide research efforts to provide equitable healthcare for all patients. Methods/Study Population: This is an analysis of the demographic and clinical data available of patients from DiRECT Cohort, a longitudinal study that prospectively follows adult cancer patients who self-identify as Black or White and undergo anti-PD-(L)1 ICI therapy. Endocrinopathies were graded using the CTCAE criteria. Kaplan–Meier method was used to calculate the incidence within the first year of treatment. Bivariate analysis (Chi-square and log-rank test) examined the associations between patient demographics, clinical characteristics, and endocrinopathies. Results/Anticipated Results: Among 955 patients, 13.20% developed endocrinopathies of any grade, most commonly hyper-/hypothyroidism and adrenal insufficiency, and 5.97% were at grade ≥2. Younger age (7.59% in age 30 vs. 4.72% in BMI ≤30, p = 0.022) showed significant associations. No significant difference was found in the incidence of grade ≥2 endocrinopathies by race (13.3 % in White and 10.79% in Black patients, p = 0.732). No association was found with cancer stage or comorbidities. Discussion/Significance of Impact: ICIs can lead to (irAEs). Endocrinopathies are a common type of irAEs, presenting a unique challenge. However, the current literature lacks real-time data and a comprehensive comparative analysis of variables like race. Identifying and understanding these variables ensures equatable access to safe and effective healthcare for all patients.

This article makes use of nearly 25,000 observations representing over 95,000 paid workdays across over 300 years to investigate individual work patterns, work availability, and the changes in work seasonality over time. This sample is comprised of workers in the construction industry, and includes unskilled men and women as well as skilled building craftsmen – the industry that is often used to estimate comparative real wages through early modern Europe. Data come predominantly from Scania, the southernmost region in modern day Sweden, and especially from Malmö, the largest town in the region.

Findings indicate that workers probably do not engage in paid labour on a purely labour-supply-based schedule, but are strongly impacted by the demand for construction labour, which was highly seasonal and impacted by local labour institutions. Seasonality was stronger further back in the past, indicating that finding long-term work may have been more difficult in earlier periods. A typical work year could probably not have been longer than 150 days, and would be made up of shorter work spells at several different sites. This is not enough work to meet standard assumptions of 250 days, or enough work for an unskilled man to support his family at a respectable level. Individual workers rarely worked more than a handful of days in a year on a construction site, even when labour demand was high, indicating that they did not maximize their income from waged labour.

Despite advances in the development of systemic anticoagulants, there remain few agents approved for utilisation in patients with mechanical heart valves. Currently, recommendations for periprocedural and long-term anticoagulation in mechanical heart valves include unfractionated heparin or vitamin K antagonists, and there are some reports for off-label use of low-molecular-weight heparins. Emerging data on parenteral direct thrombin inhibitors, such as bivalirudin, have led to increased utilisation in both extracorporeal membrane oxygenation and ventricular assist devices. We present the case of a paediatric patient with rheumatic heart disease who had significant bleeding on unfractionated heparin who successfully received prolonged bivalirudin therapy in the setting of mechanical aortic and mitral heart valves.