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The 2012 Emilia Romagna (Italy) seismic sequence has been extensively studied given the occurrence of two mainshocks, both temporally and spatially close to each other. The recent literature accounts for several fault models, obtained with different inversion methods and different datasets. Several authors investigated the possibility that the second event was triggered by the first mainshock with elusive results. In this work, we consider all the available InSAR and GPS datasets and two planar fault geometries, which are based on both seismological and geological constraints. We account for a layered, elastic half-space hosting the dislocation and compare the slip distribution resulting from the inversion and the related changes in Coulomb Failure Function (CFF) obtained with both a homogeneous and layered half-space. Finally, we focus on the interaction between the two main events, discriminating the contributions of coseismic and early postseismic slip of the mainshock on the generation of the second event and discuss the spatio-temporal distribution of the seismic sequence. When accounting for both InSAR and GPS geodetic data we are able to reproduce a detailed coseismic slip distribution for the two mainshocks that is in accordance with the overall aftershock seismicity distribution. Furthermore, we see that an elastic medium with depth dependent rigidity better accounts for the lack of the shallow seismicity, amplifying, with respect to the homogeneous case, the mechanical interaction of the two mainshocks.

Angela V Bedenbaugh,1 Machaon Bonafede,2 Elizabeth H Marchlewicz,3 Vinson Lee,4 Jeyanesh Tambiah1 1Biosplice Therapeutics, Inc., San Diego, CA, USA; 2Veradigm Life Sciences, Chicago, IL, USA; 3IBM Watson Health, Cambridge, MA, USA; 4The Kinetix Group, New York, NY, USACorrespondence: Angela V BedenbaughBiosplice Therapeutics, Inc., San Diego, CA, USATel +1 404 272 8139Email angela.bedenbaugh@biosplice.comPurpose: To determine the prevalence, healthcare resource utilization and costs (HCRU&C) of knee osteoarthritis (OA) patients versus controls.Patients and Methods: Retrospective, matched-cohort administrative claims analysis using IBM MarketScan databases (2011– 2017). Newly diagnosed, adult (18+ yrs) knee OA patients identified by ICD9/10 code were matched 1:1 to controls by age, sex, payer, and geography; alpha level set to 0.05. Prevalence was estimated for 2017. All-cause and knee OA-related HCRU&C reported per-patient-per-year (PPPY) over follow-up period up to 4 years.Results: Overall 2017 knee OA prevalence was 4% (615,514 knee OA/15.4M adults). A total of 510,605 patients meeting inclusion criteria were matched 1:1 with controls. The knee OA cohort had mean age 60 years and was 58% female. Versus controls, knee OA patients had significantly more PPPY outpatient (84.5 versus 45.0) and pharmacy (29.8 versus 19.8) claims, and significantly higher PPPY outpatient costs ($12,571 versus $6,465), and pharmacy costs ($3,655 versus $2,038). Knee OA patients incurred $7,707 more PPPY total healthcare costs than controls, of which $4,674 (60.6%) were knee OA-related medical claims and $1,926 (25%) were knee OA-related medications of interest. PPPY costs for nonselective NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, intraarticular hyaluronic acid, non-acute opioids, and knee replacement were higher for knee OA patients than controls. Using median and mean all-cause total cost ($9,330 and $24,550, respectively), the estimated sum cost of knee OA patients in MarketScan ranged from $5.7B to $15B annually.Conclusion: This retrospective analysis demonstrated an annual 2017 prevalence of 4.0% (≥ 18 years) and 13.2% (≥ 65 years) for newly diagnosed knee OA patients. Compared with controls, all-cause costs were significantly higher for knee OA patients, nearly double that of matched controls, attributable to increased medical and treatment costs and comorbidity treatment burden. Additionally, the estimated annual cost of knee OA treatment was substantial, ranging between $5.7 billion and $15 billion.Keywords: administrative claims, economic burden, arthritis, pharmacy costs

Changes in water level are commonly reported in regions struck by a seismic event. The sign and amplitude of such changes depend on the relative position of measuring points with respect to the hypocenter, and on the poroelastic properties of the rock. We apply a porous media flow model (TOUGH2) to describe groundwater flow and water-level changes associated with the first ML5.9 mainshock of the 2012 seismic sequence in Emilia (Italy). We represent the earthquake as an instantaneous pressure step, whose amplitude was inferred from the properties of the seismic source inverted from geodetic data. The results are consistent with the evolution recorded in both deep and shallow water wells in the area and suggest that our description of the seismic event is suitable to capture both timing and magnitude of water-level changes. We draw some conclusions about the influence of material heterogeneity on the pore pressure evolution, and we show that to reproduce the observed maximum amplitude it is necessary to take into account compaction in the shallow layer.

Alexander Marshall,1 Kiran Gupta,1 Michael Pazirandeh,1 Machaon Bonafede,2 Donna McMorrow21Health Economics and Outcomes Research, Bristol-Myers Squibb, Lawrenceville, NJ, USA; 2IBM Watson Health, IBM, Cambridge, MA, USAPurpose: To describe health care resource utilization (HCRU) and costs among patients with juvenile idiopathic arthritis (JIA) compared to patients without JIA and to describe treatment patterns among JIA patients who initiated biologic and non-biologic disease-modifying antirheumatic drugs (DMARDs).Patients and methods: The IBM MarketScan®, Commercial Database was used to identify patients aged 2–17 years with a new JIA diagnosis (index date) and 12 months continuous enrollment pre- and post-diagnosis from 2008 to 2016. JIA patients were matched to non-JIA patients on age, gender, region, and health plan type. Patients with other rheumatic or autoimmune conditions were excluded. Receipt of a biologic and/or non-biologic was evaluated on or after the new JIA diagnosis.Results: A total of 3,815 JIA patients were matched to 11,535 non-JIA patients (mean age 10.0 [SD=4.5], 69% female). Average total costs were greater for JIA patients than non-JIA controls ($18,611 [SD=$42,104; median=$8,189] versus $2,203 [SD=$9,309; median=$649], p

Eric T Wittbrodt,1 Lauren A Millette,1 Kristin A Evans,2 Machaon Bonafede,2 Joseph Tkacz,2 Gary T Ferguson3 1Medical Affairs, AstraZeneca, Wilmington, DE, USA; 2Life Sciences, Value-Based Care, IBM Watson Health, Cambridge, MA, USA; 3Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA Purpose: The aim of this study was to examine real-world differences in health care resource use (HRU) and costs among COPD patients in the USA treated with a dry powder inhaler (DPI) or pressurized metered-dose inhaler (pMDI) following a COPD-related hospitalization. Methods: This retrospective analysis used the Truven MarketScan® databases. Eligibility criteria included 1) age ≥40 years, 2) COPD diagnosis, 3) inpatient admission with a diagnosis of COPD exacerbation, 4) inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) prescription within 10 days of hospital discharge (index date), and 5) continuous enrollment for 12 months preindex and 90 days postindex. Outcomes included pre- and postindex HRU and costs. DPI and pMDI groups were compared on postindex outcomes via multivariate models controlling for demographic and baseline characteristics. Results: The sample included 1,960 DPI and 1,086 pMDI ICS/LABA patients. During the preindex period, pMDI patients were significantly more likely to be prescribed a short-acting β-agonist, experienced more COPD exacerbation-related hospital days, and had a greater number of pulmonologist visits compared to DPI patients (P

Machaon Bonafede,1 Joseph Feliciano,2 Qian Cai,1 Virginia Noxon,1 Nicole Princic,1 Akshara Richhariya,2 David J Straus3,4 1IBM Watson Health, Cambridge, MA, USA; 2Seattle Genetics, Inc., Bothell, WA, USA; 3Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4John P Leonard Department of Medicine, Weill Cornell Medicine, New York, NY, USA Purpose: The purpose of this study was to evaluate the economic burden of frontline failure (FLF) among classical Hodgkin lymphoma (HL) patients during and after treatment.Patients and methods: The population consisted of adult HL patients identified from January 2010 through September 2015 without any other primary cancer prior to HL diagnosis, who also had a frontline (FL) regimen indicative of curative intent. Patients were characterized as FLF (those who restart, switch to any chemotherapy; had a hematopoietic stem cell transplant; or newly initiated radiation therapy [RT] after discontinuing FL) or non-FLF (those not considered as FLF). Direct health care utilization and expenditures were measured over both fixed and variable length follow-up periods and during FL therapy.Results: There were 77 FLF and 602 non-FLF patients who met the final inclusion criteria. FLF and non-FLF patients were demographically similar with mean age 38.5 years and 47.5% females. Average per patient per month (PPPM) costs were significantly higher for FLF patients during all follow-up (US$20,266 vs US$7,772, P

Endosperm texture, i.e., the hardness or softness of the grain, is an important trait because it determines many end-use properties of wheat (Triticum aestivum L.). It is primarily controlled by the puroindoline genes (Pina and Pinb) at the Hardness (Ha) locus, mapped on the short arm of chromosome 5D. The introgression of functional Pin genes from diploid wheat Triticum monococcum L. chromosome 5Am into hexaploid wheat resulted in softer grains, suggesting that this translocation might be useful for soft wheat breeders. However, the translocated segment includes a large portion of the 5Am short arm and may carry detrimental genes for agronomic performance. In this study we have generated a backcross (BC) population of 210 individuals where 5A-5Am homeologous recombination was induced by the ph1b mutation to recover individuals with a reduced translocated segment. A map of this region was constructed using specific sequence tagged site (STS) markers for the three T. monococcum Ha-related genes, the completely linked BGGP gene, three wheat ESTs (BG606847, BF474606, and BQ168958), and two microsatellite markers. Eight plants with recombination events between XBggp and the closest proximal locus BG606847 were identified. Of these, four have the desired T. monococcum allele at the Ha locus. These plants carry a 6.3-cM segment of T. monococcum chromatin proximal to the Ha locus. This germplasm, which will be publicly available, and the molecular markers developed in this study will be valuable tools for soft wheat breeding programs. © Crop Science Society of America.

Winter wheat and barley varieties require an extended exposure to low temperatures to accelerate flowering (vernalization), whereas spring varieties do not have this requirement. In this study, we show that in these species, the vernalization gene VRN3 is linked completely to a gene similar to Arabidopsis FLOWERING LOCUS T (FT). FT induction in the leaves results in a transmissible signal that promotes flowering. Transcript levels of the barley and wheat orthologues, designated as HvFT and TaFT, respectively, are significantly higher in plants homozygous for the dominant Vrn3 alleles (early flowering) than in plants homozygous for the recessive vrn3 alleles (late flowering). In wheat, the dominant Vrn3 allele is associated with the insertion of a retroelement in the TaFT promoter, whereas in barley, mutations in the HvFT first intron differentiate plants with dominant and recessive VRN3 alleles. Winter wheat plants transformed with the TaFT allele carrying the promoter retroelement insertion flowered significantly earlier than nontransgenic plants, supporting the identity between TaFT and VRN-B3. Statistical analyses of flowering times confirmed the presence of significant interactions between vernalization and FT allelic classes in both wheat and barley (P < 0.0001). These interactions were supported further by the observed up-regulation of HvFT transcript levels by vernalization in barley winter plants (P = 0.002). These results confirmed that the wheat and barley FT genes are responsible for natural allelic variation in vernalization requirement, providing additional sources of adaptive diversity to these economically important crops.

Neil A Accortt,1 James B Chung,2 Machaon Bonafede,3 Brendan L Limone,3 David M Mannino4 1Amgen, Inc., Center for Observational Research, Thousand Oaks, CA, 2Amgen, Inc., US Medical Organization, Thousand Oaks, CA, 3Truven Health Analytics, an IBM Company, Outcomes Research, Cambridge, MA, 4University of Kentucky College of Public Health, Lexington, KY, USA Background: Limited information exists on the impact of tumor necrosis factor inhibition on COPD exacerbations. This retrospective study characterized this impact among COPD patients with underlying autoimmune conditions, exposed to tumor necrosis factor inhibitors (TNFi) and/or non-biologic disease-modifying antirheumatic drugs (DMARDs).Patients and methods: Adult COPD patients with ≥1 diagnosis for rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) before or within 6 months following the index COPD diagnosis were identified from the Truven Health MarketScan® databases. Patients were required to have a second claim for RA, PsO, PsA, AS, or DMARD use (biologic or non-biologic) prior to or up to 6 months following the index date. Incidence of COPD-related hospitalizations and emergency room (ER) visits was evaluated in relation to treatment with TNFi and/or DMARDs and other potential risk factors.Results: The study cohort included 40,687 patients (untreated, 37.7%; non-biologic DMARD, 35.4%; TNFi + non-biologic DMARD, 18%; TNFi, 8.8%). The proportion of patients with a COPD-related hospitalization and the incidence of COPD-related hospitalization (per 100 person-years) were lowest in the TNFi cohort (8.6%; 3.54, 95% confidence interval [CI]: 3.16–3.95) and the TNFi + non-biologic DMARD cohort (8.4%; 2.85, 95% CI: 2.63–3.08). In multivariate models, treatment with TNFi + non-biologic DMARD reduced the risk of COPD-related hospitalization or ER visits by 32% relative to non-biologic DMARDs (hazard ratio: 0.68; 95% CI: 0.61–0.75).Conclusion: In real-world settings, TNFi monotherapy confers similar risk for COPD-related hospitalization or ER visits as a non-biologic DMARD. Decreased risk was found among those treated with both TNFi and a non-biologic DMARD. Keywords: COPD, TNF inhibitor, exacerbation, incidence, biologic DMARD

Machaon Bonafede,1 George J Joseph,2 Neel Shah,2 Nicole Princic,1 David J Harrison2 1Truven Health Analytics, Cambridge, MA, 2Amgen Inc., Thousand Oaks, CA, USA Background: The purpose of this study was to estimate the annual cost per treated patient for the tumor necrosis factor (TNF) blockers, etanercept, adalimumab, and infliximab in rheumatoid arthritis (RA) patients covered by Medicaid. Methods: The MarketScan Medicaid Multistate Database was used to identify adult RA patients who used etanercept, adalimumab, or infliximab (index agents) from 2007 to 2011. The index date was the first claim preceded by 180 days and followed by 360 days of continuous enrollment. Patients with other conditions for which these agents are approved by the US Food and Drug Administration were excluded. “Continuing” patients had one or more pre-index claim for their index biologic, and "new" patients did not. Cost per treated patient was calculated in the 360 day post-index period for each index agent as the total index drug and administration cost to the payer and the costs of switched-to agents divided by the number of patients who received the index agent. Results: A total of 1,085 patients met the study criteria. Forty-eight percent received etanercept (n=521); 37% received adalimumab (n=405); and 15% received infliximab (n=159). Patient characteristics were similar across groups (mean age 47.4 years, 83% female). The annual cost per treated patient was lowest for etanercept ($18,466), followed by adalimumab ($20,983) and infliximab ($26,516). For all agents, annual costs were lower for new patients ($17,996 for etanercept, $18,992 for adalimumab, and $24,756 for infliximab) than for continuing patients ($19,004 for etanercept, $24,438 for adalimumab, and $28,127 for infliximab). Conclusion: Etanercept had lower costs per treated patient than adalimumab or infliximab in both new and continuing Medicaid enrollees with RA. Keywords: cost, tumor necrosis factor, rheumatoid arthritis, Medicaid