Liquefaction Susceptibility: Proposed New York City Building Code Revision

A simplified procedure is presented for evaluating liquefaction susceptibility of cohesionless saturated soils based on available technology. In 2001, a Committee of engineers working in the New York City (NYC) area was formed under the direction of the first Author, to review the liquefaction aspects of the 1995 New York City Building Code. The purpose was to gain consensus on a possible revision and augmentation of the exisiting regulations as part of the ongoing Code review by the Structural Engineers Association of New York (SEAoNY). This article summarizes the recommendations of the Committee, as compiled in 2002. The following topics are reviewed: (a) history of the current code; (b) seismicity and design motions in NYC; (c) updated screening criteria for liquefaction susceptibility. With reference to the topic in (c), recommendations are developed for Code language pertaining to: (1) method of analysis; (2) site classification schemes; (3) design considerations for bearing capacity and displacements of foundations in liquefied soil; (4) maximum depth of liquefaction; (5) field methods to evaluate soil resistance; (6) parameters to be considered in analyses; (7) treatment of sloped strata. Analytical results for typical NYC profiles subjected to 500-year rock motions are presented. Based on the these results, the Committee proposed a revised liquefaction screening diagram

IL-2/IL-2R, TL1A/TNFRSF25 or Their Combined Stimulation Results in Distinct CD4+FoxP3+ Regulatory T Cell Phenotype and Suppressive Function

CD4+Foxp3+ regulatory T cells (Tregs) are non-redundant mediators of immunity and tolerance. Transfer of Tregs has emerged as a promising therapy for graft-versus-host disease (GVHD) following allogeneic HSCT (aHSCT). Our prior work demonstrated that a 2-pathway in vivo strategy targeting TNFRSF25 (with TL1A-Ig) and IL-2 receptor (with low-dose IL-2, IL-2LD) can elicit a strong increase in Treg numbers and function. In fact, very low numbers of these in vivo expanded donor Tregs suppressed GVHD post-aHSCT. Based on these findings and the success of IL-2 in pre-clinical and clinical studies, we asked: are there phenotypic/functional differences between Tregs expanded via IL-2 LD, TL1A-Ig or their combined application? Mice were administered IL-2LD, TL1A-Ig or TL1A-Ig+IL-2LD over 6 days. Splenic and lymph node (LN) Treg phenotype was determined by flow cytometry. Treg functionality was assessed with sorted populations using an in vivo MHC-mismatched aHSCT. Treatment of B6-FoxP3RFP mice with TL1A-Ig+IL-2LD vs. IL-2LD only resulted in significantly higher levels of Treg activation/differentiation and functional markers, i.e. KLRG1, CD103, Nrp1, ICOS (Fig. 1A). Ki67 expression was higher in 2-pathway vs. IL-2LD stimulation alone (Fig.1B). Notably, TL1A-Ig treatment alone induced the above phenotype. CD25 (IL-2Rα) expression was reduced after TL1A-Ig vs. IL-2-mediated expansion further emphasizing the difference between the TNFRSF25 and IL-2 receptor stimulation (Fig. 1A). Results were corroborated using a second independent mouse strain, BALB/c, following use of these protocols. To test if the observed phenotypic differences could be related to more potent Treg function in vivo, an MHC-mismatched aHSCT (B6→BALB/c) was performed using 200,000 sorted Tregs (>98% purity by CD4+FoxP3+ selection from C57BL/6-FoxP3RFP reporter mice) from donor unexpanded, IL-2LD, or TL1A-Ig+IL-2LD treated mice + T cells. As anticipated, transfer 200,000 TL1A-Ig+IL-2LD stimulated Tregs ameliorated acute GVHD (Fig. 1C). Interestingly, lower GVHD clinical scores were obtained using the same number of IL-2LD only vs.TL1A-Ig+IL-2LD stimulated Tregs (Fig. 1C). Moreover, early post-transplant, higher LN and splenic CD4/CD8 ratios were detected in aHSCT recipients treated with IL-2LD expanded Tregs vs. TL1A-Ig+IL-2LD (Fig. 1D). Overall, TL1A-Ig+IL-2LD promotes a more activated/differentiated and proliferative Treg phenotype accompanied by less effective long-term GVHD inhibition vs. IL-2LD only stimulated Tregs. We posit that these different 1- and/or 2-pathway driven Tregs may promote development of new strategies utilizing one or both populations dependent on the desire for GVHD prophylaxis or therapeutic treatment following aHSCT

Multiple Pathways Targeting CD25 or TNFRSF25 Affect CD4+FoxP3+ Regulatory T Cell Phenotype and Suppressive Function

BACKGROUND: Regulatory T cells (Tregs) are non-redundant mediators of immunity and tolerance. Adoptive transfer of CD4+Foxp3+ Tregs has emerged as a promising therapy for graft-versus-host disease (GVHD) following allogeneic HSCT (aHSCT), solid organ transplantation and autoimmune diseases (Hanash AM, Blood 2005; Copsel S, Wolf D, Haematologica 2019; Marek-Trzonkowska N, Diabetes Care 2012; Tang Q, J Mol Cell Biol 2012). Our prior work was the first to demonstrate a two-pathway in vivo strategy targeting TNFRSF25 (with TL1A-Ig fusion protein) and CD25 (with low dose IL-2, IL-2LD) receptors can elicit a rapid and strong increase in Treg numbers and function (Wolf D, BBMT 2017). In fact, very low numbers of these in vivo expanded donor Tregs exhibited effective GVHD suppression in recipients following aHSCT (Copsel S, BBMT 2018). Based on these findings and the success of IL-2LD in pre-clinical and clinical studies, we asked: are there phenotypic/functional differences between Tregs expanded via IL-2LD, TL1A-Ig or their combined application (TL1A-Ig+IL-2LD)? METHODS: Mice were administered IL-2LD, TL1A-Ig or TL1A-Ig+IL-2LD over 6 days. Splenic and lymph node (LN) Treg phenotype was determined by flow cytometry. Treg functionality was assessed with sorted populations using an in vivo MHC-mismatched aHSCT. RESULTS: Treatment of C57BL/6-FoxP3RFP mice with TL1A-Ig+IL-2 LD versus IL-2LD only treatment resulted in significantly higher levels of activation/differentiation and functional markers on Tregs including KLRG1, CD103, Nrp1, ICOS (Fig. 1A). Ki67 expression was higher in two-pathway versus IL-2LD stimulation alone (Fig.1B). These data suggested a key role for TNFRSF25 stimulation. Notably, Treg stimulation with TL1A-Ig alone drove the above phenotype indicating a pathway difference between the TNFRSF25 and IL-2 receptors. This difference was further apparent as high affinity IL-2 receptor (CD25) expression was reduced after TL1A-Ig +/- IL-2LD -mediated expansion compared with IL-2 LD alone stimulated Tregs (Fig. 1A). Results were corroborated using a second independent mouse strain, BALB/c, following use of these protocols. To begin addressing if the observed phenotypic differences between CD25 vs. TNFRSF25 + CD25 expanded Tregs could be related to a more potent Treg in vivo suppressive activity, an initial MHC-mismatched aHSCT (donor/recipient = C57BL/6-BALB/c) was performed. We employed 200,000 sorted Tregs (>98% purity by CD4+FoxP3+ selection from C57BL/6-FoxP3RFP reporter mice) from donor unexpanded, IL-2LD, or TL1A-Ig+IL-2LD treated mice combined with 1.0 x106 T cells. As anticipated, transfer 200,000 TL1A-Ig+IL-2LD stimulated Tregs ameliorated acute GVHD (Fig. 1C). Remarkably, lower GVHD clinical scores were obtained using the same number of IL-2LD only expanded Tregs compared with TL1A-Ig+IL-2LD stimulated Tregs (Fig. 1C). Moreover, early post-transplant, higher LN and splenic CD4/CD8 ratios were detected in aHSCT recipients treated with IL-2LD expanded Tregs vs. TL1A-Ig+IL-2LD (Fig. 1D). CONCLUSION: Our donor TL1A-Ig+IL-2LD Treg expansion protocol promotes a more activated/differentiated and proliferative phenotype versus IL-2LD stimulation alone. This finding may have accounted for their initial effectiveness - but less efficient long-term GVHD amelioration compared to IL-2LD only stimulated Tregs. Multiple variables are associated with the application of Tregs for therapy including numbers, persistence, and suppressive capacity. Our findings suggest a rationale that one-pathway and / or two-pathway stimulated Tregs may be beneficial for use in aHSCT recipients dependent on whether there is a perceived need for prolonged Treg presence and the stage of GVHD. Disclosures Levy: Heat Biologics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pelican Therapeutics: Consultancy, Research Funding

Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model

•Stimulating Tregs in vivo using a “2-pathway” strategy (TNFRSF25 via TL1A-Ig and CD25 via low-dose IL-2) induces differentiation and activation markers characteristic of a distinct phenotype compared with untreated Tregs.•Two-pathway expanded Tregs show increased levels of effector molecules and mediate enhanced in vitro suppressor activity.•Low numbers of 2-pathway expanded Tregs suppressed preclinical GVHD. Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach that induces the marked expansion and selective activation of Tregs in vivo by targeting tumor necrosis factor receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Tregs to ameliorate GVHD and other disorders would be the generation of more potent Treg populations. Here we wanted to determine if very low doses of Tregs generated using the “2-pathway” stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD. Analysis of such 2-pathway expanded Tregs identified higher levels of activation and functional molecules (CD103, ICOS-1, Nrp-1, CD39, CD73, il-10, and tgfb1) versus unexpanded Tregs. Additionally, in vitro assessment of 2-pathway stimulated Tregs indicated enhanced suppressor activity. Notably, transplant of extremely low numbers of these Tregs (1:6 expanded Tregs/conventional T cells) suppressed GVHD after an MHC-mismatched aHSCT. Overall, these results demonstrate that 2-pathway stimulated CD4+ FoxP3+ Tregs were quantitatively and qualitatively more functionally effective than unexpanded Tregs. In total, the findings in this study support the notion that such 2-pathway stimulated Tregs may be useful for prevention of GVHD and ultimately promote more widespread application of aHSCT in the clinic

Direct-to-Consumer Prescription Drug Advertising and the Public

OBJECTIVE: Drug manufacturers are intensely promoting their products directly to consumers, but the impact has not been widely studied. Consumers' awareness and understanding of, attitudes toward, and susceptibility to direct-to-consumer (DTC) drug advertising were examined. DESIGN: Random-digit dialing telephone survey with a random household member selection procedure (completion and response rates, 58% and 69%, respectively). SETTING: Respondents were interviewed while they were at their residences. PARTICIPANTS: Complete data were obtained from 329 adults in Sacramento County, California. MEASUREMENTS AND MAIN RESULTS: Outcome measures included awareness of advertisements for 10 selected drugs, misconceptions about DTC advertising, attitudes toward DTC ads, and behavioral responses to such promotions. The influence of demographic characteristics, health status, attitudes, beliefs, and media exposure on awareness and behaviors was examined. On average, respondents were aware of advertisements for 3.7 of the 10 drugs; awareness varied from 8% for Buspar (buspirone) to 72% for Claritin (loratadine). Awareness was associated with prescription drug use, media exposure, positive attitudes toward DTC advertising, poorer health, and insurance status. Substantial misconceptions were revealed; e.g., 43% thought that only “completely safe” drugs could be advertised. Direct-to-consumer advertisements had led one third of respondents to ask their physicians for drug information and one fifth to request a prescription. CONCLUSIONS: Direct-to-consumer advertisements are reaching the public, but selectively so, and affecting their behaviors. Implications for public policy are examined

How Consumers’ Attitudes Toward Direct-to-Consumer Advertising of Prescription Drugs Influence Ad Effectiveness, and Consumer and Physician Behavior

Data from 1081 adults surveyed by the FDA were analyzed to explore consumers’ attitudes toward direct-to-consumer advertising (DTCA) of prescription drugs, and the relation between these attitudes and health related consumption behaviors. We report the favorableness of consumers’ reactions to DTCA, and more importantly, demonstrate that consumers’ attitudes toward DTCA are related to whether they search for more information about a drug that is advertised, and ask their physician about the drug. Finally, we document how consumers’ attitudes towards DTCA relate to the prescription writing behavior of their physicians. Mediation analyses that more fully explicate these findings are discussed. Copyright Kluwer Academic Publishers 2004direct-to-consumer advertising, consumer behavior,