Zeitschriftenartikel zum Thema „Byrne grant“

This study critically reviewed the use of financial incentives in solving health professionals’ brain drain, with the view to ascertain its effectiveness. The Systematic Assessment Quantitative Technique (SQAT) developed by Catherine Pickering and Jason Antony Byrne, was used to identify and review 21 relevant peer-reviewed journal articles that investigated six forms of financial incentives in solving health professionals’ brain drain. Evidence from 66.67% of the studies showed that financial incentives are effective in solving health professionals’ brain drain through the use of improved remuneration, funded training, return subsidy and research grant. The remaining part of the studies (33.33%) did not find the use of financial health aid and bonding effective. This study recognized that financial incentives do not fully solve healthcare brain drain and other non-financial measures need to be implemented; future research work should therefore integrate other measures with financial incentives in order to gain additional insight on solving healthcare brain drain. The use of limited but high-quality academic databases means that some articles were not considered for review.

Abstract Background The 2019 Antimicrobial Resistance Threat Report cites carbapenem-resistant Acinetobacter baumanii (CRAB) as an urgent threat causing > 700 deaths per year.1 Acinetobacter is unique in its ability to acquire resistance determinants and pan-resistant strains have been previously reported.2 It has the propensity to cause outbreaks, especially in critically ill populations due to its ability to survive on surfaces.3,4 In 2018, our hospital experienced a large CRAB outbreak. All strains were multi-drug resistant and most were identified by the Centers for Disease Control as containing OXA-23 ß-lactamase. Standard of care (SOC) was limited to agents with high toxicity potential, and thus we explored emerging therapies. In collaboration with Shionogi Inc., we obtained compassionate use cefiderocol as salvage therapy in patients failing SOC. We present our experience utilizing various treatments for CRAB infections during a hospital outbreak. Methods We performed a retrospective chart review in adult patients with a CRAB infection treated with either cefiderocol or SOC for greater than 2 days from 08/2017 - 01/2020. SOC included use > 1 of the following: tigecycline, meropenem, polymyxins, amikacin, or eravacycline. At the time of our outbreak, we developed an institutional algorithm delineating which therapy to initiate depending on infection type. Demographic characteristics, illness severity scores, type of infection, and patient outcomes were evaluated. Results The median age [IQR] for the cefiderocol group was 57.5 [42 to 69] versus 60 [50 to 65] in the SOC group. Illness severity scores were lower in the cefiderocol group: SOFA median value [IQR] 3.5 [1.5 - 5] versus 5 [2 - 7] and CCI median value [IQR] was 3 [2.00 -3.00] versus 3 [2 -5] (Table 1). In hospital mortality was similar in both groups with the cefiderocol group having 50% in hospital mortality versus 42.2% in the SOC group. 28-day mortality was 62.6% in the cefiderocol group versus 42.4% in the SOC group (Table 2). Conclusion Cefiderocol may be a viable option for salvage therapy for CRAB infection. Our cohort illustrated similar outcomes as standard therapy. This study is limited by a small sample size receiving cefiderocol and the significant delay associated with obtaining cefiderocol at the time. Disclosures Lucia Rose, PharmD, Allergan (Speaker’s Bureau)Paratek (Employee) Madeline king, PharmD, Tetraphase (Speaker’s Bureau) Henry Fraimow, MD, Astellas pharma (Grant/Research Support)Merck (Grant/Research Support)Shionogi (Consultant, Grant/Research Support, Scientific Research Study Investigator) Dana D. Byrne, MD, MSc, Merck (Employee)

Abstract Background: Achieving a first complete remission (CR1) is an important prognostic factor for transplantation outcome. However, there are no data in the setting of cord blood transplantation (CBT) indicating whether the number of induction courses (1 or 2) needed to achieve CR1, is of prognostic significance. As CBT is advantageous for acute myelogenous leukemia (AML) patients (pts) with positive pre transplant measurable residual disease (MRD) (Milano F, NEJM 2016), it is conceivable that in the CBT setting, no difference in transplantation outcome will be observed between pts achieving CR1 after 1 or 2 inductions. Methods: Using the European Society for Blood and Marrow Transplantation (EBMT)/Acute Leukemia Working Party (ALWP) registry, we compared transplantation outcomes of adult pts aged ≥18 years with AML that underwent CBT in 2005-2020 in CR1, achieved following 1 versus (vs) 2 induction courses. Multivariate analysis (MVA) adjusting for differences between the induction groups was performed using a Cox's proportional-hazards regression model for main outcomes. Results: Three hundred and twenty-five pts were included comprising 243 (75%) with 1 and 82 (25%) with 2 induction chemotherapy courses. Median (range) follow-up was 65.4 (57.4-73.5) and 51.0 (34.8-61.5) months, respectively (p=0.6). Median age was 49.4 (19.0-70.9) and 52.1 (19.2-71.5) years (p=0.8), respectively. For patients with 1 and 2 induction courses, respectively, 49.4% and 57.3% were male, 225 (92.6%) and 78 (95.1%) pts had de novo AML, and 18 (7.4%) and 4 (4.9%) had secondary AML (p=0.6). Pts with 1 and 2 induction courses, respectively, were classified by cytogenetic risk as follows: intermediate, 62.0% and 79.2%, adverse, 33.2% and 19.5%, and favorable, 4.8% and 1.3% (p=0.02) (missing data~25%). The FLT3-ITD mutation was harbored by 33.7% and 32.3% of the pts (p=0.8), respectively (missing data ~6%). Conditioning was myeloablative (MAC) in 43.0% and 36.6% and reduced intensity (RIC) in 57.0% and 63.4%, respectively (p=0.31). Karnofsky performance score (KPS) was > 90 in 74.7% and 71% of the pts, respectively (p=0.5). The most frequent anti-graft-versus-host disease (GVHD) prophylaxis was cyclosporin A (CSA) and mycophenolate mofetil (MMF) in 75.6% and 82.5 %, or CSA with or without steroids in 16.1 % and 11.2%, respectively. Anti-thymocyte globulin (ATG) was administered to 32.9% and 25.6% of the CBT recipients, respectively (p=0.2). Engraftment rates were lower for pts achieving CR1 after 1 vs 2 induction courses (91.3% and 98.8% p=0.02) with corresponding day 60 absolute neutrophil count (ANC) > 0.5 x 10 9/L in 89.6% vs 96.3% of the pts (p=0.03). Day 180 incidence of acute GVHD grades II-IV was similar in both induction groups, 38.3% and 37.2% (p=0.8), as was 2-year total chronic GVHD, 23.4% and 27.5 %, respectively (p=0.6). In univariate analysis, the 2--year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were similar between patients achieving CR1 with 1 vs 2 induction courses with 22.6% vs 23.6% (p=0.87) 25.1% vs 30.4% (p=0.4), 52.3% vs 46.0% (p=0.3), 58.6% vs 50.0% (p=0.2), and 44% vs 44.1% (p=0.66), respectively. Similarly in MVA, there was no significant association between 2 courses of induction and NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p=0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p=0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p=0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p=0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p=0.5). Conclusions: In CBT recipients, we did not find any significant differences in outcomes in patients achieving CR1 after one or two induction courses. Notably, engraftment was better in patients receiving two courses of induction chemotherapy. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Forcade: Novartis: Other: travel grant. Sierra: Amgen: Other: Educational grant; Roche: Other: Educational grant; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Other: Educational grant; Jazz Pharmaceuticals: Research Funding; Janssen: Other: Educational grant; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria; BMS Celgene: Honoraria, Research Funding. Byrne: Incyte: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

BackgroundWhile protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination has been demonstrated in term-born infants from healthy mothers[1], no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy.ObjectivesIn this pilot-study, we explored whether treatment with Tumor Necrosis Factor alpha inhibitors (TNFis) in pregnant patients with rheumatic disease interferes with Tdap vaccine responses and/or affects maternal IgG antibody concentrations against the relevant antigens in the newborns.MethodsPatients included by a rheumatologist during pregnancy received a Tdap vaccination in their late-second or early-third trimester. Blood samples were drawn during the first trimester, three months after delivery and from the umbilical cord. IgG antibody levels against Tdap-included antigens were measured using a bead-based multiplex immunoassay. Findings on patients exposed to TNFis were compared with those from TNFi-unexposed patients and with data from a historical comparator study among healthy Tdap vaccinated mother-infant-pairs (n=53). [2]Results66 patients (46 exposed and 20 unexposed to TNFIs) were enrolled. No differences in IgG antibody levels against Tdap-included antigens were observed between TNFi-exposed and unexposed patients before and after Tdap vaccination (Figure 1). In cord sera however, antibody levels against pertussis toxin were significantly lower after TNFi-treatment (35.94IU/mL, 95%CI 20.68-62.45) compared with no TNFis (94.61IU/mL, 95%CI 48.89-183.07) and with cord blood from the comparison cohort of healthy women-infant-pairs (125.12IU/mL, 95%CI 90.75-172.50). We observed similar differences for filamentous hemagglutinin, pertactin, tetanus toxoid, and diphtheria toxoid.ConclusionThese preliminary data indicate no reduced IgG antibody response upon maternal Tdap vaccination in pregnant women following immune-modulating treatment, although our findings suggest that TNFis during pregnancy induce lower maternal antibody levels against Tdap-included antigens in newborns.References[1] Byrne L, Campbell H, Andrews N, Ribeiro S, Amirthalingam G. Hospitalisation of preterm infants with pertussis in the context of a maternal vaccination programme in England. Arch Dis Child. 2018;103(3):224-9.[2] Barug D, Pronk I, van Houten MA, Versteegh FGA, Knol MJ, van de Kassteele J, et al. Maternal pertussis vaccination and its effects on the immune response of infants aged up to 12 months in the Netherlands: an open-label, parallel, randomised controlled trial. Lancet Infect Dis. 2019;19(4):392-401.Figure 1.Anti-Pertussis toxin (anti-PT IgG) concentrations (IU/mL) before and after vaccination and in cord sera, represented for women exposed or unexposed to TNFis, or healthy pregnant women, including their offspring. X-axis: type and time-point of blood sample draw. Y-axis: IgG antibody concentration against pertussis toxin (IU/mL). Significance *p<0.05, **p<0.01, ***p<0.001.Acknowledgements:NIL.Disclosure of InterestsNafise Ghalandari Grant/research support from: Financial support for printing PhD book from UCB Pharma., Employee of: From June 2022 till February 2023 worked as a medical science liaison (MSL) at UCB Pharma., Maarten Immink: None declared, Esther Röder: None declared, Patricia Bruijning-Verhagen: None declared, Hieronymus TW Smeele: None declared, Hubertina Johanna Maria Josephina Crijns: None declared, Nicoline van der Maas: None declared, Mireille Bekker: None declared, Lieke Sanders: None declared, Radboud Dolhain Speakers bureau: from AbbVie, AstraZeneca, Eli Lily, Galapagos, Novartis, Roche, UCB., Grant/research support from: an unrestricted grant from Galapagos, UCB Pharma B.V.

Abstract The primary source published here provides a rare and detailed account of a trip to state socialist Hungary in 1962, written by an American historian and expert on the Soviet Bloc, Robert F. Byrnes (1917–97). The document is prefaced by a short introduction that gives a brief presentation of Byrnes’s career and contextualizes his visit to Hungary as the representative of the Inter-University Committee on Travel Grants.

BackgroundThere are limited real world data on the use of JAK inhibitors (JAKi). In 2022, the EMA suggested that JAKi should only be used if alternative therapies are not available in patients over 65 years, smokers or in those with cardiovascular or cancer risk factors.ObjectivesWe conducted a retrospective study to describe the demographics, duration of therapy and adverse events profile of patients prescribed JAKi.MethodsBaseline data including age, gender, smoking status, ethnicity, co-morbidities, cardiovascular risk factors, rheumatic diagnosis, concomitant csDMARD use and prior biological therapies was collected. Duration on therapy and reasons for stopping JAKi were identified. A Cox proportional hazard model was used to plot survival of drug therapy, by JAKi drug. Data was analysed on the STATA platform.ResultsIn total, 151 patients were prescribed a JAKi since 2017. The average age was 55, with a female predominance, (n=125, 83%), and the majority had rheumatoid arthritis. Baricitinib and Filgotinib represented the most commonly prescribed JAKi. Over ¼ of the cohort were using JAKi monotherapy (28%). For those on combination therapy, methotrexate was the most commonly prescribed (53%). The median number of prior biologics was 1 (IQR 1-2), with TNFi the most frequently prescribed (66%). 48% had cardiovascular risk factors or cardiovascular disease; this was more prevalent in patients prescribed baricitinib or tofacitinib compared to upadacitinib or filgotinib (57%) versus (39%). During JAKi therapy 3 patients developed cancer, 2 had VTEs (both on Baricitinib) and 5 had new mental health diagnoses. The reason for stopping therapy was equally spilt between drug failure (46%) and adverse events (45%). Drug survival over 2 years was numerically higher for Filgotinib and Upadacitinib. Cycling between JAKi occurred in 28 patients. Patients prescribed a second JAKi (n=26) or a third JAKi (n=2) had cycled through more prior biologics than patients prescribed their first JAKi [median number prior biologics 2 (IQR 1-3) versus 1 (IQR 1-2) p=0.007].ConclusionOur real world experience of JAKi is broadly similar to expectations from clinical trials. The differences in patient characteristics and drug survival between individual JAKi are likely to reflect drug availability and emergence of safety warnings over time.Table 1.TotalBaricitinibFilgotinibTofacitinibUpadacitinibN=151N=43N=43N=32N=33P valueAge, (median, SD)55 (14)54 (16)57 (13)58 (11)51 (13)0.10Gender, female (n,%)125 (82.8%)36 (83.7%)37 (86.0%)28 (87.5%)24 (72.7%)0.36Smoking status, (n, %)Ex-smoker9 (6.0%)3 (7.0%)3 (7.0%)1 (3.1%)2 (6.2%)0.36Current Smoker8 (5.3%)4 (9.3%)03 (9.4%)1 (3.1%)0.46Ethnicity, (n, %)White69 (47.3%)24 (58.5%)18 (41.9%)14 (46.7%)13 (40.6%)0.25Black28 (19.2%)7 (17.1%)9 (20.9%)9 (30.0%)3 (9.4%)South Asian26 (17.8%)5 (12.2%)7 (16.3%)5 (16.7%)9 (28.1%)Mixed23 (15.8%)5 (12.2%)9 (20.9%)2 (6.7%)7 (21.9%)Diagnosis, (n,%)RA146 (96.7%)42 (97.7%)43 (100.0%)30 (93.8%)31 (93.9%)0.27Other - PsA3 (2.0%)001 (3.1%)2 (6.1%)Ank Spon1 (0.7%)001 (3.1%)0CTD overlap1 (0.7%)1 (2.3%)000Year JAK commenced20172017202120172019<0.001CVS risk factor/diseaseex/current smoker, DM, Chol73 (48.3%)25 (58.1%)21 (48.8%)18 (56.2%)9 (27.3%)0.04Prior JAK comorbidityVTE4 (2.6%)02 (4.7%)2 (6.2%)1 (3.0)0.23Cancer9 (6.0%)4 (9.3%)1 (2.3%)1 (3.1%)3 (9.1%)0.41Mental health33 (21.9%)7 (16.3%)11 (25.6%)8 (25.0%)7 (21.2%)0.72Post JAK new comorbidityCholesterol11 (7.3%)4 (9.3%)03 (9.4%)4 (12.1%)0.17Diabetes3 (2.0%)2 (4.7%)001 (3.0%)0.35IHD1 (0.7%)1 (2.3%)0000.47VTE2 (1.3%)002 (6.2%)00.06Cancer3 (2.0%)1 (2.3%)02 (6.2%)00.21Mental health5 (3.3%)1 (2.3%)1 (2.3%)03 (9.1%)0.19JAKi therapy stopped56 (37.0%)25 (58.1%)3 (6.9%)20 (62.5%)8 (24.2%)<0.001Reason for stoppingAE25 (44.6%)7 (28.0%)1 (33.3%)15 (75.0%)2 (25.0%)0.028Primary failure14 (25.0%)7 (28.0%)1 (33.3%)2 (10.0%)4 (50.0%)Secondary failure12 (21.4%)8 (32.0%)0 (0.0%)2 (10.0%)2 (25.0%)Death2 (3.6%)1 (4.0%)1 (33.3%)0 (0.0%)0 (0.0%)Not documented3 (5.4%)2 (8.0%)0 (0.0%)1 (5.0%)0 (0.0%)Figure 1.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsDeepak Nagra Consultant of: Fees from abbvie, Katie Bechman Grant/research support from: Versus Arthritis and NIHR, Mark Russell Speakers bureau: Lilly, Galapagos, Biogen and Menarini, and support.for attending meetings from Lilly, Pfizer, Janssen and UCB, Consultant of: lilly, Edward Alveyn: None declared, christopher baldwin: None declared, georgina bird: None declared, Sophia Steer: None declared, Corrine Byrne: None declared, Kirsty Lawan: None declared, valeria vescovi: None declared, maryam adas Consultant of: Abbvie, Meryem Nursoy: None declared, Sam Norton Speakers bureau: janssen and pfizer, Arti Mahto Speakers bureau: Speaker fees galapagos, abbvie, GE, Andrew Rutherford: None declared, James Galloway Speakers bureau: Abbvie, Biovitrum, BMS, Celgene, Chugai, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi,Sobi and UCB, Consultant of: Abbvie, Biovitrum, BMS, Celgene, Chugai, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi,Sobi and UCB, Elena Nikiphorou Speakers bureau: celltrion, pfizer, sanofi, gillead, galapagos, abbvie, lilly, fresenius, Grant/research support from: pfizer and lilly.

-Bridget Brereton, Emilia Viotti Da Costa, Crowns of glory, tears of blood: The Demerara slave rebellion of 1823. New York: Oxford University Press, 1994. xix + 378 pp.-Grant D. Jones, Assad Shoman, 13 Chapters of a history of Belize. Belize city: Angelus, 1994. xviii + 344 pp.-Donald Wood, K.O. Laurence, Tobago in wartime 1793-1815. Kingston: The Press, University of the West Indies, 1995. viii + 280 pp.-Trevor Burnard, Howard A. Fergus, Montserrat: History of a Caribbean colony. London: Macmillan Caribbean, 1994. x + 294 pp.-John L. Offner, Joseph Smith, The Spanish-American War: Conflict in the Caribbean and the Pacific, 1895-1902. London: Longman, 1994. ix + 262 pp.-Louis Allaire, John M. Weeks ,Ancient Caribbean. New York: Garland, 1994. lxxi + 325 pp., Peter J. Ferbel (eds)-Aaron Segal, Hilbourne A. Watson, The Caribbean in the global political economy. Boulder CO: Lynne Rienner, 1994. ix + 261 pp.-Aaron Segal, Anthony P. Maingot, The United States and the Caribbean. London: Macmillan Caribbean, 1994. xi + 260 pp.-Bill Maurer, Helen I. Safa, The myth of the male breadwinner: Women and industrialization in the Caribbean. Boulder CO: Westview, 1995. xvi + 208 pp.-Peter Meel, Edward M. Dew, The trouble in Suriname, 1975-1993. Westport CT: Praeger, 1994. xv + 243 pp.-Henry Wells, Jorge Heine, The last Cacique: Leadership and politics in a Puerto Rican city. Pittsburgh PA: University of Pittsburgh Press, 1993. ix + 310 pp.-Susan Eckstein, Jorge F. Pérez-López, Cuba at a crossroads: Politics and economics after the fourth party congress. Gainesville: University Press of Florida, 1994. xviii + 282 pp.-David A.B. Murray, Marvin Leiner, Sexual politics in Cuba: Machismo, homosexuality, and AIDS. Boulder CO: Westview, 1994. xv + 184 pp.-Kevin A. Yelvington, Selwyn Ryan ,Sharks and sardines: Blacks in business in Trinidad and Tobago. St. Augustine, Trinidad: Institute of social and economic studies, University of the West Indies, 1992. xiv + 217 pp., Lou Anne Barclay (eds)-Catherine Levesque, Allison Blakely, Blacks in the Dutch world: The evolution of racial imagery in a modern society. Bloomington: Indiana University Press, 1993. xix + 327 pp.-Dennis J. Gayle, Frank Fonda Taylor, 'To hell with paradise': A history of the Jamaican tourist industry. Pittsburgh: University of Pittsburgh Press, 1993. ix + 239 pp.-John P. Homiak, Frank Jan van Dijk, Jahmaica: Rastafari and Jamaican society, 1930-1990. Utrecht: ISOR, 1993. 483 pp.-Peter Mason, Arthur MacGregor, Sir Hans Sloane: Collector, scientist, antiquary, founding Father of the British Museum. London: British Museum Press, 1994.-Philip Morgan, James Walvin, The life and times of Henry Clarke of Jamaica, 1828-1907. London: Frank Cass, 1994. xvi + 155 pp.-Werner Zips, E. Kofi Agorsah, Maroon heritage: Archaeological, ethnographic and historical perspectives. Kingston: Canoe Press, 1994. xx + 210 pp.-Michael Hoenisch, Werner Zips, Schwarze Rebellen: Afrikanisch-karibischer Freiheitskampf in Jamaica. Vienna Promedia, 1993. 301 pp.-Elizabeth McAlister, Paul Farmer, The uses of Haiti. Monroe ME: Common Courage Press, 1994. 432 pp.-Robert Lawless, James Ridgeway, The Haiti files: Decoding the crisis. Washington DC: Essential Books, 1994. 243 pp.-Bernadette Cailler, Michael Dash, Edouard Glissant. Cambridge: Cambridge University Press, 1995. xii + 202 pp.-Peter Hulme, Veronica Marie Gregg, Jean Rhys's historical imagination: Reading and writing the Creole. Chapel Hill: University of North Carolina Press, 1995. xi + 228 pp.-Silvia Kouwenberg, Francis Byrne ,Focus and grammatical relations in Creole languages. Amsterdam/Philadelphia: John Benjamins, 1993. xvi + 329 pp., Donald Winford (eds)-John H. McWhorter, Ingo Plag, Sentential complementation in Sranan: On the formation of an English-based Creole language. Tübingen: Max Niemeyer, 1993. ix + 174 pp.-Percy C. Hintzen, Madan M. Gopal, Politics, race, and youth in Guyana. San Francisco: Mellen Research University Press, 1992. xvi + 289 pp.-W.C.J. Koot, Hans van Hulst ,Pan i rèspèt: Criminaliteit van geïmmigreerde Curacaose jongeren. Utrecht: OKU. 1994. 226 pp., Jeanette Bos (eds)-Han Jordaan, Cornelis Ch. Goslinga, Een zweem van weemoed: Verhalen uit de Antilliaanse slaventijd. Curacao: Caribbean Publishing, 1993. 175 pp.-Han Jordaan, Ingvar Kristensen, Plantage Savonet: Verleden en toekomst. Curacao: STINAPA, 1993, 73 pp.-Gerrit Noort, Hesdie Stuart Zamuel, Johannes King: Profeet en apostel in het Surinaamse bosland. Zoetermeer: Boekencentrum, 1994. vi + 241 pp.

Purpose The purpose of this paper is to empirically test common explanations for the growth of police militarization and to determine whether federal funding, such as Byrne grants, had a significant effect on the growth and normalization of SWAT teams. Design/methodology/approach Drawing from data spanning the years 1986-1998, an interrupted time series analysis is used to assess whether federal funding has a significant influence on the growth of SWAT teams and their mobilization for narcotics grants. Findings The findings of this analysis suggest that, at the time where federal funding was at its peak (the year 1990), there was a significant decrease in SWAT team creation compared to the years prior. There was likewise a significant decrease in SWAT mobilization for narcotics warrant in the years following 1990. Research limitations/implications The main limitation of this study is that unmeasured exogenous factors in the year 1990 may have influenced militarization trends. However, given the counterintuitive findings of this study, it is essential that more nuanced research is conducted regarding police militarization to gain a clearer understanding of trends in police culture. As this study finds that militarization is not significantly driven by federal funding, future research must incorporate other factors to explain police organizational change. Originality/value This paper provides an advanced empirical analysis that is one of the first to directly test commonly held explanations for police militarization. This analysis adds complexity to the issue of US police militarization and demonstrates that further research is essential in this area.

BACKGROUND. Cutaneous erythema and histopathology features in patients post allogeneic hematopoietic cell transplantation (HCT) are nonspecific, making it difficult to distinguish acute graft-versus-host disease (aGVHD) from engraftment syndrome, drug reactions, viral infections, and other etiologies. Biopsies from different locations on the same patient frequently differ in aGVHD grade, and serial biopsies of a single lesion are not possible. Proper biopsy site selection, timing, and serial noninvasive microscopic monitoring may improve our understanding and management of aGVHD. In this study, we tested the feasibility of noninvasive reflectance confocal microscopy (RCM) to detect key histopathology features of cutaneous aGVHD. STUDY POPULATION. We enrolled 11 patients with high clinical suspicion of cutaneous aGVHD, as determined by a transplant physician. In total, 16 lesions of cutaneous aGVHD-affected site were imaged by RCM (6x6 mm2en face images at four different depths) and subsequently biopsied (4x4 mm punch biopsy). 9 out of 11 patients had only skin involvement, and 2 patients had skin and gut aGVHD. 5 patients had >50% body surface area (BSA) affected, 1 had 18-50% BSA, and 5 had <18% BSA. 8 out of 11 patients required systemic corticosteroids and 3 patients received topical corticosteroids. All patients were imaged before starting treatment. METHODS. We used a clinical confocal microscope (Vivascope 1500, Caliber I.D.), which enables real-time evaluation of epidermal and superficial dermal tissue at sub-cellular resolution. Four reflectance confocal microscopists blinded to histopathology independently evaluated the presence or absence of 18 RCM features1. Concurrently, four dermatopathologists blinded to clinical and confocal information determined the presence or absence of 19 histopathology features, as well as the Lerner aGVHD grade. A histologic feature was determined as "present" in a lesion when marked by most experts (expert vote) or resolved by a fifth expert in case of a disagreement among four experts. The reflectance confocal microscopist vote was then correlated to the dermatopathologist expert vote for 17 overlapping features. We also evaluated the interrater variability among microscopists and among dermatopathologists. RESULTS. The main aGVHD features by Lerner grade had > 88% correlation between RCM and histopathology: (1) basal vacuolar change, (2) presence of dyskeratotic keratinocytes, and (3) dermal inflammation. By contrast, dyskeratotic cells and inflammation at the adnexal structures had <50% correlation. This may be attributed to the fact that more adnexal structures are typically visible in the 6x6 mm2 RCM horizontal tissue view compared to vertical section histopathology. We found a similar interrater variability among RCM experts (70%) and dermatopathologists (68%). CONCLUSIONS. In this pilot study, we show that noninvasive label-free RCM of skin enables detection of the main Lerner grade features of cutaneous aGVHD. We found a similar interrater variability among reflectance confocal microscopists and among dermatopathologists who each independently evaluated the presence or absence of a list of aGVHD features. Future studies can build on this work to evaluate the feasibility of RCM to determine cutaneous aGVHD grade, as well as distinguish between rash due to aGVHD and drug reactions. ACKNOWLEDGEMENT. This work was supported in part by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service. Saknite I, Gill M, Alessi-Fox C, Byrne M, Jagasia M, Gonzalez S, Ardigo M, Tkaczyk ER. Features of cutaneous acute graft-versus-host disease by reflectance confocal microscopy. Br J Dermatol (2019). Disclosures Christi: Caliber I.D.: Employment, Equity Ownership. Byrne:Karyopharm: Research Funding. Jagasia:Kadmon: Consultancy; Incyte: Consultancy; Janssen: Research Funding. Tkaczyk:Incyte: Consultancy.

BACKGROUND. The nature and kinetics of leukocyte migration are intimately connected to the pathophysiology of acute graft-versus-host disease (aGVHD). Real-time visualization of leukocyte-endothelial interactions in patients post hematopoietic transplantation (HCT) may augment clinical diagnosis and patient management. In this cross-sectional pilot study, we aimed to test the feasibility of parameters characteristic of leukocyte motion in skin capillaries as potential imaging biomarkers to detect aGVHD. STUDY POPULATION. We enrolled 16 post-HCT patients: 8 patients with any organ aGVHD and 8 patients with no organ aGVHD on the day of the imaging. Diagnoses were retrospectively confirmed on day 100 by a transplant physician (MB), who was blinded to the results of the confocal imaging. 7 out of 8 aGVHD patients had only skin involvement: stage 1 (N=2 patients), stage 2 (N=2), and stage 3 (N=3) cutaneous aGVHD, whereas one patient had stage 1 gut aGVHD with no skin involvement. 6 out of 8 aGVHD group patients required systemic therapy with steroids. METHODS. To noninvasively visualize leukocyte motion in the topmost capillaries of post-HCT patients' skin, we used a clinical reflectance confocal microscope (Vivascope 1500, Caliber I.D.). It enables real-time en face view of individual cells at 9 frames per second. We took twenty 30-second videos of different capillaries in the left volar forearm and left upper chest. We counted the number of adherent and rolling leukocytes per 10 minutes of videos per patient. RESULTS. We found increased leukocyte rolling in the aGVHD group (average of 3 rolling leukocytes per patient), compared to post-HCT controls (average of 1 rolling leukocyte). Highest leukocyte rolling (>8 rolling leukocytes) was associated with increased all-cause mortality, but not predictive of transplant-related mortality (TRM). Similarly, we found increased leukocyte adhesion in the aGVHD group (average of 3 adherent leukocytes per patient), compared to post-HCT controls (average of 1 adherent leukocyte). Interestingly, we observed 7 adherent leukocytes in one patient who had isolated gut aGVHD and no skin involvement. DISCUSSION. Our preliminary results show altered leukocyte-endothelial interactions in the skin capillaries of aGVHD patients, suggesting that confocal microscopy may be an important tool in augmenting the clinical diagnosis and managing post-HCT patients. Future studies should test whether there is a difference in the pattern of change in parameter values between patients who did and who did not develop aGVHD. ACKNOWLEDGEMENT. This work was supported in part by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service. Disclosures Byrne: Karyopharm: Research Funding. Jagasia:Janssen: Research Funding; Kadmon: Consultancy; Incyte: Consultancy. Tkaczyk:Incyte: Consultancy.

Abstract Background: Myelofibrosis (MF) is a lethal hematological malignancy associated with somatic mutations in JAK2, CALR or MPL. Ruxolitinib is the first JAK1/2 inhibitor approved for treatment of MF. Ruxolitinib does not prevent disease progression and thus, allogeneic hematopoietic stem cell transplantation (HSCT) remains the recommended therapy for eligible patients treated with curative intent. Ruxolitinib discontinuation, in preparation for HSCT is challenging as patients experience return of symptoms/splenomegaly. Therefore, ruxolitinib is often continued during and after HSCT in an off-label fashion, yet little is known about the safety of this approach. In addition, ruxolitinib is now utilized to treat steroid refractory acute and chronic graft versus host disease (GVHD) irrespective of underlying disease. Methods: This is a phase II, multi-center, investigator-initiated trial investigating ruxolitinib given pre-, during- and post-HSCT for patients with primary or secondary MF (NCT03427866). The study utilizes ruxolitinib during and after HSCT in MF patients for one year after HSCT. The accrual goal is 48 patients with 1-year GVHD free and relapse free survival (GRFS) as the primary endpoint. Secondary endpoints include overall and progression free survival, engraftment and incidence of acute and chronic GVHD, respectively. Patients are treated with reduced intensity conditioning with fludarabine (30mg/m 2/day x 5 days) and melphalan (100mg/m 2 or 140mg/m 2 x 1). HSCT grafts are with 7/8 or 8/8 HLA-matched peripheral blood stem cells with tacrolimus and methotrexate as standard GVHD prophylaxis. Results: This pre-planned interim analysis includes 26 MF patients who underwent HSCT between September 2018 and January 2021. An interim analysis was included in the trial design to ensure safety of this approach midway through accrual. Median age was 66 (range, 46-75) and 65% were male. 88% had 8/8 matched related grafts, and 92% had intermediate-2 or high DIPSS risk at the time of transplant. 14 (54%) patients were previously treated with ruxolitinib. At HSCT, 58% had JAK2, 12% CALR, 12% MPL, and 35% ASXL1 mutations (Figure A). There were no unexpected toxicities related to ruxolitinib therapy. The most common grade 3/4 hematologic adverse events (AE) were anemia (n=4), thrombocytopenia (n=3). There were few observed grade 3/4 non hematologic AEs and included infection (n=2) and hypertriglyceridemia (n=1). Median time to neutrophil engraftment was 15 days (range 11-38) after HSCT. All but one patient achieved successful neutrophil engraftment. Median day 30 donor all cell chimerism was 100% (range 95-100). Clinical outcomes are summarized in Figure B. With median follow-up among survivors of 12 months (range 3-24), 1-yr GRFS was 65%. OS, PFS, and cumulative incidence of NRM and disease relapse were 77%, 71%, 13% and 17%, respectively (Figure C). There was no grade IV acute GVHD and only one case of grade III acute GVHD. Cumulative incidence of all chronic GVHD and moderate-severe chronic GVHD was 14% and 5%, respectively. There was no severe chronic GVHD and only one patient developed moderate chronic GVHD. As part of the study, next generation sequencing (NGS) was obtained pre- and 100 days post-HSCT. 14 patients have paired samples, including 6 with ASXL1 mutations. All but one patient, who remains in remission at last follow up, no longer had mutations detected by NGS at day 100 (Figure D). Ongoing studies will assess for the presence of low-level mutation not detectable by clinical NGS testing. Discussion: The interim results of our multicenter study demonstrate safety of ruxolitinib administration pre, during and post-HCT with very favorable engraftment rates and no unexpected toxicities of ruxolitinib use. In addition, we demonstrate superior PFS, OS and GRFS compared to historical observations. Incidence of severe acute and chronic GVHD are thus far minimal, indicating excellent GVHD control with prophylactic and continued ruxolitinib use. Figure 1 Figure 1. Disclosures Hobbs: Bayer: Research Funding; Incyte Corporation: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; AbbVie.: Consultancy; Merck: Research Funding; Novartis: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding. Byrne: Karyopharm: Research Funding. Defilipp: Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Omeros, Corp.: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Will describe the use of ruxolitinib in the ongoing clinical trial.

Abstract INTRODUCTION: Myelodysplastic Syndrome (MDS) is a heterogenous disease which is almost incurable without an allogeneic hematopoietic cell transplantation (allo-HCT). Within the revised international scoring system (R-IPSS), MDS with poor and very poor cytogenetics have a much worse outcome after allo-HCT. The very poor cytogenetic subgroup refers to patients harboring more than 3 abnormalities and is therefore a highly heterogenous group. We have shown in acute myeloid leukemia (AML) that beyond complex karyotype, specific adverse cytogenetic features such as 7q abnormalities (abn7q), 5q abnormalities (abn5q), 17p abnormalities (abn17p) and monosomal karyotype (MK) worsen the outcomes after allo-HCT. We have therefore retrospectively reviewed MDS with very poor cytogenetics and studied the impact of adverse cytogenetic features on outcomes after transplant. METHODS: We selected MDS patients who underwent allo-HCT between 2001 and 2018 from a matched related or unrelated donor, for whom a full cytogenetic report was available in the EBMT registry. We then stratified them according to the presence of abn7q, abn5q, abn17p, MK and the number of abnormalities (≤5, 6-9 and ≥10). Graft-versus-host disease (GvHD) and relapse-free survival (GRFS) was defined as survival without grade II-IV acute GvHD, extensive chronic GvHD or relapse. RESULTS: A total of 154 patients were identified in the registry. One hundred twenty-three patients (81%) had MDS with excess of blasts and 4 (3%) had secondary AML. Median age was 59 years (interquartile range (IQR), 51-64) and the median follow-up was 38 months (95% confidence interval (CI), 34-60). The time from diagnosis to allo-HCT was a median of 6 months (IQR, 4-8). Two thirds of patients received a reduced-intensity conditioning regimen (N = 103, 67%) and 87 patients had a matched unrelated donor (57%). Almost all patients were in first complete remission at time of transplant (N= 149, 97%). Regarding specific cytogenetic features, 87 patients had abn7q (57%), 99 abn5q (64%), 59 abn17p (38%) and 120 MK (78%) with considerable overlap between groups. The 2-year overall survival (OS) and progression-free survival (PFS) was 34% (95% CI 26-42%) and 24% (95% CI 17-31%), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 59% (95% CI 51-67%) and 18% (95% CI 12-24%), respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 33% (95% CI 25-40%) and 44% (95% CI 36-53%) by day 100 and 2 years respectively. The 2-year GRFS was 12% (95% CI 6-17%). The presence of abn5q was associated with a significantly decreased PFS of 17% (95% CI 9-25%) versus 36% (95% CI 23-49%); p=0.05) and GRFS (6% (95% CI 1-11%) versus 23% (95% CI 11-34%); p=0.04). The presence of abn7q was associated with significantly increased NRM (25% (15-34%) versus 9% (2-16%); p=0.02) which did not translate into OS. There were no specific cytogenetic features that had an independent impact on the cumulative incidence of relapse, but age over 55 years did increase the relapse risk (&lt;55: 45% (95% CI 31-59%); 55-65: 65% (95% CI 54-77%); &gt;65: 66% (95% CI 50-83%); p=0.03). A continuous effect was also observed (per decade increase: HR=1.24, 95%CI 1.02-1.52; p=0.03). Patients with an interval of more than 6 months from diagnosis to allo-HCT had almost double the OS (45% (95% CI 32-58%)) compared to patients with an interval less than 6 months (27% (95% CI 17-37%); p=0.04), however a continuous effect was not observed. CONCLUSION: MDS with very poor cytogenetics according to R-IPSS is a very bad group with dismal outcomes after allo-HCT. Within this high-risk group, specific adverse cytogenetic features such as the number of abnormalities, abn7q, abn5q, abn17p or MK did not stratify outcomes further, except for abn5q which was associated with a decreased PFS. Our results might be explained in part by the low number patients and by the over-representation of adverse features within this cohort. Despite that, advancing age was associated with increased relapse. Whilst allo-HCT remains the best therapeutic option for this very high-risk patient group, efforts should focus on post-transplant preemptive intervention strategies to prevent relapse. Disclosures Byrne: Incyte: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Blaise: Jazz Pharmaceuticals: Honoraria. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Scheid: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Abstract Background Mutations in the tumor suppressor gene TP53 are found in up to 20% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Allogeneic hematopoietic SCT remains the only potentially curative therapy however outcomes remain poor, with a 1-year relapse-free survival (RFS) of ~30% and median overall survival (OS) of ~8 months. Prior data on post-SCT maintenance therapies, including AZA, have failed to demonstrate improved post-SCT outcomes. Eprenetapopt, a small molecule p53 stabilizer, targets cellular redox balance resulting in tumor cell apoptosis and ferroptosis as well as immune modulation of the tumor microenvironment. Pre-clinical data demonstrates synergistic myeloid cell cytotoxicity in vitro and in vivo AML burden reduction when eprenetapopt is combined with AZA. Additionally, the known tolerability of this combination in AML/MDS patients makes it an attractive maintenance strategy. Methods This is a multi-center, open label, Phase II clinical trial to assess the safety and efficacy of eprenetapopt in combination with AZA as maintenance therapy after SCT for patients with TP53 mutant AML and MDS. Patients with MDS and AML with a known TP53 mutation were prescreened prior to SCT and protocol eligibility was confirmed post-SCT. Treatment consisted of up to 12 cycles of eprenetapopt 3.7 g/day Days 1-4 with AZA 36 mg/m 2/day IV/SC on Days 1-5 every 28 days. The primary objectives of this study are to assess RFS and the safety and tolerability of the combination. Additional endpoints include OS, time to progression (TTP), non-relapse mortality (NRM) and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). Results The study enrolled a total of 33 patients (19 MDS, 14 AML) for active therapy. Demographics across all patients included median age 65 years (range: 40-74), 64% males, and Karnofsky performance status of ≥ 80 in 79%. The majority (76%) received a reduced intensity conditioning regimen. At initial diagnosis, 97% (32) had TP53 mutations, 9% (3) had &gt;1 TP53 mutation, 82% (27) had complex cytogenetics (&gt;=3), 45% (15) had chromosome (chr) 17, 76% (25) had chr 5, and 45% (15) had chr 7 abnormalities. Among 25 patients with available molecular data from a pre-SCT sample, 22 (88%) patients had a residual detectable TP53 gene mutation, 8 (36%) had &gt; 1 TP53 mutation, and 9 (36%) patients had non-TP53 gene mutations: ASXL1 (2 ), JAK2 (4), DNMT3A (3), IDH2 (2), IDH1 (2), NRAS (1) and SF3B1 (1). As of the data cutoff date of 22 June 2021, patients completed a median of 7 cycles (1,12) of study treatment with 6 patients (18.2%) remaining on study treatment. The primary reasons for study treatment discontinuation among 27 patients, were completion of 12 cycles of treatment (9) and disease relapse (9). With median duration of RFS follow up of 413 days the median RFS was 368 days [95% CI (233-not evaluable)] and the 1-year RFS was 58%. With median duration of OS follow up of 429 days the median OS was 586 days [95% CI (369-not evaluable)] and 1-year OS 79%. All-grade treatment emergent adverse events (TEAEs) occurring in ≥20% of patients included nausea (61%), platelet count decreased (49%), vomiting (46%), anemia, dizziness, and white blood cell count decreased (39% each), fatigue (36%), diarrhea and tremor (33% each), cough, neutrophil count decreased, pruritus, and pyrexia (24% each), abdominal pain, constipation, decreased appetite, headache and hypocalcemia (21% each). Grade ≥3 TEAEs in ≥10% of patients were platelet count decreased (36%), white blood cell count decreased (33%), anemia (27%), neutrophil count decreased (24%), thrombocytopenia and hypertension (12% each). SAEs in ≥2 patients were pyrexia (12%), febrile neutropenia and dyspnea (6% each). Two patients (6%) experienced TEAEs leading to discontinuation of study treatment. Acute and chronic GVHD events of any grade were reported in 12% and 30% of patients, respectively. Conclusions Post-SCT maintenance therapy with eprenetapopt in combination with AZA was safe and tolerable with favorable results in patients with TP53 mutant MDS and AML, with 9 patients completing 12 cycles of therapy at the data cutoff date and the majority of reported TEAEs comprising known complications of high-risk MDS and AML patients in the post-SCT period. In addition, the observed RFS and OS data are highly encouraging compared to the historical outcomes for this high-risk group of patients with unmet medical need. Disclosures Mishra: Novartis: Research Funding. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrne: Karyopharm: Research Funding. Chen: Gamida: Consultancy; Incyte: Consultancy. Gallacher: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wennborg: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kaylor Hickman: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Attar: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Fernandez: Incyte: Honoraria. OffLabel Disclosure: The presentations includes the use of experimental agent eprenetapopt (APR-246) and the agent azacitidine in the post-transplant maintenance setting.

Introduction: AML pts who relapse after allogeneic hematopoietic cell transplantation (HCT) face poor clinical outcomes and short overall survival (OS) (Schmid et al, Blood2012). The delivery of optimal salvage therapy is challenging as some pts do not tolerate high intensity regimens, and lower intensity therapies may not yield sufficient disease control. Favorable responses in older, treatment naïve AML pts with venetoclax (VEN) in combination with low-dose cytarabine (LDAC) or DNA methyltransferase inhibitor (DNMTi) led to its approval. Off-label use in relapsed/refractory AML is increasing (DiNardo et al, Am J Hematol2018; Aldoss et al, Haematologica2018). We retrospectively evaluated the overall response rate (ORR = CR+CRi+PR+MLFS) and report our clinical experience with VEN-based salvage in post-HCT relapsed AML. Methods: After IRB approval, consecutive pts with post-HCT relapsed AML treated with VEN+LDAC or VEN+DNMTi from May 2018 to July 2019 were retrospectively analyzed. Selection of VEN partner and dosing were at the discretion of the treating physician based on institutional guidelines and published prescribing information. Responses were assigned based on the AML IWG criteria. The Kaplan-Meier method was used to describe OS. ORR and treatment complications were summarized via descriptive statistics. Results: 18 pts with post-HCT relapsed AML who received at least 1 cycle of VEN-based salvage chemotherapy were included. Median age at HCT was 64.5 years (range 34.5-73.7 years). Most pts were poor risk: 6/18 pts had an antecedent hematologic malignancy, 12/18 had an abnormal or complex karyotype (CK) prior to HCT, and 4/12 pts with CK also were TP53mut. 15/18 (83.3%) received reduced intensity conditioning and MUD was the predominant graft type (50%). All pts received PBSCs. Additional disease and response characteristics are reported in Fig 1A. Median time from HCT to relapse was 5.5 mos (range: 0.9 to 44.9 mos); 27.8% of pts relapsed within 100 days and 55.6% relapsed within 6 mos of HCT. At relapse, 1 patient had grade 2 aGVHD and 1 had severe, extensive cGVHD. No pts experienced a GVHD flare or progression during treatment. 14/18 (77.8%) of pts were receiving immunosuppressive therapy (IST) at relapse and received VEN concurrently with IST. VEN-based salvage chemotherapy began shortly after confirmed relapse (range: 4-46 days); 4/18 pts received VEN with LDAC and 14/18 were treated with a DNMTi partner. 15/18 pts were evaluable for response. IWG responses were seen in 8 pts with an ORR of 53%. There were 0 CR, 6 CRi, 0 PR, 2 MLFS, 7 pts had progressive disease (4 by BM, 3 by PB, Fig 1B). 3/18 additional pts had a ≥50% reduction in circulating blasts indicating treatment effect but were non-evaluable given lack of surveillance BM biopsy. Pts received a median of 2.5 cycles (range 1-9). 15/18 pts had treatment held or delayed due to fever/infection (7), PB cytopenias (4), combination (3), or non-hematologic toxicity (1). 6/8 pts who achieved a CRi/MLFS had VEN dosing reduced or administered as a single-agent. One patient achieved CRi with dose interruptions lasting ≥3 mos, maintained this response, and subsequently cleared a TP53 mutation. The majority of pts 13/18 (72.2%) experienced infectious complications during treatment: 7 developed bacterial pneumonia (4 associated with sepsis), 4 fungal penumonia, and 2 oral infections (both associated with sepsis). 8/18 pts had active infections at the time of death. Time from HCT or IST status did not appear to impact the frequency or severity of infectious complications. After a median of 2.7 mos of follow up (range 0.6-8.9 mos), the mOS after the start of VEN was 130 days. Consolidation with donor lymphocyte infusion or second HCT is planned for several pts. Conclusions: Transplant related- and disease related-mortality are difficult to disentangle in post-HCT AML relapse making it challenging to ascertain the benefit of therapy. In this cohort, the majority of pts relapsed within 6 mos of HCT and were receving IST at the start of salvage therapy. In spite of this, VEN-based salvage induced meaningful responses. To convert these responses to long term survival benefit, as VEN-based salvage is more widely used in this setting, consideration of immunosuppression and previous marrow injury should inform alternative dosing regimens, careful monitoring for infectious complications in close follow-up, and broad spectrum antimicrobial prophylaxis. Disclosures Byrne: Karyopharm: Research Funding. Dholaria:Celgene: Honoraria. Ferrell:Incyte: Research Funding; Agios: Consultancy; Forma Therapeutics: Research Funding; Astex Pharmaceuticals: Research Funding. Jagasia:Kadmon: Consultancy; Incyte: Consultancy; Janssen: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Savona:Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Venetoclax use in relapsed/refractory AML

This volume of Frontiers contains through-provoking articles, essays and book reviews that span a number of important areas in the field of education abroad. The authors provide useful insights into critical topics and deepen our understanding of the experience of our student sojourners. Shames and Alden of The Landmark School provide an overview of and present their own research on a critically important topic for education abroad: the impact of study abroad on identity development in students with learning disabilities and/or attention deficit hyperactivity disorder. The number of students with learning disabilities participating in study abroad has grown dramatically in recent years, and it is essential that we better understand these students and the nature of their study abroad experience. The authors suggest that some of the distinctive features of study abroad programs may contribute to positive identity development in these students. A study of North American students in Israel and the relationship between various aspects of their experience presents useful data not only for understanding Israel as a study abroad destination, but also other areas of the world where heritage study abroad, language learning, and ethnic identity interrelate. Donitsa-Schmidt and Vadish explore important relationships between study abroad elements that often influence student learning, and in so doing shed light on how the study abroad experience in Israel influences students’ identities, attitudes, and Hebrew language proficiency. In his article examining returning study abroad students, Hadis present his research on the determinants of “academic focusing” gains that we often observe in students returning from abroad, thereby contributing to our understanding of the experience of re-entry. Utilizing multiple regression and path analyses, he describes and analyzes student growth in terms of “Academic maturation” and the cluster of factors that contribute to their placing a priority on their academic work when they return from abroad. Using US models for understanding the international student experience, Grayson examines the experience of international students in Canada in his pilot for a three-year research study. This valuable study compares the experiences of domestic students with those of international students, and also the relationship between their experiences and outcomes. This research provides useful information regarding the factors that impact student success in another culture. The controversial decision by the US government to restrict educational travel to Cuba has meant that only a few US academic programs have been able to operate in Cuba. Bond, Koont, and Stephenson present data from their survey of students participating in three different short-term programs in Cuba with a focus on what they describe as the promotion of a “culture of peace,” alerting us to an important but often overlooked potential outcome of study abroad. Their article provides evidence for the value of short-term programs to Cuba. The Institute for International Education of Students continues to mine its extensive alumni database for important results on study abroad outcomes. In their article, Mohajeri Norris and Dwyer provide evidence that refutes the commonly-held assumption that direct enrollment, or so-called “full immersion programs,” lead to a fuller range of student learning outcomes than other program models. Drawing on IES alumni who studied abroad on both direct enrollment and hybrid programs, this study helps to inform this debate. In his article, Peppas addresses the outcomes for non-traditional students participating in short-term business tours abroad. Increasingly, students in fields such as the natural sciences, engineering, and business, all of which have been traditionally underrepresented, are participating in greater numbers in study abroad programs. Peppas offers insights into non-traditional adult study abroad students, many for whom the only option for study abroad is the short-term tour. Jane Jackson’s study provides further analysis of short-term study abroad through employing a qualitative measure: an analysis of students’ introspective accounts of their experience. Her use of diaries with her Hong Kong Chinese students studying abroad for five weeks in England suggests a model for both encouraging reflective learning and assessing it. The themes that emerge in the students’ reflections provide evidence of the value of short-term study. For the first time in our history, we are pleased to include in this volume an institutional case study. Drake University’s approach to campus internationalization and education abroad has received much attention. In this case study, Skidmore, Marston and Olson report on how this effort has progressed, and in doing so provide information that should prove useful for our work on our own campuses. This volume of Frontiers contains two essays that examine study abroad learning from broad perspectives. Slimbach presents a philosophical framework for understanding the “transcultural journey” that deepens our understanding of how students may be transformed by their sojourns. He draws upon a variety of sources to describe the psychological processes that, in many respects, are the most powerful and lasting aspects of study abroad. We hope that our readers appreciate the opportunity to read essays from faculty colleagues who have served as directors of abroad programs. After directing a program in China, Byrnes has developed his ideas concerning what he labels “other-regarding travel,” and in doing so provides a valuable faculty perspective on the study abroad learning process. This volume of Frontiers contains provocative book reviews that should inspire us to broaden our consideration of resources that can provide insights into our work. We are indeed fortunate to be in a profession that relates to so many intellectual traditions that inform our field. Our book reviews not only inspire us to read and consider a multiplicity of sources to make education abroad more meaningful, but also opens doors for discussions with faculty colleagues in related disciplines. In November, 2005, we will publish a Special Issue presenting seven outstanding student research projects completed as part of study abroad programs, along with faculty essays that reflect on the context for and the purposes of this research within their discipline, and within undergraduate education as a whole. These manuscripts were selected as part of the Forum on Education Abroad’s Undergraduate Research Award competition. The student articles were each blind-reviewed by the Frontiers Editorial Board. The resulting articles themselves are an exciting mix of high-quality research that spans several academic fields and geographic regions of the world. This Special Issue, made possible in part through a grant from the IFSA Foundation, we hope will be influential in shaping student learning in education abroad. With this volume, we welcome new sponsors to Frontiers and extend our thanks to them. The support of these new and of our continuing sponsoring institutions is testimony to their strong commitment to study abroad and their belief in the mission of Frontiers. Brian Whalen, Dickinson College

The editors acknowledge the support of the National Research Foundation of South Africa, Grant no. 105159, for the following articles: “Towards Decolonising Poetry in Education” (Newfield and Byrne); “Mapping Pathways for Indigenous Poetry Pedagogy” (Mavhiza and Prozesky); “That’s Schoolified” (Cooper); “Dancing with Mountains” (Ndlovu); “South African Indian Indigeneity” (Govender); “Reflections on Decoloniality from a South African Indian Perspective” (Naicker); “Poetic Bodies” (Genis); “Research That Is Real and Utopian” (de Villiers, Botha and Maungedzo); “Moments That Glow” (Naidu and Newfield); “Transforming Data into Poems” (d’Abdon and van Rooyen).

This abstract relates to the following paper: WilliamsR. L., AnzsarJ., BulmerR., BuntineJ., ByrneM., GedallaB., GoswamyP., GrantJ., HeahW., KeshaniS. & ShahJ.Application of the Solvency II Actuarial Function to general insurance firms. British Actuarial Journal. doi: 10.1017/S1357321716000052.

Abstract Background/Aims Hospitalisations for gout flares have doubled in England during the last 15 years. Despite this, no studies have evaluated strategies designed to increase the uptake of urate-lowering therapy (ULT) in people hospitalised for gout flares. Methods We conducted a prospective cohort study in people hospitalised for gout flares. We designed and evaluated an intervention package that consisted of an optimal, in-hospital management pathway based upon BSR, EULAR and ACR guidelines, which encouraged ULT initiation prior to discharge, followed by a nurse-led, post-discharge review. Outcomes including: i) ULT initiation; ii) serum urate target attainment, and iii) re-hospitalisation rates were compared between patients hospitalised for flares in the 12 months post-implementation vs. a retrospective cohort of hospitalised patients from 12 months pre-implementation. Results 119 and 108 patients, respectively, were hospitalised for gout flares in the 12 months before and after the intervention was launched. For patients with six-month follow-up data available (n = 94 and n = 97, respectively), the proportion of patients who were newly initiated on ULT increased to 92% post-implementation, from 49% pre-implementation (age and sex-adjusted odds ratio (aOR) 11.5; 95% CI 4.36-30.5; p &lt; 0.001). More patients achieved a serum urate ≤360 micromol/L within six months of discharge (27% post-implementation vs. 11% pre-implementation; aOR 3.04; 95% CI 1.36-6.78; p = 0.007). The proportion of patients who were re-hospitalised for flares was 9% post-implementation vs. 15% pre-implementation (aOR 0.53, 95% CI 0.22 to 1.32; p = 0.18). Conclusion Following implementation of a strategy designed to optimise care during gout hospitalisations, more than 90% of ULT-naïve patients were initiated on ULT - nearly double the pre-implementation baseline. Despite greater initiation of ULT in the acute flare setting, recurrent hospitalisations did not increase following implementation; supporting the use of ULT in this setting. Improvements were seen in urate target attainment post-discharge; however, focused approaches to optimise ULT dose escalation to achieve target urate levels are required. Disclosure M.D. Russell: Honoraria; AbbVie, Biogen, Eli Lilly, Galapagos, Menarini. Grants/research support; Eli Lilly, Janssen, Pfizer, UCB. L. Ameyaw-Kyeremeh: None. F. Dell'Accio: None. H. Lapham: None. N. Head: None. C. Stovin: None. V. Patel: None. B. Clarke: None. D. Nagra: None. E. Alveyn: None. M.A. Adas: None. K. Bechman: Grants/research support; Versus Arthritis/Pfizer. M.A. de la Puente: None. B. Ellis: None. C. Byrne: None. R. Patel: None. A.I. Rutherford: Other; Educational support from Eli Lilly, UCB. F. Cantle: None. S. Norton: None. E. Roddy: None. J. Hudson: None. A.P. Cope: Honoraria; BMS, AbbVie, GSK/Galvini. Grants/research support; BMS. J.B. Galloway: Honoraria; Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, UCB.

Sara Baume has become one of most brilliant recent voices in the literary and artistic panorama of contemporary Ireland. She has managed to combine in a unique way an already established career as a writer with her vast knowledge of art and her own artistic projects. Baume has written two unanimously critically acclaimed novels, spill simmer falter wither (2015) and A Line Made by Walking (2017) and a handful of short stories which have been published in prestigious literary magazines and collections such as The Stinging Fly, Granta, The Moth, The Dublin Review, or The Davy Byrnes Collection. More recently, she published Handiwork (2020), a most intimate account of her life, interests and projects as a writer and as an artist, as well as a deeply felt personal homage to the figure of her dead father. In the present interview, the writer comments on the contemporary panorama of Irish literature, on the social and economic changes that have taken place recently in her native country, and on the two languages between which she has always felt caught, the one that goes down on paper and the one that goes down in small painted objects. These two languages have been put at the service of one of the most obvious and recurrent interests of the writer, her endless fascination for and deep concern with nature and animals.

Photograph by Gonzalo Echeverria (2010)“I must plunge again and again in the water of doubt” (Wittgenstein 1e). The Holy Grail in the phenomenology of religion (and, to a lesser extent, the sociology of religion) is a definition of religion that actually works, but, so far, this seems to have been elusive. Classical definitions of religion—substantive (e.g. Tylor) and functionalist (e.g. Durkheim)—fail, in part because they attempt to be in three places at once, as it were: they attempt to distinguish religion from non-religion; they attempt to capture what religions have in common; and they attempt to grasp the “heart”, or “core”, of religion. Consequently, family resemblance definitions of religion replace certainty and precision for its own sake with a more pragmatic and heuristic approach, embracing doubt and putting forward definitions that give us a better understanding (Verstehen) of religion. In this paper, I summarise some “new” definitions of religion that take this approach, before proposing and defending another one, defining religion as non-propositional and “apophatic”, thus accepting that doubt is central to religion itself, as well as to the analysis of religion.The question of how to define religion has had real significance in a number of court cases round the world, and therefore it does have an impact on people’s lives. In Germany, for example, the courts ruled that Scientology was not a religion, but a business, much to the displeasure of the Church of Scientology (Aldridge 15). In the United States, some advocates of Transcendental Meditation (TM) argued that TM was not a religion and could therefore be taught in public schools without violating the establishment clause in the constitution—the separation of church and state. The courts in New Jersey, and federal courts, ruled against them. They ruled that TM was a religion (Barker 146). There are other cases that I could cite, but the point of this is simply to establish that the question has a practical importance, so we should move on.In the classical sociology of religion, there are a number of definitions of religion that are quite well known. Edward Tylor (424) defined religion as a belief in spiritual beings. This definition does not meet with widespread acceptance, the notable exception being Melford Spiro, who proposed in 1966 that religion was “an institution consisting of culturally patterned interaction with culturally postulated super-human beings” (Spiro 96, see also 91ff), and who has bravely stuck to that definition ever since. The major problem is that this definition excludes Buddhism, which most people do regard as a religion, although some people try to get round the problem by claiming that Buddhism is not really a religion, but more of a philosophy. But this is cheating, really, because a definition of religion must be descriptive as well as prescriptive; that is, it must apply to entities that are commonly recognised as religions. Durkheim, in The Elementary Forms of Religious Life, proposed that religion had two key characteristics, a separation of the sacred from the profane, and a gathering together of people in some sort of institution or community, such as a church (Durkheim 38, 44). However, religions often reject a separation of the sacred from the profane. Most Muslims and many Calvinist Christians, for example, would insist strongly that everything—including the ostensibly profane—is equally subject to the sovereignty of God. Also, some religions are more oriented to a guru-pupil kind of relationship, rather than a church community.Weber tried to argue that religion should only be defined at the end of a long process of historical and empirical study. He is often criticised for this, although there probably is some wisdom in his argument. However, there seems to be an implicit definition of religion as theodicy, accounting for the existence of evil and the existence of suffering. But is this really the central concern of all religions?Clarke and Byrne, in their book Religion Defined and Explained, construct a typology of definitions, which I think is quite helpful. Broadly speaking, there are two types of classical definition. Firstly, there are substantive definitions (6), such as Tylor’s and Spiro’s, which posit some sort of common “property” that religions “have”—“inside” them, as it were. Secondly, functionalist definitions (Clarke and Byrne 7), such as Durkheim’s, define religion primarily in terms of its social function. What matters, as far as a definition of religion is concerned, is not what you believe, but why you believe it.However, these classical definitions do not really work. I think this is because they try to do too many things. For a strict definition of religion to work, it needs to tell us (i) what religions have in common, (ii) what distinguishes religion on the one hand from non-religion, or everything that is not religion, on the other, and (iii) it needs to tell us something important about religion, what is at the core of religion. This means that a definition of religion has to be in three places at once, so to speak. Furthermore, a definition of religion has to be based on extant religions, but it also needs to have some sort of quasi-predictive capacity, the sort of thing that can be used in a court case regarding, for example, Scientology or Transcendental Meditation.It may be possible to resolve the latter problem by a gradual process of adjustment, a sort of hermeneutic circle of basing a definition on extant religions and applying it to new ones. But what about the other problem, the one of being in three places at once?Another type identified by Clarke and Byrne, in their typology of definitions, is the “family resemblance” definition (11-16). This derives from the later Wittgenstein. The “family resemblance” definition of religion is based on the idea that religions commonly share a number of features, but that no one religion has all of them. For example, there are religious beliefs, doctrines and mythos—or stories and parables. There are rituals and moral codes, institutions and clergy, prayers, spiritual emotions and experiences, etc. This approach is of course less precise than older substantive and functional definitions, but it also avoids some of the problems associated with them.It does so by rethinking the point of defining religion. Instead of being precise and rigorous for the sake of it, it tries to tell us something, to be “productive”, to help us understand religion better. It eschews certainty and embraces doubt. Its insights could be applied to some schools of philosophy (e.g. Heideggerian) and practical spirituality, because it does not focus on what is distinctive about religion. Rather, it focuses on the core of religion, and, secondarily, on what religions have in common. The family resemblance approach has led to a number of “new” definitions (post-Durkheim definitions) being proposed, all of which define religion in a less rigorous, but, I hope, more imaginative and heuristic way.Let me provide a few examples, starting with two contrasting ones. Peter Berger in the late 1960s defined religion as “the audacious attempt to conceive of the entire universe as humanly significant”(37), which implies a consciousness of an anthropocentric sacred cosmos. Later, Alain Touraine said that religion is “the apprehension of human destiny, existence, and death”(213–4), that is, an awareness of human limitations, including doubt. Berger emphasises the high place for human beings in religion, and even a sort of affected certainty, while Touraine emphasises our place as doubters on the periphery, but it seems that religion exists within a tension between these two opposites, and, in a sense, encompasses them both.Richard Holloway, former Bishop of Edinburgh in the Scottish Episcopal Church and arch-nemesis of the conservative Anglicans, such as those from Sydney, defines religion as like good poetry, not bad science. It is easy to understand that he is criticising those who see religion, particularly Christianity, as centrally opposed to Darwin and evolution. Holloway is clearly saying that those people have missed the point of their own faith. By “good poetry”, he is pointing to the significance of storytelling rather than dogma, and an open-ended discussion of ultimate questions that resists the temptation to end with “the moral of the story”. In science (at least before quantum physics), there is no room for doubt, but that is not the case with poetry.John Caputo, in a very energetic book called On Religion, proposes what is probably the boldest of the “new” definitions. He defines religion as “the love of God” (1). Note the contrast with Tylor and Spiro. Caputo does not say “belief in God”; he says “the love of God”. You might ask how you can love someone you don’t believe in, but, in a sense, this paradox is the whole point. When Caputo says “God”, he is not necessarily talking in the usual theistic or even theological terms. By “God”, he means the impossible made possible (10). So a religious person, for Caputo, is an “unhinged lover” (13) who loves the impossible made possible, and the opposite is a “loveless lout” who is only concerned with the latest stock market figures (2–3). In this sense of religious, a committed atheist can be religious and a devout Catholic or Muslim or Hindu can be utterly irreligious (2–3). Doubt can encompass faith and faith can encompass doubt. This is the impossible made possible. Caputo’s approach here has something in common with Nietzsche and especially Kierkegaard, to whom I shall return later.I would like to propose another definition of religion, within the spirit of these “new” definitions of religion that I have been discussing. Religion, at its core, I suggest, is non-propositional and apophatic. When I say that religion is non-propositional, I mean that religion will often enact certain rituals, or tell certain stories, or posit faith in someone, and that propositional statements of doctrine are merely reflections or approximations of this non-propositional core. Faith in God is not a proposition. The Eucharist is not a proposition. Prayer is not, at its core, a proposition. Pilgrimage is not a proposition. And it is these sorts of things that, I suggest, form the core of religion. Propositions are what happen when theologians and academics get their hands on religion, they try to intellectualise it so that it can be made to fit within their area of expertise—our area of expertise. But, that is not where it belongs. Propositions about rituals impose a certainty on them, whereas the ritual itself allows for courage in the face of doubt. The Maundy Thursday service in Western Christianity includes the stripping of the altar to the accompaniment of Psalm 22 (“My God, my God, why hast Thou forsaken me”), ending the service without a dismissal (Latin missa, the origin of the English “mass”) and with the church in darkness. Doubt, confusion, and bewilderment are the heart and soul of this ritual, not orthodox faith as defined propositionally.That said, religion does often involve believing, of some kind (though it is not usually as central as in Christianity). So I say that religion is non-propositional and apophatic. The word “apophatic”, though not the concept, has its roots in Greek Orthodox theology, where St Gregory Palamas argues that any statement about God—and particularly about God’s essence as opposed to God’s energies—must be paradoxical, emphasising God’s otherness, and apophatic, emphasising God’s essential incomprehensibility (Armstrong 393). To make an apophatic statement is to make a negative statement—instead of saying God is king, lord, father, or whatever, we say God is not. Even the most devout believer will recognise a sense in which God is not a king, or a lord, or a father. They will say that God is much greater than any of these things. The Muslim will say “Allahu Akhbar”, which means God is greater, greater than any human description. Even the statement “God exists” is seen to be well short of the mark. Even that is human language, which is why the Cappadocian fathers (Saints Basil the Great, Gregory of Nyssa, and Gregory Naziansus) said that they believed in God, while refusing to say that God exists.So to say that religion is at its core non-propositional is to say that religious beliefs are at their core apophatic. The idea of apophasis is that by a process of constant negation you are led into silence, into a recognition that there is nothing more that can be said. St Thomas Aquinas says that the more things we negate about God, the more we say “God is not…”, the closer we get to what God is (139). Doubt therefore brings us closer to the object of religion than any putative certainties.Apophasis does not only apply to Christianity. I have already indicated that it applies also to Islam, and the statement that God is greater. In Islam, God is said to have 99 names—or at least 99 that have been revealed to human beings. Many of these names are apophatic. Names like The Hidden carry an obviously negative meaning in English, while, etymologically, “the Holy” (al-quddu-s) means “beyond imperfection”, which is a negation of a negation. As-salaam, the All-Peaceful, means beyond disharmony, or disequilibrium, or strife, and, according to Murata and Chittick (65–6), “The Glorified” (as-subbuh) means beyond understanding.In non-theistic religions too, an apophatic way of believing can be found. Key Buddhist concepts include sunyata, emptiness, or the Void, and anatta, meaning no self, the belief or realisation that the Self is illusory. Ask what they believe in instead of the Self and you are likely to be told that you are missing the point, like the Zen pupil who confused the pointing finger with the moon. In the Zen koans, apophasis plays a major part. One well-known koan is “What is the sound of one hand clapping?” Any logical answers will be dismissed, like Thomas Aquinas’s statements about God, until the pupil gets beyond logic and achieves satori, or enlightenment. Probably the most used koan is Mu—Master Joshu is asked if a dog has Buddha-nature and replies Mu, meaning “no” or “nothing”. This is within the context of the principle that everything has Buddha-nature, so it is not logical. But this apophatic process can lead to enlightenment, something better than logic. By plunging again and again in the water of doubt, to use Wittgenstein’s words, we gain something better than certainty.So not only is apophasis present in a range of different religions—and I have given just a few examples—but it is also central to the development of religion in the Axial Age, Karl Jaspers’s term for the period from about 800-200 BCE when the main religious traditions of the world began—monotheism in Israel (which also developed into Christianity and Islam), Hinduism and Buddhism in India, Confucianism and Taoism in China, and philosophical rationalism in Greece. In the early Hindu traditions, there seems to have been a sort of ritualised debate called the Brahmodya, which would proceed through negation and end in silence. Not the silence of someone admitting defeat at the hands of the other, but the silence of recognising that the truth lay beyond them (Armstrong 24).In later Hinduism, apophatic thought is developed quite extensively. This culminates in the idea of Brahman, the One God who is Formless, beyond all form and all description. As such, all representations of Brahman are equally false and therefore all representations are equally true—hence the preponderance of gods and idols on the surface of Hinduism. There is also the development of the idea of Atman, the universal Self, and the Buddhist concept anatta, which I mentioned, is rendered anatman in Sanskrit, literally no Atman, no Self. But in advaita Hinduism there is the idea that Brahman and Atman are the same, or, more accurately, they are not two—hence advaita, meaning “not two”. This is negation, or apophasis. In some forms of present-day Hinduism, such as the International Society for Krishna Consciousness (commonly known as the Hare Krishnas), advaita is rejected. Sometimes this is characterised as dualism with respect to Brahman and Atman, but it is really the negation of non-dualism, or an apophatic negation of the negation.Even in early Hinduism, there is a sort of Brahmodya recounted in the Rig Veda (Armstrong 24–5), the oldest extant religious scripture in the world that is still in use as a religious scripture. So here we are at the beginning of Axial Age religion, and we read this account of creation:Then was not non-existent nor existent: there was no realm of air, no sky beyond it.Death was not then, nor was there aught immortal.Darkness there was: at first concealed in darkness this All was indiscriminated chaos.All that existed then was void and form less.Sages who searched with their heart's thought discovered the existent's kinship in the non-existent.Who verily knows and who can here declare it, whence it was born and whence comes this creation?The Gods are later than this world's production. Who knows then whence it first came into being?He, the first origin of this creation, whether he formed it all or did not form it,Whose eye controls this world in highest heaven, he verily knows it, or perhaps he knows not.(Rig Veda Book 10, Hymn 129, abridged)And it would seem that this is the sort of thought that spread throughout the world as a result of the Axial Age and the later spread of Axial and post-Axial religions.I could provide examples from other religious traditions. Taoism probably has the best examples, though they are harder to relate to the traditions that are more familiar in the West. “The way that is spoken is not the Way” is the most anglicised translation of the opening of the Tao Te Ching. In Sikhism, God’s formlessness and essential unknowability mean that God can only be known “by the Guru’s grace”, to quote the opening hymn of the Guru Granth Sahib.Before I conclude, however, I would like to anticipate two criticisms. First, this may only be applicable to the religions of the Axial Age and their successors, beginning with Hinduism and Buddhism, Taoism and Confucianism, and early Jewish monotheism, followed by Jainism, Christianity, Islam and so on. I would like to find examples of apophasis at the core of other traditions, including Indigenous Australian and Native American ones, for example, but that is work still to be done. Focusing on the Axial Age does historicise the argument, however, at least in contrast with a more universal concept of religion that runs the risk of falling into the ahistorical homo religiosus idea that humans are universally and even naturally religious. Second, this apophatic definition looks a bit elitist, defining religion in terms that are relevant to theologians and “religious virtuosi” (to use Weber’s term), but what about the ordinary believers, pew-fillers, temple-goers? In response to such criticism, one may reply that there is an apophatic strand in what Niebuhr called the religions of the disinherited. In Asia, devotion to the Buddha Amida is particularly popular among the poor, and this involves a transformation of the idea of anatta—no Self—into an external agency, a Buddha who is “without measure”, in terms of in-finite light and in-finite life. These are apophatic concepts. In the Christian New Testament, we are told that God “has chosen the foolish things of this world to shame the wise, the weak to shame the strong…, the things that are not to shame the things that are” (1 Corinthians 1:27). The things that are not are the apophatic, and these are allied with the foolish and the weak, not the educated and the powerful.One major reason for emphasising the role of apophasis in religious thought is to break away from the idea that the core of religion is an ethical one. This is argued by a number of “liberal religious” thinkers in different religious traditions. I appreciate their reasons, and I am reluctant to ally myself with their opponents, who include the more fundamentalist types as well as some vocal critics of religion like Dawkins and Hitchens. However, I said that I would return to Kierkegaard, and the reason is this. Kierkegaard distinguishes between the aesthetic, the ethical and the religious. Of course, religion has an aesthetic and an ethical dimension, and in some religions these dimensions are particularly important, but that does not make them central to religion as such. Kierkegaard regarded the religious sphere as radically different from the aesthetic or even the ethical, hence his treatment of the story of Abraham going to Mount Moriah to sacrifice his son, in obedience to God’s command. His son was not killed in the end, but Abraham was ready to do the deed. This is not ethical. This is fundamentally and scandalously unethical. Yet it is religious, not because it is unethical and scandalous, but because it pushes us to the limits of our understanding, through the waters of doubt, and then beyond.Were I attempting to criticise religion, I would say it should not go there, that, to misquote Wittgenstein, the limits of my understanding are the limits of my world, whereof we cannot understand thereof we must remain silent. Were I attempting to defend religion, I would say that this is its genius, that it can push back the limits of understanding. I do not believe in value-neutral sociology, but, in this case, I am attempting neither. ReferencesAldridge, Alan. Religion in the Contemporary World. Cambridge: Polity, 2000.Aquinas, Thomas. “Summa of Christian Teaching”. An Aquinas Reader. ed. Mary Clarke. New York: Doubleday, 1972.Armstrong, Karen. The Great Transformation. New York: Alfred A. Knopf, 2006.Barker, Eileen. New Religious Movements: a Practical Introduction. London: HMSO, 1989.Berger, Peter. The Social Reality of Religion. Harmondsworth: Penguin, 1973.Caputo, John. On Religion. London: Routledge, 2001.Clarke, Peter, and Peter Byrne, eds. Religion Defined and Explained. New York: St Martin’s Press. 1993.Durkheim, Emile. The Elementary Forms of Religious Life. New York: Free Press, 1995.Holloway, Richard. Doubts and Loves. Edinburgh: Caqnongate, 2002.Jaspers, Karl. The Origin and Goal of History. Westport, Connecticut: Greenwood Press, 1977.Kierkegaard, Søren. Either/Or. London: Penguin, 1992.———. Fear and Trembling. London: Penguin, 1986.Murata, Sachiko, and William Chittick. The Vision of Islam. St Paul, Minnesota: Paragon House, 1994.Niebuhr, H. Richard. The Social Sources of Denominationalism. New York: Holt, 1929.Spiro, Melford. “Religion: Problems of Definition and Explanation.” Anthropological Approaches to the Study of Religion. Ed. Michael Banton. London: Tavistock, 1966. 85–126.Touraine, Alain. The Post-Industrial Society. London: Wilwood House, 1974.Tylor, Edward. Primitive Culture. London: Murray, 1903.Weber, Max. The Sociology of Religion. Boston: Beacon Press, 1991.Wittgenstein, Ludwig. Remarks on Frazer’s Golden Bough. Nottingham: Brynmill Press, 1979.

Alfred Hermida recently posited ‘ambient journalism’ as a new framework for para- and professional journalists, who use social networks like Twitter for story sources, and as a news delivery platform. Beginning with this framework, this article explores the following questions: How does Hermida define ‘ambient journalism’ and what is its significance? Are there alternative definitions? What lessons do current platforms provide for the design of future, real-time platforms that ‘ambient journalists’ might use? What lessons does the work of Brian Eno provide–the musician and producer who coined the term ‘ambient music’ over three decades ago? My aim here is to formulate an alternative definition of ambient journalism that emphasises craft, skills acquisition, and the mental models of professional journalists, which are the foundations more generally for journalism practices. Rather than Hermida’s participatory media context I emphasise ‘institutional adaptiveness’: how journalists and newsrooms in media institutions rely on craft and skills, and how emerging platforms can augment these foundations, rather than replace them. Hermida’s Ambient Journalism and the Role of Journalists Hermida describes ambient journalism as: “broad, asynchronous, lightweight and always-on communication systems [that] are creating new kinds of interactions around the news, and are enabling citizens to maintain a mental model of news and events around them” (Hermida 2). His ideas appear to have two related aspects. He conceives ambient journalism as an “awareness system” between individuals that functions as a collective intelligence or kind of ‘distributed cognition’ at a group level (Hermida 2, 4-6). Facebook, Twitter and other online social networks are examples. Hermida also suggests that such networks enable non-professionals to engage in ‘communication’ and ‘conversation’ about news and media events (Hermida 2, 7). In a helpful clarification, Hermida observes that ‘para-journalists’ are like the paralegals or non-lawyers who provide administrative support in the legal profession and, in academic debates about journalism, are more commonly known as ‘citizen journalists’. Thus, Hermida’s ambient journalism appears to be: (1) an information systems model of new platforms and networks, and (2) a normative argument that these tools empower ‘para-journalists’ to engage in journalism and real-time commentary. Hermida’s thesis is intriguing and worthy of further discussion and debate. As currently formulated however it risks sharing the blind-spots and contradictions of the academic literature that Hermida cites, which suffers from poor theory-building (Burns). A major reason is that the participatory media context on which Hermida often builds his work has different mental models and normative theories than the journalists or media institutions that are the target of critique. Ambient journalism would be a stronger and more convincing framework if these incorrect assumptions were jettisoned. Others may also potentially misunderstand what Hermida proposes, because the academic debate is often polarised between para-journalists and professional journalists, due to different views about institutions, the politics of knowledge, decision heuristics, journalist training, and normative theoretical traditions (Christians et al. 126; Cole and Harcup 166-176). In the academic debate, para-journalists or ‘citizen journalists’ may be said to have a communitarian ethic and desire more autonomous solutions to journalists who are framed as uncritical and reliant on official sources, and to media institutions who are portrayed as surveillance-like ‘monitors’ of society (Christians et al. 124-127). This is however only one of a range of possible relationships. Sole reliance on para-journalists could be a premature solution to a more complex media ecology. Journalism craft, which does not rely just on official sources, also has a range of practices that already provides the “more complex ways of understanding and reporting on the subtleties of public communication” sought (Hermida 2). Citizen- and para-journalist accounts may overlook micro-studies in how newsrooms adopt technological innovations and integrate them into newsgathering routines (Hemmingway 196). Thus, an examination of the realities of professional journalism will help to cast a better light on how ambient journalism can shape the mental models of para-journalists, and provide more rigorous analysis of news and similar events. Professional journalism has several core dimensions that para-journalists may overlook. Journalism’s foundation as an experiential craft includes guidance and norms that orient the journalist to information, and that includes practitioner ethics. This craft is experiential; the basis for journalism’s claim to “social expertise” as a discipline; and more like the original Linux and Open Source movements which evolved through creative conflict (Sennett 9, 25-27, 125-127, 249-251). There are learnable, transmissible skills to contextually evaluate, filter, select and distil the essential insights. This craft-based foundation and skills informs and structures the journalist’s cognitive witnessing of an event, either directly or via reconstructed, cultivated sources. The journalist publishes through a recognised media institution or online platform, which provides communal validation and verification. There is far more here than the academic portrayal of journalists as ‘gate-watchers’ for a ‘corporatist’ media elite. Craft and skills distinguish the professional journalist from Hermida’s para-journalist. Increasingly, media institutions hire journalists who are trained in other craft-based research methods (Burns and Saunders). Bethany McLean who ‘broke’ the Enron scandal was an investment banker; documentary filmmaker Errol Morris first interviewed serial killers for an early project; and Neil Chenoweth used ‘forensic accounting’ techniques to investigate Rupert Murdoch and Kerry Packer. Such expertise allows the journalist to filter information, and to mediate any influences in the external environment, in order to develop an individualised, ‘embodied’ perspective (Hofstadter 234; Thompson; Garfinkel and Rawls). Para-journalists and social network platforms cannot replace this expertise, which is often unique to individual journalists and their research teams. Ambient Journalism and Twitter Current academic debates about how citizen- and para-journalists may augment or even replace professional journalists can often turn into legitimation battles whether the ‘de facto’ solution is a social media network rather than a media institution. For example, Hermida discusses Twitter, a micro-blogging platform that allows users to post 140-character messages that are small, discrete information chunks, for short-term and episodic memory. Twitter enables users to monitor other users, to group other messages, and to search for terms specified by a hashtag. Twitter thus illustrates how social media platforms can make data more transparent and explicit to non-specialists like para-journalists. In fact, Twitter is suitable for five different categories of real-time information: news, pre-news, rumours, the formation of social media and subject-based networks, and “molecular search” using granular data-mining tools (Leinweber 204-205). In this model, the para-journalist acts as a navigator and “way-finder” to new information (Morville, Findability). Jaron Lanier, an early designer of ‘virtual reality’ systems, is perhaps the most vocal critic of relying on groups of non-experts and tools like Twitter, instead of individuals who have professional expertise. For Lanier, what underlies debates about citizen- and para-journalists is a philosophy of “cybernetic totalism” and “digital Maoism” which exalts the Internet collective at the expense of truly individual views. He is deeply critical of Hermida’s chosen platform, Twitter: “A design that shares Twitter’s feature of providing ambient continuous contact between people could perhaps drop Twitter’s adoration of fragments. We don’t really know, because it is an unexplored design space” [emphasis added] (Lanier 24). In part, Lanier’s objection is traceable back to an unresolved debate on human factors and design in information science. Influenced by the post-war research into cybernetics, J.C.R. Licklider proposed a cyborg-like model of “man-machine symbiosis” between computers and humans (Licklider). In turn, Licklider’s framework influenced Douglas Engelbart, who shaped the growth of human-computer interaction, and the design of computer interfaces, the mouse, and other tools (Engelbart). In taking a system-level view of platforms Hermida builds on the strength of Licklider and Engelbart’s work. Yet because he focuses on para-journalists, and does not appear to include the craft and skills-based expertise of professional journalists, it is unclear how he would answer Lanier’s fears about how reliance on groups for news and other information is superior to individual expertise and judgment. Hermida’s two case studies point to this unresolved problem. Both cases appear to show how Twitter provides quicker and better forms of news and information, thereby increasing the effectiveness of para-journalists to engage in journalism and real-time commentary. However, alternative explanations may exist that raise questions about Twitter as a new platform, and thus these cases might actually reveal circumstances in which ambient journalism may fail. Hermida alludes to how para-journalists now fulfil the earlier role of ‘first responders’ and stringers, in providing the “immediate dissemination” of non-official information about disasters and emergencies (Hermida 1-2; Haddow and Haddow 117-118). Whilst important, this is really a specific role. In fact, disaster and emergency reporting occurs within well-established practices, professional ethics, and institutional routines that may involve journalists, government officials, and professional communication experts (Moeller). Officials and emergency management planners are concerned that citizen- or para-journalism is equated with the craft and skills of professional journalism. The experience of these officials and planners in 2005’s Hurricane Katrina in the United States, and in 2009’s Black Saturday bushfires in Australia, suggests that whilst para-journalists might be ‘first responders’ in a decentralised, complex crisis, they are perceived to spread rumours and potential social unrest when people need reliable information (Haddow and Haddow 39). These terms of engagement between officials, planners and para-journalists are still to be resolved. Hermida readily acknowledges that Twitter and other social network platforms are vulnerable to rumours (Hermida 3-4; Sunstein). However, his other case study, Iran’s 2009 election crisis, further complicates the vision of ambient journalism, and always-on communication systems in particular. Hermida discusses several events during the crisis: the US State Department request to halt a server upgrade, how the Basij’s shooting of bystander Neda Soltan was captured on a mobile phone camera, the spread across social network platforms, and the high-velocity number of ‘tweets’ or messages during the first two weeks of Iran’s electoral uncertainty (Hermida 1). The US State Department was interested in how Twitter could be used for non-official sources, and to inform people who were monitoring the election events. Twitter’s perceived ‘success’ during Iran’s 2009 election now looks rather different when other factors are considered such as: the dynamics and patterns of Tehran street protests; Iran’s clerics who used Soltan’s death as propaganda; claims that Iran’s intelligence services used Twitter to track down and to kill protestors; the ‘black box’ case of what the US State Department and others actually did during the crisis; the history of neo-conservative interest in a Twitter-like platform for strategic information operations; and the Iranian diaspora’s incitement of Tehran student protests via satellite broadcasts. Iran’s 2009 election crisis has important lessons for ambient journalism: always-on communication systems may create noise and spread rumours; ‘mirror-imaging’ of mental models may occur, when other participants have very different worldviews and ‘contexts of use’ for social network platforms; and the new kinds of interaction may not lead to effective intervention in crisis events. Hermida’s combination of news and non-news fragments is the perfect environment for psychological operations and strategic information warfare (Burns and Eltham). Lessons of Current Platforms for Ambient Journalism We have discussed some unresolved problems for ambient journalism as a framework for journalists, and as mental models for news and similar events. Hermida’s goal of an “awareness system” faces a further challenge: the phenomenological limitations of human consciousness to deal with information complexity and ambiguous situations, whether by becoming ‘entangled’ in abstract information or by developing new, unexpected uses for emergent technologies (Thackara; Thompson; Hofstadter 101-102, 186; Morville, Findability, 55, 57, 158). The recursive and reflective capacities of human consciousness imposes its own epistemological frames. It’s still unclear how Licklider’s human-computer interaction will shape consciousness, but Douglas Hofstadter’s experiments with art and video-based group experiments may be suggestive. Hofstadter observes: “the interpenetration of our worlds becomes so great that our worldviews start to fuse” (266). Current research into user experience and information design provides some validation of Hofstadter’s experience, such as how Google is now the ‘default’ search engine, and how its interface design shapes the user’s subjective experience of online search (Morville, Findability; Morville, Search Patterns). Several models of Hermida’s awareness system already exist that build on Hofstadter’s insight. Within the information systems field, on-going research into artificial intelligence–‘expert systems’ that can model expertise as algorithms and decision rules, genetic algorithms, and evolutionary computation–has attempted to achieve Hermida’s goal. What these systems share are mental models of cognition, learning and adaptiveness to new information, often with forecasting and prediction capabilities. Such systems work in journalism areas such as finance and sports that involve analytics, data-mining and statistics, and in related fields such as health informatics where there are clear, explicit guidelines on information and international standards. After a mid-1980s investment bubble (Leinweber 183-184) these systems now underpin the technology platforms of global finance and news intermediaries. Bloomberg LP’s ubiquitous dual-screen computers, proprietary network and data analytics (www.bloomberg.com), and its competitors such as Thomson Reuters (www.thomsonreuters.com and www.reuters.com), illustrate how financial analysts and traders rely on an “awareness system” to navigate global stock-markets (Clifford and Creswell). For example, a Bloomberg subscriber can access real-time analytics from exchanges, markets, and from data vendors such as Dow Jones, NYSE Euronext and Thomson Reuters. They can use portfolio management tools to evaluate market information, to make allocation and trading decisions, to monitor ‘breaking’ news, and to integrate this information. Twitter is perhaps the para-journalist equivalent to how professional journalists and finance analysts rely on Bloomberg’s platform for real-time market and business information. Already, hedge funds like PhaseCapital are data-mining Twitter’s ‘tweets’ or messages for rumours, shifts in stock-market sentiment, and to analyse potential trading patterns (Pritchett and Palmer). The US-based Securities and Exchange Commission, and researchers like David Gelernter and Paul Tetlock, have also shown the benefits of applied data-mining for regulatory market supervision, in particular to uncover analysts who provide ‘whisper numbers’ to online message boards, and who have access to material, non-public information (Leinweber 60, 136, 144-145, 208, 219, 241-246). Hermida’s framework might be developed further for such regulatory supervision. Hermida’s awareness system may also benefit from the algorithms found in high-frequency trading (HFT) systems that Citadel Group, Goldman Sachs, Renaissance Technologies, and other quantitative financial institutions use. Rather than human traders, HFT uses co-located servers and complex algorithms, to make high-volume trades on stock-markets that take advantage of microsecond changes in prices (Duhigg). HFT capabilities are shrouded in secrecy, and became the focus of regulatory attention after several high-profile investigations of traders alleged to have stolen the software code (Bray and Bunge). One public example is Streambase (www.streambase.com), a ‘complex event processing’ (CEP) platform that can be used in HFT, and commercialised from the Project Aurora research collaboration between Brandeis University, Brown University, and Massachusetts Institute of Technology. CEP and HFT may be the ‘killer apps’ of Hermida’s awareness system. Alternatively, they may confirm Jaron Lanier’s worst fears: your data-stream and user-generated content can be harvested by others–for their gain, and your loss! Conclusion: Brian Eno and Redefining ‘Ambient Journalism’ On the basis of the above discussion, I suggest a modified definition of Hermida’s thesis: ‘Ambient journalism’ is an emerging analytical framework for journalists, informed by cognitive, cybernetic, and information systems research. It ‘sensitises’ the individual journalist, whether professional or ‘para-professional’, to observe and to evaluate their immediate context. In doing so, ‘ambient journalism’, like journalism generally, emphasises ‘novel’ information. It can also inform the design of real-time platforms for journalistic sources and news delivery. Individual ‘ambient journalists’ can learn much from the career of musician and producer Brian Eno. His personal definition of ‘ambient’ is “an atmosphere, or a surrounding influence: a tint,” that relies on the co-evolution of the musician, creative horizons, and studio technology as a tool, just as para-journalists use Twitter as a platform (Sheppard 278; Eno 293-297). Like para-journalists, Eno claims to be a “self-educated but largely untrained” musician and yet also a craft-based producer (McFadzean; Tamm 177; 44-50). Perhaps Eno would frame the distinction between para-journalist and professional journalist as “axis thinking” (Eno 298, 302) which is needlessly polarised due to different normative theories, stances, and practices. Furthermore, I would argue that Eno’s worldview was shaped by similar influences to Licklider and Engelbart, who appear to have informed Hermida’s assumptions. These influences include the mathematician and game theorist John von Neumann and biologist Richard Dawkins (Eno 162); musicians Eric Satie, John Cage and his book Silence (Eno 19-22, 162; Sheppard 22, 36, 378-379); and the field of self-organising systems, in particular cyberneticist Stafford Beer (Eno 245; Tamm 86; Sheppard 224). Eno summed up the central lesson of this theoretical corpus during his collaborations with New York’s ‘No Wave’ scene in 1978, of “people experimenting with their lives” (Eno 253; Reynolds 146-147; Sheppard 290-295). Importantly, he developed a personal view of normative theories through practice-based research, on a range of projects, and with different creative and collaborative teams. Rather than a technological solution, Eno settled on a way to encode his craft and skills into a quasi-experimental, transmittable method—an aim of practitioner development in professional journalism. Even if only a “founding myth,” the story of Eno’s 1975 street accident with a taxi, and how he conceived ‘ambient music’ during his hospital stay, illustrates how ambient journalists might perceive something new in specific circumstances (Tamm 131; Sheppard 186-188). More tellingly, this background informed his collaboration with the late painter Peter Schmidt, to co-create the Oblique Strategies deck of aphorisms: aleatory, oracular messages that appeared dependent on chance, luck, and randomness, but that in fact were based on Eno and Schmidt’s creative philosophy and work guidelines (Tamm 77-78; Sheppard 178-179; Reynolds 170). In short, Eno was engaging with the kind of reflective practices that underpin exemplary professional journalism. He was able to encode this craft and skills into a quasi-experimental method, rather than a technological solution. Journalists and practitioners who adopt Hermida’s framework could learn much from the published accounts of Eno’s practice-based research, in the context of creative projects and collaborative teams. In particular, these detail the contexts and choices of Eno’s early ambient music recordings (Sheppard 199-200); Eno’s duels with David Bowie during ‘Sense of Doubt’ for the Heroes album (Tamm 158; Sheppard 254-255); troubled collaborations with Talking Heads and David Byrne (Reynolds 165-170; Sheppard; 338-347, 353); a curatorial, mentor role on U2’s The Unforgettable Fire (Sheppard 368-369); the ‘grand, stadium scale’ experiments of U2’s 1991-93 ZooTV tour (Sheppard 404); the Zorn-like games of Bowie’s Outside album (Eno 382-389); and the ‘generative’ artwork 77 Million Paintings (Eno 330-332; Tamm 133-135; Sheppard 278-279; Eno 435). Eno is clearly a highly flexible maker and producer. 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