Journal articles: '665.7.038.5 (043.5)'

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Semenova, Lioubov I., and Allan H. White. "Structural Systematics of Rare Earth Complexes. XIX (Hydrated) 1 : 2 Mononuclear Adducts of Lanthanoid(III) Chlorides with 2,2′-Bipyridine and 1,10-Phenanthroline." Australian Journal of Chemistry 52, no. 6 (1999): 571. http://dx.doi.org/10.1071/ch98052.

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Room-temperature single-crystal X-ray structure determinations are recorded for a number of adducts of hydrated lanthanoid(III) trichlorides with 2,2′-bipyridine (‘bpy’) and 1,10-phenanthroline (‘phen’), crystallized from water, methanol or ethanol solutions, containing mononuclear arrays with 1 : 2 Ln/bpy or phen stoichiometry. LaCl3/phen/H2O(1 : 3 : 9), [(phen)2La(OH2)5]Cl3.phen.4H2O, although of overall 1 : 3 LaCl3/phen stoichiometry, has a lattice phen; it is orthorhombic, Pnna, a 19·947(7), b 16·457(5), c 12·213(2) Å, Z = 4; conventional R on |F| was 0·030 for No 2567 ‘observed’ (I >3σ(I)) diffractometer reflections. LaCl3/phen/H2O/MeOH (1 : 2 : 6 : 1), [(phen)2La(OH2)5]Cl3.H2O.MeOH, is triclinic, P 1, a 19·060(3), b 9·252(3), c 8·994(3) Å, α 69·33(3), β 86·81(2), γ 89·66(2)°, Z = 2, R 0·037 for No 5452. LaCl3/bpy/H2O (1 : 2 : 6), [(bpy)2La(OH2)4Cl]Cl2.2H2O, is monoclinic, P 21/c, a 19·389(3), b 9·071(1), c 16·873(2) Å, β 114·10(1)°, Z = 4, R 0·029 for No 4699. All three of these complexes have a nine-coordinate [(N,N′-bidentate)2La(unidentate)5] coordination environment with quasi-2 symmetry; that of the remaining compounds following is eight-coordinate [(N,N′-bidentate)2Ln(unidentate)4]. LuCl3/phen/H2O (1 : 2 : 6), [(phen)2Lu(OH2)4]Cl3.2H2O, is monoclinic, C 2/c, a 11·045(7), b 17·660(6), c 14·474(9) Å, β 92·82(5)°, Z = 4, R 0·042 for No 1695, the Lu lying on a crystallographic 2 -axis. Crystals of LnCl3/phen/H2O(1 : 2 : 4), [(phen)2Ln(OH2)3Cl]Cl2.H2O (Ln = Dy, Er, Y), are triclinic, P 1, a≈ 12·6, b ≈ 10·5, c ≈ 10·4 Å, α ≈ 93·3, β ≈ 109·3, γ ≈ 96·8°, Z = 2, R 0·030, 0·040, 0·052 for No 4221, 5100, 2690 respectively. PrCl3/bpy/H2O/EtOH (1 : 2 : 1 : 0·5), [(bpy)2Pr(OH2)Cl3].½EtOH, is triclinic, P 1, a 13·331(3), b 10·734(2), c 9·758(2) Å, α 63·67(2), β 78·99(2), γ 71·24(2)°, Z = 2, R 0·033 for No 4596, while [(bpy)2Pr(OH2)2Cl2]Cl is monoclinic, C 2/c, a 15·921(15), b 11·314(8), c 14·114(8) Å, β 116·70(6)°, Z = 4, R 0·041 for No 2269. ErCl3/bpy/H2O(1 : 2 : 2 (also)), [(bpy)2Er(OH2)2Cl2]Cl, is cubic, I 23, a 26·032(4) Å, Z = 24, R 0·066 for No 1644. Crystals of LnCl3/phen/H2O/MeOH (1 : 2 : 1 : 1), [(phen)2Ln(OH2)Cl3].MeOH (Ln = La, Pr, Nd, Eu), are monoclinic, P 21/a, a ≈ 13·2, b ≈ 10·7, c ≈ 18·5 Å, β ≈ 102·1°, Z = 4, R 0·054, 0·032, 0·040, 0·054 for No 2872, 4792, 3179, 2847 respectively. LnCl3/bpy/H2O/EtOH (1 : 2 : 1 : 1), [(bpy)2Ln(OH2)Cl3].EtOH (Ln = Nd, Eu), are triclinic, P 1, a ≈ 11·3, b ≈ 10·9, c ≈ 10·4 Å, α ≈ 75·5, β ≈ 89·8, γ ≈ 78·0°, Z = 2, R 0·044, 0·056 for No 4979, 3596 respectively. LaCl3/bpy/EtOH (1 : 2 : 0·5) is binuclear [(bpy)2Cl2La(µ-Cl)2LaCl2(bpy)2].EtOH, monoclinic, P 21/c, a 9·6878(2), b 17·5696(3), c 16·1341(2) Å, β 123·10(1)°, Z = 2, R 0·033 for No 4256. A totally unsolvated array is found for YbCl3/bpy (1 : 2), [(bpy)2YbCl3], monoclinic, P 21/c, a 15·065(8), b 8·598(4), c 16·92(1) Å, β 112·46(5)°, Z = 4, R 0·032 for No 3548, in which, alone, the metal atom is seven-coordinate.

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Effendy, Warren J. Grigsby, Robert D. Hart, Colin L. Raston, Brian W. Skelton, and Allan H. White. "Structural Characterization of Some Novel Oxidation Products of Triphenylstibine." Australian Journal of Chemistry 50, no. 6 (1997): 675. http://dx.doi.org/10.1071/c96042.

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Room-temperature single-crystal X-ray structural characterizations of two oxidation products of triphenylstibine of the form XPh3SbOSbPh3X are recorded for X = Cl, NO3. ClPh3SbOSbPh3Cl is monoclinic, P 21/c, Z = 4 f.u., a 9·109(4), b 19·809(8), c 19·30(2) Å, β 109·27(5)°, conventional R on F being 0·038 for No 4431 ‘observe’ (I > 3σ(I)) independent reflections. In this complex, Sb-O-Sb is quasi-linear, 173·1(3)°, in contrast to the previously recorded benzene solvate, in which it is 139·0(3)°; in the nitrate, [(O2NO)Ph3SbOSbPh3(ONO2)], triclinic, P-1, Z = 2 f.u., a 15·609(5), b 13·238(4), c 10·140(2) Å, α 87·11(2), β 88·46(7), γ 72·93(2)°, R 0·036 for No 5275, it is also bent (137·0(2)°). The anionic substituent is opposed to the oxo bridge in the trigonal bipyramidal five-coordinate array about the metal in both complexes. A redetermination of the structure of Ph8Sb4O6 is recorded, presenting a non-disordered model in a triclinic P-1 cell, a 19·98(3), b 11·635(2), c 9·739(2) Å, α 92·28(1), β 98·98(1), γ 99·74(1)°, Z = 2 f.u., R 0·046 for No 3578. A new (‘β’) phase of triphenylstibine, crystallized from hexane/toluene is also recorded: monoclinic, P 21/c, a 15·386(8), b 11·304(5), c 19·078(8) Å, β11·64(4)°, Z = 8, R 0·045 for No 3393.

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Álvarez-Reguera, C., J. J. Gaitán-Valdizán, R. Fernández-Ramón, R. Demetrio-Pablo, J. L. Martín-Varillas, L. Sanchez-Bilbao, D. Martínez-López, I. González-Mazón, M. Á. González-Gay, and R. Blanco. "POS0740 EPIDEMIOLOGY AND CLINICAL FEATURES OF OCULAR SARCOIDOSIS. STUDY OF 65 PATIENTS OF A SERIES OF 384 PATIENTS FROM A SINGLE UNIVERSITY HOSPITAL." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 621.2–622. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1930.

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Background:Ocular involvement in sarcoidosis can be present in up to 80% of patients. If not treated, it can lead to significant visually complications (1-5).Objectives:Our aim was to assess the main a) epidemiology and b) clinical features of ocular sarcoidosis in a wide and unselected series from a single university hospital.Methods:Study of a large cohort (n=384) of all consecutive patients diagnosed with sarcoidosis from January 1, 1999 to December 31, 2019. Finally, 344 patients were included according to the ATS/ERS/WASOG criteria (Eur Respir J. 1999;14:735-7).Results:65 (33 men/32 women) of 344 (18.9%) patients had ocular involvement. Mean age at diagnosis was 45.6±15.9 years. The most frequent extraocular clinical clusters were respiratory (80%), osteoarticular (30.8%) and cutaneous (29.2%) (figure 1). Ocular manifestations and complications are shown in table 1. Uveitis (83.1%), orbital lesions (7.7%) and retinal vasculitis (6.2%) were the most common ocular lesions. Median Best Corrected Visual Acuity (BCVA) at diagnosis and after one year of follow-up was 0.6 [0.3-0.8] and 0.9 [0.30-1], respectively. Retinal vasculitis was associated to the worst BCVA outcome, and panuveitis to more frequent and severe complications.Conclusion:Ocular manifestations, especially uveitis, are frequent in sarcoidosis. A more aggressive and early treatment may be indicated in panuveitis and retinal vasculitis.References:[1]Riancho-Zarrabeitia L, et al. Semin Arthritis Rheum 2015;45:361-8.[2]Riancho-Zarrabeitia L et al. Clin Exp Rheumatol 2014; 32:275-84.[3]Vegas-Revenga N, et al. Am J Ophthalmol 2019; 200:85-94.[4]Calvo-Río V, et al. Clin Exp Rheumatol 2014; 32 (4 Suppl 84): S54-7. Epub 2014 Jul 8.[5]Cordero-Coma et al. Mediators Inflamm. 2014; 2014:717598.Figure 1.Clinical clusters of associations in ocular sarcoidosis.Table 1.Ocular manifestations and associated complications after 1 year of follow-up of 65 patients with ocular sarcoidosis.Type of ocular affectationN (%)Median BCVA at onset[IQR]Median BCVA after 1 year of follow-up[IQR]CataractN (%)OPN (%)OHTN (%)CMEN (%)ERMN (%)Uveitis, pattern54 (83.1)0.6 [0.3-0.8]0.9 [0.6-1]18 (27.7)11 (16.9)7 (10.8)7 (10.8)8 (12.3)Anterior31 (47.7)0.7 [0.3-0.8]0.8 [0.5-1]13 (41.9)2 (6.5)2 (6.5)2 (6.5)2 (6.5)Panuveitis16 (24.6)0.4 [0.2-0.7]0.9 [0.5-1]5 (31.3)7 (43.8)4 (25)5 (31.3)5 (31.3)Posterior5 (5.2)0.5 [0.1-0.9]0.9 [0.9-1]02 (40)1 (20)00Intermediate2 (3.1)0.50.700001Orbitary lesions5 (7.7)0.5 [0.1-0.6]1 [0.1-1]1 (20)01 (20)00Retinal vasculitis4 (6.2)0.6 [0.5-0.8]1 [0.6-1]00001 (25)Dry eye4 (6.2)10.900000Scleritis10.61.000000Abbreviations: BCVA: Best corrected visual acuity; CME: Cystoid macular edema ERM: Epiretinal membrane; OP: Optic Papillitis; OHT: Ocular hypertension.Disclosure of Interests:Carmen Álvarez-Reguera: None declared, Jorge Javier Gaitán-Valdizán: None declared, Raúl Fernández-Ramón: None declared, Rosalía Demetrio-Pablo: None declared, José Luis Martín-Varillas: None declared, Lara Sanchez-Bilbao: None declared, David Martínez-López: None declared, Iñigo González-Mazón: None declared, Miguel Á. González-Gay Speakers bureau: Abbvie, Pfizer, Roche, Sanofi and MSD., Grant/research support from: Abbvie, MSD, Janssen and Roche., Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myer, Janssen, Lilly and MSD., Grant/research support from: Abbvie, MSD and Roche.

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Curtis, Neil F., Olga P. Gladhikh, Keith R. Morgan, and Sarah L. Heath. "A Centrosymmetrical Di-thiolato-bridged Dinuclear Nickel(II) Compound; Bis-µ-S-(7-amino-2,4-dimethyl-5-azahept-4-ene-2-thiolato)dinickel(II) Perchlorate." Australian Journal of Chemistry 51, no. 1 (1998): 49. http://dx.doi.org/10.1071/c97005.

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The title compound, formed by reaction of 4-mercapto-4-methylpentan-2-one with bis(ethane-1,2-diamine)nickel(II) perchlorate, has a centrosymmetrical dinuclear cation. Each singlet ground-state nickel(II) ion is in tetrahedrally twisted square-planar coordination by the primary amine and imine nitrogen atoms and the thiolato sulfur atom of one molecule of 7-amino-2,4-dimethyl-5-azahept-4-ene-2-thiolate (adet¯), and the sulfur atom of another molecule, with the sulfur atoms of two ligands forming a planar Ni2S2 bridging group {[Ni2-µ-(adet)2] (ClO4)2, C16H34C12N4Ni2O8S2, Mr 662·9, monoclinic, P21/c, a 8·267(1), b 9·952(1), c 16·234(2) Å, β 103·010(2)°, R1 0·033 for 2531 reflections}.

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Duarte, Rafael F., Julio Delgado-Gonzalez, Bronwen E. Shaw, David Wrench, Mark Ethell, David Patch, Amar P. Dhillon, Stephen Mackinnon, Michael Potter, and Alberto F. Quaglia. "Pathologic Features May Predict the Clinical Outcome of Hepatic Graft Versus Host Disease (H-GVHD)." Blood 104, no. 11 (November 16, 2004): 5079. http://dx.doi.org/10.1182/blood.v104.11.5079.5079.

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Abstract Liver histology is regarded as inadequate for grading the severity of H-GVHD. Thus, liver biopsies (LB) are only performed to rule out other causes of liver injury when the results may lead to a radical therapeutic change. In this study we reviewed the pathologic features in LB from 33 consecutive evaluable patients with at least one LB, confirmed diagnosis of H-GVHD and no other concomitant causes of liver dysfunction. We asked whether the pathologic features in the first LB may predict their clinical outcome. Underlying diseases were AML (9), ALL (8), CML (7), MM (4), MDS (3), NHL (1) and AA (1). H-GVHD developed after BM (15) or PB (11) allo-HSCT, or DLI (7). Twenty-eight donors were related and 5 unrelated, 30 HLA-matched and 3 mismatched. All patients received myeloablative TBI-based (31) or chemotherapy only (2) conditioning regimens, and GVHD prophylaxis with cyclosporine-methotrexate (21) or T-cell depletion (12). The onset was acute in 22 (median day 35, range 5–86) and chronic in 11 (median day 139, range 103–545). The median overall survival (OS) from the onset of liver dysfunction was 6.2 months, with a non-relapse mortality (NRM) of 73.2% at 1 year (CI95=50.2–96.2). The causes of NRM were infection (8), liver failure (3), hemorrhage (3) and others (4). The first LB was performed at a median of 14 days (4–68) from the onset of abnormal liver function tests. The commonest pathologic finding in this series was bile duct damage, but ductopenia was uncommon (4). Neither the presence nor the degree of bile duct damage associated with the clinical outcome. Lobular inflammation (LI) was present in 25 cases (grade 1: 16; grade 2: 6; grade 3: 3). Higher degree of LI in the first LB associated with a reduced NRM (P=.001) and improved OS (P<.001). Patients with LI grades 2/3 had higher median OS than those with grades 0/1 (not-reached vs 4.3 months; P=.012), and were more likely to respond to primary treatment (RPT) with steroids (P=.044), the most important clinical prognostic factor for OS in our series (HR=4.3; P=.001). Presentation of H-GVHD as hepatitis, with markedly increased aminotransferases levels, has been reported, in particular after DLI. In our group, there was no association between DLI-induced H-GVHD and LI, or between LI and aminotrasferases peak or biopsy-time levels. No study to date has shown that LI in the LB associated with clinical outcome in H-GVHD. In liver transplantation however, a histologically documented lobular hepatitic phase has been shown to anticipate ductopenia in chronic rejection, and associate with good response to treatment. In addition to LI, hepatocyte ballooning (HB) was associated with NRM (P=.003) and OS (P=.018) in our series. Patients with HB grades 0/1 had higher median OS than those with grades 2/3 (6.5 months vs 1.3 months; P=.004). HB did not associate with RPT. In multivariate analysis the effects of LI and HB on NRM (HR=5.1, P=.033; and HR=5.5, P=. 018, respectively) and OS (HR=4.0, P=.032; and HR=4.2, P=.037, respectively) remained significant. All other pathologic features examined had no association with patient clinical outcome. Our results suggest that LI and HB in the first diagnostic LB from patients with H-GVHD may predict the probability of RPT, NRM and OS. These results should be considered in the indications of LB and the selection of candidate patients with H-GVHD for new experimental therapies and in the design of future trials. Prospective validation of our findings is under way.

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Joh, Jae Won, Angel Callejas, Wendy Wong, Harvey Joel Cohen, Kari Nadeau, and Michael Jeng. "Role of Fas/FasL Pathway in Pediatric Idiopathic Neutropenia." Blood 110, no. 11 (November 16, 2007): 3291. http://dx.doi.org/10.1182/blood.v110.11.3291.3291.

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Abstract Idiopathic neutropenia in children is marked by low neutrophil counts (<1500/ul) circulating in the peripheral blood in patients whose disease spontaneously develops unrelated to drugs, cancers, specific antibodies, or known genetic deficiencies. Neutrophils, PBMCs and plasma were purified/obtained from 24 subjects (n=17 acute and n=7 chronic) with idiopathic neutropenia, aged 3 months to 11 yrs. After screening a number of cytokines (IL-2, IL-4 IL-6, IL-8, IL-10, IFN-γ, TNF-α), growth factors (GCSF), cell death factors (Fas, FasL, Granzymes/Perforin), and chemokines (CCL5, XCL1, XCR1), QT-PCR studies of neutropenic subjects’ neutrophils indicated an up-to-14-fold increase in Fas transcripts compared to age-matched healthy control neutrophils. FACS analysis on patient neutrophils demonstrated increased expression of Fas (93%+/− 15%) compared to healthy control neutrophils (41%+/−11%). No increase in Fas surface expression was seen on PBMCs or on CD4+T cells from neutropenia patients compared to healthy controls. Studies of patient plasma showed increased FasL in acute and chronic patients (up to 40-fold higher). Increased IL-6 and IL-10 levels in plasma were another distinctive characteristic of neutropenic patients. Healthy control neutrophils incubated in neutropenic patient plasma for 4 hrs showed greater rates of apoptosis (evaluated by PI/Annexin; up to 38-fold higher) compared to incubation with healthy control plasma. Heat denaturation, IgG exclusion, and size separation studies suggest that the killing factor(s) is a heat-sensitive protein which is not IgG and has a MW between 35 and 100 kD. Blocking with anti-FasL antibodies incubated with patient plasma caused a statistically significant 5-fold to 11-fold decrease in neutrophil apoptosis, approaching the rates of healthy controls, implicating FasL as a major mediator of neutrophil regulation. Thus, the Fas/FasL pathway may play an important role in idiopathic neutropenia. Patient number Chronicity Age FasL (pg/ml) Anti-neutrophil Ab Fold increase in neutrophil death over control plasma Fold increase in apoptosis over control plasma 1 chronic 2 yrs 7±1 positive 6.5±0.7 8.5±0.8 2 chronic 18 mo. 6±1 positive 7.3±0.5 8.1±0.2 3 chronic 23 mo. 5±0.5 wk positive/neg 7.8±0.6 8.5±0.4 4 chronic 1 yr 5±2 positive 6.5±0.5 7.3±0.6 5 chronic 5 yrs 7±1 wk positive 6.1±0.9 2.7±0.2 6 chronic 20 mo. 10±1 negative 11.3±1.4 2.1±0.5 7 chronic 11 mo. 6±1 negative 6.1±0.8 5.7±0.6 8 acute 2 yrs 16±2 N/A 18.7±1.3 22.4±2.9 9 acute 2 yrs 18±3 negative 12.0±2.1 19.1±2.5 10 acute 5 yrs 4±1 negative 2.5±0.5 2.6±0.4 11 acute 11 mo. 3±0.6 N/A 1.5±0.3 2.1±0.2 12 acute 3 yrs 17±1 negative 15.3±1.2 19.2±0.8 13 acute 2 yrs 40±3 negative 22.9±1.4 38.4±2.4 14 acute 2 yrs 21±2 N/A 14.3±1.0 20.5±1.2 15 acute 8 mo. 10±0.9 N/A 9.6±0.8 12.0±1.6 16 acute 17 mo. 19±3 negative 21.3±2.2 26.7±3.5 17 acute 6 yrs 8±1 N/A 6.7±1.3 11.5±2.1 18 acute 3 yrs 9±2 N/A 7.2±2.6 8.8±1.5 19 acute 11 yrs 12±2 negative 14.8±0.9 17.4±1.9 20 acute 5 yrs 6±1 negative 3.4±0.6 5.2±0.7 21 acute 4 mo. 8±2 N/A 6.2±1.0 8.1±2.2 22 acute 3 mo. 27±3 N/A 21.4±3.5 39.4±2.4 23 acute 11 yrs 22±1 negative 17.2±3.0 24.3±2.8 24 acute 2 yrs 18±2 positive 15.8±1.2 25.0±1.7 Representative control N/A 4 yrs 1.3±0.4 N/A 1.2±0.3 0.8±0.4

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SACAR, S., S. SAYIN KUTLU, H. TURGUT, N. CEVAHIR, D. HIRCIN CENGER, and K. TEKIN. "Epidemiology and associated factors for nosocomial methicillin-resistant Staphylococcus aureus infection in a tertiary-care hospital." Epidemiology and Infection 138, no. 5 (November 2, 2009): 697–701. http://dx.doi.org/10.1017/s0950268809991063.

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SUMMARYWe analysed nosocomial MRSA cases between January 2004 and December 2006 in a retrospective case-control study in a 250-bed tertiary-care teaching hospital. During the study period, 265 nosocomial Staphylococcus aureus infections were identified in 231 patients. There was a significant increase in methicillin resistance in isolates (MRSA) from these infections with frequencies for 2004 of 39/88 (44·3%), 2005 (62/80, 77·5%), and 2006 (75/97, 77·3%) (P<0·001). Multivariate analysis showed that associated factors for nosocomial MRSA infection were prolonged hospitalization (OR 3·982, 95% CI 2·235–7·094, P<0·001), mechanical ventilation (OR 3·052, 95% CI 1·666–5·590, P<0·001), surgical operation (OR 2·032, 95% CI 1·102–3·748, P=0·023), and male sex (OR 2·000, 95% CI 1·081–3·699, P=0·027). The determination of associated factors for methicillin resistance in nosocomial S. aureus infections in hospitals will play an important role in efforts to reduce MRSA infection rates.

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Semenova, Lioubov I., Brian W. Skelton, and Allan H. White. "Structural Systematics of Rare Earth Complexes. XVIII (Hydrated) Mononuclear 1 : 1 Adducts of Lanthanoid(III) Chlorides with 2,2′-Bipyridine." Australian Journal of Chemistry 52, no. 6 (1999): 551. http://dx.doi.org/10.1071/ch98049.

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Room-temperature single-crystal X-ray structure determinations are recorded for a number of adducts of hydrated lanthanoid(III) chlorides with 2,2′-bipyridine, ‘bpy’, crystallized from water/ethanol solutions, which contain mononuclear arrays with 1 : 1 Ln/bpy stoichiometry. Extended isomorphous series have been defined pertinent to the heavy end of the Ln series: crystals of LnCl3/bpy/H2O (1 : 1 : 6) ([(bpy)Ln(OH2)6]Cl3), seemingly inclusive of (at least) the range Ln = Ho(-)Lu and Y, are monoclinic, P 21/n, a ≈ 14·2, b ≈ 7·7, c ≈ 17·4 Å, β ≈ 91°, Z = 4, with an eight-coordinate LnN2O6 array; conventional R values on |F| were 0·043, 0·029, 0·057 for No 2435, 3120, 1846 independent ‘observed’ (I > 3σ(I)) diffractometer reflections (Ln = Ho, Lu, Y). Crystals of LnCl3/bpy/H2O (1 : 1·5 : 8) ([(bpy)Ln(OH2)6]Cl3.½bpy.2H2O), seemingly encompassing (at least) the range Ln = Er(-)Lu and Y, are triclinic, P 1, a ≈ 11·7, b ≈ 11·0, c ≈ 10·1 Å, α ≈ 85·8, β ≈ 74·7, γ ≈ 79·5°, Z = 2, R 0·038, 0·033, 0·048 for No 3897, 4377, 3130, and contain similar [(bpy)Ln(OH2)6]3+ cations as does HoCl3/bpy/H2O (1 : 2 : 7), [(bpy)Ho(OH2)6]Cl3.bpy.H2O, orthorhombic, Pbca, a 18·02(2), b 20·06(2), c 15·051(9) Å, Z = 8, R 0·057 for No 3009. By contrast, only sporadic, diverse and unrelated forms are thus far defined among the lighter Ln: EuCl3/bpy/H2O(1 : 1 : 5) ([(bpy)Eu(OH2)4Cl2]Cl.H2O), triclinic, P 1, a 11·506(7), b 11·098(5), c 6·974(8) Å, α 77·35(7), b 85·1(1), γ 89·54(4)°, Z = 2, R 0·063 for No 4633, also contains a mononuclear [(N,N′-bidentate)Ln(unidentate)6] array. PrCl3/bpy/H2O(1 : 1 : 3)(× 4) is a remarkable compound, being 2[(bpy)Pr(OH2)3Cl3] [(bpy)(H2O)2Cl2Pr(µ-Cl)2PrCl2(OH2)2(bpy)].2H2O, triclinic, P 1, a 13·490(4), b 11·121(2), c 10·162(1) Å, α 96·06(1), β 90·08(2), γ 96·43(2)°, Z = 2 f.u., R 0·045 for No 4127, with a mononuclear species of PrCl3/bpy/H2O (1 : 1 : 3) stoichiometry and a binuclear species of 1 : 1 : 2 stoichiometry. A binuclear ethanol solvated array has been characterized for LaCl3/bpy/EtOH (1 : 1 : 2) [(bpy)(EtOH)2Cl2La(µ-Cl)2LaCl2(HOEt)2(bpy)], with eight-coordinate lanthanum; this complex is triclinic, P 1, a 11·426(8), b 10·673(7), c 10·453(7) Å, α 109·60(5), β 113·10(5), γ 105·80(5)°, Z = 1 dimer, R 0·046 for No 2786.

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Gómez-Seguí, Inés, Bartlomiej P. Przychodzen, Kenichi Yoshida, Matthew Ruffalo, Andres Jerez, Hideki Makishima, Satoru Miyano, et al. "Mutational Spectrum of Myelodysplastic Syndrome Malignancies Revealed by Whole Exome Sequencing." Blood 120, no. 21 (November 16, 2012): 307. http://dx.doi.org/10.1182/blood.v120.21.307.307.

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Abstract Abstract 307 Whole-exome (WES) sequencing revealed tremendous mutational heterogeneity in leukemia. While WES can be applied for discovery, it also has potential as a diagnostic tool that can overcome the shortcomings of current methods. We theorized that, in addition to mutation discovery, systematic application of WES in MDS may reveal distinct mutational patterns allowing for new molecular classification. We performed WES in 116 paired exomes, including MDS (n=57), MDS/MPN (n=36), and sAML (n=23). We also included comparative analysis with pAML (N=202; TCGA), and other publicly available data for a total of 333 exomes; 10 patients were studied serially. Paired DNA (marrow/CD3+ cells) was subjected to WES, sequence-aligned by BW Aligner, and variants detected via GATK pipeline (Broad Institute). We used defined criteria to minimize false-positives: P<.001 tumor/control, alterations ≥10% of total tumor reads, <25% in germline, >5% prevalence, and not found in ex/internal SNP databases. This narrowed the spectrum to 645 mutations (54 genes) for analysis with clinical/phenotypic correlations. Mutations were isolated or grouped by pathway, e.g., PRC2, cohesin complex, plexins and dyneins, etc. In MDS, examples of prevalent mutations include SF3B1 (14%), DNMT3A (11%) and U2AF1/2 (9%). In MDS/MPN: TET2 (36%), SRSF2 (22%) and ASXL1 (19%) and SETBP1 (6%); in sAML: NRAS/RAS (16%), RUNX1 (16%) and cohesin mutations (12%), in contrast to pAML with mutational spectrum dominated by FLT3, DNMT3A, NMP1 or SMC3/1A (cohesin complex). The exome panel did not cover 20% patients, suggesting that their pathogenesis may be related to less recurrent events (613 candidates: 2nd screening phase). When mutational spectrum of sAML vs pAML were compared, mutants of SF3B1 (7 vs 1%, P=.04), BCOR (7 vs 1%, P=.04), CDH11/23 (13 vs. 1%, P=.003), FMN2 (7 vs. 1%, P=.04), PPFIA2 (7% vs 0%, P=.01), SPTAN1 (7% vs 0%, P=.01) and VPS8 (7 vs 0%, P=.017) were more frequent in sAML while DNMT3A and NPM1 were less common. Analysis of MDS/MPN revealed mutations in PRC2 (2 vs 11%, P=.05), SRSF2 (5 vs. 22%, P=.010) and TET2 (3 vs. 33%, P<.001) more frequent than in MDS. Mutations in SF3B1 were more recurrent in low/Int-1 IPSS categories compared to Int-2/high/sAML (21 vs. 3%, P=.01), in which mutations in N/KRAS (0 vs. 14%, P=.01) and TP53 (0 vs. 14%, P=.01) were more frequent. Functional group comparisons revealed that lesions in epigenetic (56 vs 23%, P=.001) and signal transduction genes (36 vs 9%, P=.001) were more prevalent in MDS/MPN compared to MDS in which they accumulated according to risk (high vs low: 36 vs 5%, P=.001 or 52% in pAML). Spliceosomal mutations were overrepresented in MDS/MPN vs MDS (58 vs 37%, P=.031), in sAML vs pAML (23 vs 9%, P=.032), and in low risk vs high risk cases (45 vs 22%, P=.02). Cytoskeleton organization gene mutations were overrepresented in sAML vs pAML (39 vs 13%, P=.001). TSG were more frequent in high-risk vs low-risk MDS (30 vs 5%, P=.003). Moreover, TET2 mutations coincided with SRSF2 and PRC2 mutations (P<.001 and P=.010); DNMT3 mutations with SF3B1 and BCOR (P=.04 and P=.004); SRSF2 with ASXL1 (P=.017); RUNX1 with cohesin and BCOR (P=.003 and P=.04), CBL mutations with PRPF8 and ASXL1 (P=.04 or P=.003); TP53 with PRPF8 (P=.04). After analyzing survival impact of individual mutations, functional groups, cytogenetic category and clinical parameters, we found TP53, ETV6, PRPF8, FMN2, UMODL1, KIT, GATA2, complex karyotype and chr. 5 anomalies had a prognostic impact on OS. However, in multivariate analyses, the first variable to stratify our cohort was, as expected, the diagnosis subtype (HR 2.2, P<.001), but also mutations in PRPF8 (HR 5.4, P=.004). In MDS and grouped MDS/MPN, significant variables included KIT (HR 12, P=.022) and TP53 mutations (HR 3.6, P=.045). Apart from traditional analyses, we also applied a recursive partitioning algorithm to construct an unbiased survival tree encompassing every mutation: e.g., PRPF8, CSMD1, U2AF2, IDH2, PPFIA2, SF3B1 and NRAS showed the highest difference in OS with this method. In sum, mutational spectrum of myeloid neoplasms can be assessed with WES. The pattern of frequency and concurrence in each diagnostic subtype differs substantially, a feature that can be exploited diagnostically. Despite heterogeneity, mutations and their combinations can be found to categorize patients and serve as prognostic markers. Analysis of additional cases is ongoing and will be presented at the meeting. Disclosures: Makishima: Scott Hamilton CARES Initiative: Research Funding. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.

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Pagnamenta, Alberto, Céline Dewachter, Kathleen McEntee, Pierre Fesler, Serge Brimioulle, and Robert Naeije. "Early right ventriculo-arterial uncoupling in borderline pulmonary hypertension on experimental heart failure." Journal of Applied Physiology 109, no. 4 (October 2010): 1080–85. http://dx.doi.org/10.1152/japplphysiol.00467.2010.

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Pulmonary hypertension on heart failure (HF) limits exercise capacity and survival probably because of associated right ventricular (RV) failure. This study investigated the mechanisms of RV function adaptation to early pulmonary hypertension in experimental HF. Seven weeks of rapid ventricular pacing in six dogs induced a HF characterized by cardiomegaly and decreased left ventricular ejection fraction. Compared with eight control dogs, pulmonary hypertension was borderline, with a mean pulmonary artery pressure increased to only 23 ± 2 (means ± SE) mmHg. However, the pulmonary vascular impedance spectrum was globally shifted to higher pressures, with an increase in 0 Hz impedance (resistance) to 662 ± 69 vs. 455 ± 41 dynes·cm−5·m2 in controls ( P < 0.01) and in characteristic impedance to 183 ± 20 vs. 104 ± 7 dynes·cm−5·m2 in controls ( P < 0.01). There was no change in RV end-systolic elastance (Ees), but arterial elastance (Ea) was increased to 1.8 ± 0.3 vs. 0.9 ± 0.1 mmHg/ml in controls so that RV-arterial coupling defined by the Ees-to-Ea ratio (Ees/Ea) was decreased to 0.8 ± 0.1 vs. 1.5 ± 0.1 in controls ( P < 0.01). Inhaled nitric oxide, 40 ppm or 5 μg·kg−1·min−1 nitroprusside iv, did not affect Ees/Ea. Fifty milligrams (iv) of milrinone increased Ees/Ea to 1.6 ± 0.2 by an isolated increase in Ees. We conclude that overpacing-induced HF is accompanied by a borderline pulmonary hypertension but profound RV-arterial uncoupling explained by the failure of RV systolic function to adapt combined effects of increased pulmonary arterial resistance and elastance.

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Smith, Geoffrey B., and A. G. Wollum II. "Physicochemical and D-galactose-mediated interactions in the attachment of Bradyrhizobium japonicum to roots of Glycine max." Canadian Journal of Microbiology 39, no. 2 (February 1, 1993): 245–51. http://dx.doi.org/10.1139/m93-034.

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The roles of electrostatic, hydrophobic, and lectin-mediated interactions in the attachment of Bradyrhizobium japonicum to soybean (Glycine max [L.] Merr.) seedling roots were examined. Cell suspensions (104 cfu/mL) of B. japonicum strain USDA 110 were exposed to excised root segments during 2-h adhesion assays. The presence of the specific hapten for the soybean seed lectin, the sugar N-acetyl-D-galactosamine (GalNac), did not inhibit attachment, but D-galactose did (29% of untreated control). Some D-galactose inhibition (69% of control) was observed when the bacteria were preincubated in the presence of the sugar before the attachment assay but not when the roots were preincubated. Attachment was pH dependent, reaching maximum values between pH 6.0 and 6.5. The polycations DEAE-dextran and poly-L-lysine stimulated adhesion 12- and 5-fold to excised root segments, respectively; DEAE-dextran caused a 7-fold attachment stimulation to intact seedling roots. Segregation of bacterial cells into hydrophobic and nonhydrophobic fractions by preexposure to polystyrene did not affect attachment to roots, nor did the presence of two detergents, sodium dodecyl sulfate and Tween 80. These results indicate that hydrophobic interactions are not involved in the attachment, but anionic repulsion may limit attachment between B. japonicum cells and G. max roots (both surfaces are negatively charged at the assay medium pH of 6.3). The attachment is not via the GalNac-specific soybean lectin but apparently is mediated by a D-galactose-binding moiety located on the bacterial cell surface.Key words: bradyrhizobia, attachment, bacterial lectins, polycations

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Rivera Teran, V., D. Alpizar-Rodriguez, S. Sicsik, F. Irazoque-Palazuelos, D. Miranda, D. Vega-Morales, J. C. Casasola, et al. "FRI0546 GENDER DIFFERENCES OF RHEUMATIC DISEASES IN MEXICAN POPULATION: DATA FROM THE MEXICAN BIOLOGICS REGISTRY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 874–75. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6091.

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Background:Most autoimmune diseases are more prevalent in women. Symptom severity, disease progression, response to therapy and overall survival differ between males and females with rheumatic diseases.Objectives:To identify the characteristics of autoimmune diseases presentation and treatment between male and female population using information from the Mexican Adverse Events Registry (BIOBADAMEX).Methods:BIOBADAMEX is a Mexican ongoing cohort that collects the information of patients using biologic and biosimilar drugs since 2016. For this study we included all patients enrolled in the registry and compared baseline clinical and disease characteristics, treatment and presence of adverse events between genders. We used logistic regression to analyze univariable associations.Results:A total of 655 participants were analysed, of which 82% were female (Table 1). We found women were older with a median of 53 years compared to 46 years in men (OR 1.02, CI 1.0-1.1). Smoking was higher in men (16%) compared to women (5%), (OR 0.3, CI 0.2-0.6). Women had longer disease duration, 9 years compared to 7 years in men (OR 1, CI 1.0-1.1). Rheumatoid arthritis (RA) was more prevalent in women (OR 2.7, CI 1-6.9), while ankylosing spondylitis (AS) and psoriatic arthritis (PsA) were more prevalent in men (OR 0.2, CI 0.1-0.4, and OR 0.3, CI 0.1-0.9 respectively). Women had more comorbidities than men (OR 1.8, CI 1.1-2.8) and used steroids more frequently (OR 1.7, CI 1.1-2.7). Differences in disease activity were not found, however we noticed high activity scores among participants.Table 1.Baseline characteristics in the cohort by sexWomenn=532 (82%)Menn=123 (18%)UnivariableaOR(95%CI)Age, median (IQR)53 (44-60)47 (34-55)1.02 (1.0-1.1)*Body Mass Index, median (IQR)27 (23-31)26 (23-30)1.0 (0.9-1.1)Smoking, n(%)28 (5)18 (16)0.3 (0.2- 0.6)*Disease duration, median (IQR)9 (4-16)7 (2-13)1.0 (1.0-1.1)*Diagnosis, n(%): RA414 (78)37 (30)2.4 (1.0-5.7)* AIJ12 (2)5 (4)0.5 (0.1-1.9) AS37 (7)56 (46)0.1 (0.1-0.4)* PsA19 (4)15 (12)0.3 (0.1-0.8)* SLE17 (3)3 (2)1.2 (0.3-5.2) Others33 (6)7 (6)1Disease Activity indexes, median (IQR) DAS28a4.9 (3.6-5.9)4.9 (3.0-5.9)1.1 (0.9-1.3) BASDAIb4.8 (2.9-8)5.3 (2.8-7.5)0.9 (0.8- 1.1) ASDASc3.2 (1.9-4.5)3.9 (2.5-4.7)0.8 (0.6-1.2) SLEDAId14.5 (5.0-19.5)25 (25.0-31.0)0.6 (0.4-1.1)High blood pressure, n(%)77 (15)14 (12)1.3 (0.7-2.4)Diabetes mellitus, n(%)46 (9)7 (6)1.5 (0.7-3.5)High cholesterol, n(%)41 (8)8 (7)1.2 (0.4-2.6)Other comorbidities, n(%):173 (33)26 (21)1.8 (1.1 -2.8)*Use of previous biologic, n(%):216 (40)44 (36)1.2 (0.8- 1.8)Use of steroids, n(%):215 (42)34 (29)1.7 (1.1 -2.7)*Use of DMARD, n(%):418 (79)89 (72)1.4 (0.9-2.2)Adverse eventsb, n(%):69 (13)14 (11)1.2 (0.7-2.1) Severeb, n(%):12 (17)3 (21)0.8 (0.2-3.1)Univariable logistic regression analysis. *p<0.05.an=469,bn=99,cn=71,dn=19,Table 1.Analysis of association between change (Δ) in FMD and relevant parameters by univariate and multivariate linear regression analysis.UnivariateRho (p)MultivariateBeta (p)Δ FMD (%)(r2=0.30)ChangeADMA (µmol/l)-0.63 (<0.001)-0.25 (0.01)MDA (nmol/ml)-0.58 (<0.001)-0.18 (0.02)SOD (U/ml)0.48 (<0.001)NSGSH (U/ml)0.02 (0.75)NSHOMA-0.21 (0.001)NSeGFR (ml/min/ 1.73 m2)-0.03 (0.62)NShsCRP (mg/l)-0.45 (<0.001)NSPTX3 (ng/ml)-0.49 (<0.001)-0.21 (0.01)SBP (mmHg)-0.26 (<0.001)NSDBP (mmHg)-0.11 (0.12)NSHemoglobin (g/dl)0.07 (0.32)NSTotal Cholesterol (mg/dl)-0.05 (0.49)NSTriglyceride (mg/dl)-0.11 (0.12)NSLDL (mg/dl)-0.12 (0.07)NSHDL (mg/dl)0.02 (0.82)NSHbA1c (%)-0.26 (<0.001)NSFigure 1.Scatter-plot graphs between FMD and ADMA, MDA, CuZn-SOD, PTX-3.Conclusion:In our study we found sex differences regarding age and disease duration, being higher in women. As expected, the prevalence of RA was higher in women and AS and PsA in men. Overall, women used more steroids than men. An interesting finding was that patients had high disease activity. Future longitudinal analyses will allow us to analyse sex differences in disease progression and treatment response.References:[1] Ortona E et al. Ann Ist Super Sanita 2016;52(2):205-12[2] Ngo ST et al. Front Neuroendocrinol 2014;3(3):347-69Disclosure of Interests:Vijaya Rivera Teran: None declared, Deshire Alpizar-Rodriguez: None declared, Sandra Sicsik: None declared, Fedra Irazoque-Palazuelos Consultant of: Bristol-Myers Squibb, Janssen, Pfizer Inc, Roche and UCB, Dafhne Miranda: None declared, David Vega-Morales: None declared, Julio Cesar Casasola: None declared, Sandra Carrilo: None declared, angel castillo: None declared, Sergio Duran Barragan: None declared, Omar Muñoz: None declared, Aleni Paz: None declared, Angélica Peña: None declared, Alfonso Torres: None declared, Daniel Xavier Xibille Friedmann Consultant of: Lilly, Abbvie, Speakers bureau: Lilly, Abbvie, Azucena Ramos: None declared, José Francisco Moctezuma: None declared, Francisco Aceves: None declared, Estefania Torres: None declared, Natalia Santana: None declared, Miguel Vazquez: None declared, Erick Zamora: None declared, Francisco Guerrero: None declared, Claudia Zepeda: None declared, Melanea Rivera: None declared, Kitzia Alvarado: None declared, Cesar Francisco Pacheco Tena: None declared

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Hochhaus, Andreas, D. W. Kim, P. Rousselot, P. E. Dorlhiac-Llacer, J. Milone, S. Francis, E. Bleickardt, and H. Kantarjian. "Dasatinib (SPRYCEL®) 50mg or 70mg BID Versus 100mg or 140mg QD in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Resistant or Intolerant to Imatinib: Results of the CA180-034 Study." Blood 108, no. 11 (November 16, 2006): 166. http://dx.doi.org/10.1182/blood.v108.11.166.166.

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Abstract Phase II studies of dasatinib (SPRYCEL®, formerly BMS-354825), an oral multi-targeted kinase inhibitor of BCR-ABL and SRC kinases, have demonstrated the efficacy and safety of a 70mg twice daily (BID) dose in CML-CP patients (pts) with resistance or intolerance to imatinib (im). A phase I trial of dasatinib (N Engl J Med 2006;354:2531–41) had shown complete hematologic responses (CHR) and major cytogenetic responses (MCyR) at total daily doses of 100mg and 140mg daily in both BID and once daily (QD) schedule in CML-CP pts. The primary objective of the present study was to compare 6 month (mo) cytogenetic response (CyR) rates among the BID and QD regimens of dasatinib. Secondary objectives included estimating differences in CyR rates between the total daily doses of 100 and 140mg, and safety across the arms to optimize the dose and schedule of the drug. Dasatinib was administered according to one of 4 arms: 50mg BID, 70mg BID, 100mg QD or 140mg QD. Dose escalation to 90mg BID or 180mg QD and reduction to 40mg BID or 80mg QD were allowed for inadequate response or adverse events (AEs), respectively. Evaluation included complete blood counts every 2 weeks x 6 then every 3 mo; bone marrow cytogenetics at mo 3, 6 and then every 6 mo; and qPCR monthly x 3 then every 3 mo. A total of 670 pts were randomized and 663 treated in 139 worldwide sites from July 2005 to March 2006. Median age was 55 years and 47% were male. The median time from CML diagnosis to randomization was 54 mo. All pts received prior im: <1% had <400mg/d, 66% had 400–600mg/d and 34% had >600mg/d. The best previous response to im was CHR in 83% and MCyR in 42%. Prior treatment for CML included interferon alpha in 52%, chemotherapy in 27% and stem cell transplantation in 5% of cases. With a median follow-up of 3 mo, the overall CHR rate for the entire population is 80% and MCyR rate is 37% as of August 2006. 44% of pts required a dose interruption; 25% were due to hematologic toxicity and 14% due to non-hematologic toxicity; 28% required a dose reduction of which 13% were due to hematologic toxicity and 6% due to non-hematologic toxicity; the remainder of dose interruptions and reductions were due to other (including dosing error) or unknown reasons. 3% of pts had a dose escalation typically due to lack of CHR after 3 mo or no decrease in WBC after 1 mo. 601 (90%) pts remain on the trial with the majority of discontinuations for disease progression or study drug toxicity. Grade 3–4 neutropenia and thrombocytopenia occurred in 35% and 30% of pts, respectively. AEs considered drug related by the investigators included headache 24%, diarrhea 20%, nausea 16%, fatigue 12%, rash 11%, edema 10%, dyspnea 7%, pleural effusion 7%, myalgia 7%, arthralgia 5%, anorexia 4%, pneumonia 1%, and gastrointestinal hemorrhage 1%. Rare AEs that were considered drug-related by the investigators included congestive heart failure in 4 pts, and cardiac dysfunction, pulmonary hypertension, pulmonary edema and pericardial effusion in 3 pts each. Other AEs regardless of relationship to study drug included grade 3–4 creatinine elevation in 4%, grade 3–4 transaminase elevation in <1%, and grade 3–4 hypocalcemia in 1% of pts. Updated safety and efficacy data on all treatment groups with a minimum of 6-months of follow-up will be presented at the meeting.

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Quintás-Cardama, Alfonso, Hagop Kantarjian, Neil P. Shah, Charles A. Schiffer, Philipp le Coutre, Giuseppe Saglio, Francois Guilhot, et al. "Patients with Chronic Myeloid Leukemia In Chronic Phase Carrying More Than One BCR-ABL Kinase Domain Mutation Exhibit Poorer Response Rates and Outcomes to Second-Line Dasatinib Compared to Those with No or Only One BCR-ABL Mutation." Blood 116, no. 21 (November 19, 2010): 2297. http://dx.doi.org/10.1182/blood.v116.21.2297.2297.

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Abstract Abstract 2297 Background: BCR-ABL kinase domain mutations occur in 30%-90% of patients (pts) who develop resistance to imatinib. A recent analysis reported that 48% of pts with imatinib resistance or suboptimal response had a baseline mutation at the start of dasatinib therapy (Müller 2009). After 2 years of follow-up, dasatinib treatment of imatinib-resistant pts resulted in notable response rates (complete cytogenetic response [CCyR]: 43% vs 47%) and promising progression-free survival (PFS, 70% vs 80%) in pts with or without baseline mutations, respectively. However, some pts present with two or more co-existing mutations in one or more clones. The outcome of these pts after dasatinib therapy has not been described in detail. Methods: This is a retrospective analysis of pts with CML in chronic phase (CML-CP) receiving dasatinib who were imatinib resistant or intolerant and who had >1 BCR-ABL mutation at baseline. Pts with CML-CP from the phase 3 dose optimization trial (-034) and phase 2 START-C (-013) and START-R (-017; dasatinib only population) studies were evaluated. Since the frequency of >1 mutation was expected to be lower than the rates reported for the presence of any mutation, the inclusion of all 3 studies provided a larger population to determine pt responses and outcomes. A 2-year database was used for all 3 studies. Mutations were detected by conventional Sanger sequencing (sensitivity 10%-20%) after nested RT-PCR amplification of the BCR-ABL transcript. BCR-ABL polymorphisms were excluded from analysis. 1150 pts were included in the analysis: -034 (n=662), -013 (n=387), and -017 (n=101). Similar baseline characteristics among those analyzed included: median age (51-55 years), male (47%-53%), median duration of CML (54-64 months [mos]), prior imatinib therapy lasting >3 years (41%-53%) and prior response rates to imatinib (complete hematologic response [82%-92%], major cytogenetic response [MCyR, 28%-42%], and CCyR [15%-21%]). Only the rate of imatinib intolerance differed among the 3 trials: 26% for -034 and -013, whereas imatinib-intolerant pts were not eligible for the -017 study. Results: Of 1150 pts analyzed, baseline mutation data were available for 1043 dasatinib-treated pts (Table); 641 (61%) had no baseline mutation (202 intolerant) and 402 (39%) had a baseline mutation (18 intolerant). Of those with mutations, 70 (17%) had >1 mutation (4 intolerant) and 16 (4%) had >2 mutations. The TKI-resistant T315I mutation occurred in 21/402 (5%) and 5/70 (7%) of those with 1 or >1 mutation, respectively–with G250E also occurring in 2 of those 5 pts. The 24-mo response rates for pts with >1 mutation at baseline were lower than the rates in those who had only 1 mutation, or no mutations at baseline for MCyR (52.2% vs 56.4% vs 65%) and CCyR (36% vs 45% vs 56%). The 24-mo PFS rates on dasatinib for those with >1, 1, and no mutation were 57%, 73%, and 83%, respectively. While pts who achieved CCyR at 12 mos had excellent 2-year PFS, regardless of whether they had no, 1, or >1 mutation, pts who achieved partial cytogenetic response (PCyR) or less than PCyR at 12 mos had lower 2-year PFS if they carried >1 mutation compared to those with no or 1 mutation. The 2-year overall survival (OS) rates were 93.5% for those without a mutation and similar for those with 1 or >1 mutation (89%). Conclusion: Dasatinib shows considerable efficacy in pts with or without baseline BCR-ABL mutations. However, pts with baseline mutations tended to have lower rates of response and PFS compared with those without mutations at baseline. In addition, the presence of >1 mutation compared with the presence of only 1 mutation yielded the lowest rates of response and PFS. Disclosures: Quintás-Cardama: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Kantarjian: Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; Novartis: Consultancy, Research Funding. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Schiffer: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Cellgenix: Consultancy. le Coutre: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Saglio: Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Guilhot: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Hochhaus: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bahceci: Bristol-Myers Squibb: Employment. Lambert: Bristol-Myers Squibb: Employment. Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.

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Porter, J., C. Borgna-Pignatti, M. Baccarani, A. Saviano, S. Abish, R. Malizia, H. Nick, et al. "Iron Chelation Efficiency of Deferasirox (Exjade®, ICL670) in Patients with Transfusional Hemosiderosis." Blood 106, no. 11 (November 16, 2005): 2690. http://dx.doi.org/10.1182/blood.v106.11.2690.2690.

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Abstract Iron excretion can be calculated according to Angelucci et al (NEJM 2000). As applied to the novel oral iron chelator deferasirox (DSX), chelation efficiency can then be determined as the % iron excretion vs theoretical iron binding capacity of chelator dose: % efficiency = [iron excretion (mg/kg/day)/chelator dose (mg/kg/day)] x [374/56] x 2 x 100 (374 and 56 represent the molecular weights of DSX and iron; factor 2 accounts for the tridentate ligand). In a total of 325 patients with β-thalassemia (n=285) or rare anemias, such as MDS (n=13), DBA (n=14) or other anemias (n=13), included in the DSX Phase II and III Studies 0108 and 0107, liver iron concentration (LIC) was evaluated by liver biopsy at baseline and study end. All patients were treated with once-daily oral DSX 5, 10, 20 or 30 mg/kg according to baseline LIC (2–3, >3–7, >7–14 and >14 mg Fe/g dw, respectively). In these patients, the average dose during study was 22.8 ± 7.6 mg/kg. The average iron intake was 0.37 mg/kg/day and was similar between dose cohorts. Efficiency of daily DSX treatment (mean ± SD) Baseline LIC 2–3 >3–7 >7–14 >14 DSX, mg/kg 5 (n=9) 10 (n=49) 20 (n=81) 30 (n=186) Iron excretion (mg/kg/day) 0.14 ± 0.1 0.21 ± 0.1 0.39 ± 0.1 0.57 ± 0.2 Iron intake (mg/kg/day) 0.39 ± 0.1 0.37 ± 0.1 0.38 ± 0.1 0.36 ± 0.1 Ratio iron excretion/intake 0.33 ± 0.2 0.53 ± 0.4 1.09 ± 0.5 1.66 ± 0.8 Efficiency (%) 31.6 ± 26.4 27.5 ± 18.4 27.1 ± 10.3 27.3 ± 12.4 There were no differences in the chelation efficiency of DSX between the overall initial dose groups, and thus between different LIC categories at baseline, or between age and disease groups. Using the estimated efficiency of 27%, and the formula above, the approximate dose (mg) needed to achieve iron balance corresponds to an iron intake in mg Fe/kg/day divided by 0.02. For a patient receiving 0.2, 0.4 or 0.6 mg/kg Fe/day the doses of 10, 20 or 30 mg/kg, respectively, are estimated to achieve iron balance (eg for a 44 kg person receiving 4 units of blood/month a dose of 30 mg/kg would be required to achieve iron balance). Further analysis reveals that chelation efficiency does appear to increase somewhat with iron intake: in patients with <0.3 mg/kg/day Fe (average 0.23) the estimated efficiency is 22%, but becomes 34% in those with >0.5 mg/kg/day Fe (average 0.55). Applying different chelation efficiency estimates for low and high iron intake, 14 and 22 mg/kg/day DSX, respectively, would be required to chelate the transfused iron. In Study 0107, 230 patients were treated with deferoxamine (DFO) at an average daily dose of 45 mg/kg (5 days/week). Using the molecular weight of DFO (656) and a factor of 1 for a hexadentate ligand in the calculation, the overall chelation efficiency for DFO is 13% (10–17% in the lowest and highest iron intake categories, respectively). These calculations, based on the formula of Angelucci et al, correspond well to the overall observation in the DSX clinical studies, that iron balance or net negative iron balance is achieved by daily doses of 20–30 mg/kg in regularly transfused patients. The results also confirm that the estimated chelation efficiency of DSX is around twice that of DFO.

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Álvarez-Reguera, C., J. J. Gaitán-Valdizán, R. Fernández-Ramón, R. Demetrio-Pablo, J. L. Martín-Varillas, L. Sanchez-Bilbao, D. Martínez-López, I. González-Mazón, M. Á. González-Gay, and R. Blanco. "OP0091 TREATMENT OF OCULAR SARCOIDOSIS. STUDY OF 65 PATIENTS OF A SERIES OF 384 PATIENTS FROM A SINGLE UNIVERSITY HOSPITAL." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 50.1–50. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1896.

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Background:Ocular involvement is a relatively frequent and potentially severe complication of sarcoidosis. Oral corticosteroids (OCS) are the first-line treatment. Conventional immunosuppressive agents (cIS) and biological therapy (BT) can be used in refractory cases (1-5).Objectives:To evaluate the treatment and visual outcomes of a cohort of patients diagnosed with ocular sarcoidosis.Methods:Study of a large cohort (n=384) of all consecutive patients diagnosed with sarcoidosis from January 1, 1999 to December 31, 2019 at a single University Hospital. Finally, 344 patients were included according the ATS/ERS/WASOG criteria (Eur Respir J. 1999; 14:735-7). Different ocular manifestations and the following systemic treatments were assessed: a) OCS, b) cIS), c) monoclonal TNF inhibitors, d) Etanercept (ETN), e) Tocilizumab (TCZ). Best Corrected Visual Acuity (BCVA) according to different systemic treatments was compared at diagnosis and after one year of follow-up (Kruskall Wallis test).Results:344 patients were reviewed. From these, 65 (18.9%) presented ocular manifestations as uveitis (83.1%), orbital lesions (7.7%), retinal vasculitis (6.2%), dry eye (6.2%) and scleritis (1.5%). All of them received systemic treatment. BT was particularly used in patients with retinal vasculitis (100%), panuveitis (75%) and orbital lesions (40%). Systemic treatment and BCVA outcome according to ocular manifestations are shown in table. Median BCVA at onset and after one year was 0.6 [interquartile range (IQR) 0.3-0.8] and 0.9 [0.6-1], respectively. No statistically significant differences were observed between systemic treatments in BCVA of patients with uveitis after 1 year of follow-up (Figure).Figure 1.Median [25,75 IQR] BVCA after one year follow up according to type of systemic treatment in sarcoid uveitis.Median BCVA after one year Systemic treatmentAbbreviations: BCVA: Best Corrected Visual Acuity; OCS: Oral Corticosteroids; Conventional IS: Conventional immunosupressants; Monoclonal TNFi: monoclonal tumour necrosis factor inhibitors; ETN: Etanercept; TCZ: Tocilizumab.Conclusion:Panuveitis, intermediate uveitis and orbital lesions, require a more aggressive treatment than other manifestations of ocular sarcoidosis. In uveitis, an important improvement in BCVA after 1 year of follow-up was observed regardless of the type of treatment used.References:[1]Riancho-Zarrabeitia L, et al. Semin Arthritis Rheum 2015;45(3):361-8. PMID: 26092330[2]Riancho-Zarrabeitia L et al. Clin Exp Rheumatol 2014;32(2):275-84. PMID: 24321604[3]Vegas-Revenga N, et al. Am J Ophthalmol 2019; 200:85-94. PMID: 30660771[4]Cordero-Coma et al. Mediators Inflamm 2014; 2014:717598. PMID: 24976689[5]Calvo-Río V, et al. Clin Exp Rheumatol 2014; 32 (4 Suppl 84): S54-7. PMID: 25005576Table 1.Median BCVA at onset and after one year according to ocular manifestations and type of systemic therapy.Type of ocular affectationn (%)Median BCVA at onset [IQR]Median BCVA after 1 year [IQR]OCSn (%)cISn (%)monoclonal TNFin (%)ETNn (%)TCZn (%)Uveitis54 (83.1)0.6 [0.3-0.8]0.9 [0.6-1]44 (81.5)29 (53.7)16 (29.6)3 (5.5)3 (5.5) -Anterior31 (47.7)0.7 [0.3-0.8]0.8 [0.5-1]22 (70.9)12 (38.7)2 (6.5)2 (6.5)0 -Intermediate2 (3.1)0.50.72 (100)1 (50)1 (50)1 (50)1 (50) -Posterior5 (5.2)0.5 [0.1-0.9]0.9 [0.9-1]4 (80)4 (80)3 (60)00 -Panuveitis16 (24.6)0.4 [0.2-0.7]0.9 [0.5-1]16 (100)12 (75)10 (62.5)02 (12.5)Orbital lesions5 (7.7)0.5 [0.1-0.6]1 [0.1-1]4 (80)2 (40)2 (40)01 (20)Retinal vasculitis4 (6.2)0.6 [0.5-0.8]1 [0.6-1]4 (100)4 (100)1 (25)01 (25)Dry eye4 (6.2)10.92 (50)1 (25)000Scleritis1 (1.5)111 (100)0000Abbreviations: BCVA: Best Corrected Visual Acuity; IQR: Interquartile Range; OCS: Oral Corticosteroid; cIS: Conventional Immunosuppressants; Monoclonal TNFi: monoclonal tumour necrosis factor inhibitors; ETN: Etanercept; TCZ: Tocilizumab.Disclosure of Interests:Carmen Álvarez-Reguera: None declared, Jorge Javier Gaitán-Valdizán: None declared, Raúl Fernández-Ramón: None declared, Rosalía Demetrio-Pablo: None declared, José Luis Martín-Varillas: None declared, Lara Sanchez-Bilbao: None declared, David Martínez-López: None declared, Iñigo González-Mazón: None declared, Miguel Á. González-Gay Speakers bureau: Abbvie, Pfizer, Roche, Sanofi and MSD., Grant/research support from: Abbvie, MSD, Janssen and Roche., Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD., Grant/research support from: Abbvie, MSD and Roche.

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Schmidt-Tanguy, Aline, Bernard Desablens, Thierry Lamy, Marc Bernard, Delphine Senecal, Jean-Francois Abgrall, Philippe Casassus, et al. "High Dose and Conventional Anthracycline Regimen for Adult Non-Hodgkin’s Primary Bone Lymphoma (PBL). A GOELAMS’s Trial." Blood 104, no. 11 (November 16, 2004): 2495. http://dx.doi.org/10.1182/blood.v104.11.2495.2495.

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Abstract Between March 1986 and May 1998, 28 patients (pts) (60,7% M, 39.3% F) with localized high-grade PBL were enrolled in the 02 (< 60 years, 20 pts) or 03 (≥ 60 years, 8 pts) GOELAMS trial. The aim of the study was to evaluate the OS, DFS and FFR after 3 VCAP courses (eldisine 3 mg/m² d1, doxorubicin 60 mg/m² d1, cyclophosphamide 1500 mg/m² d1, prednisone 80 mg/m² d1–5 every 3 weeks) in younger pts and after 3 VCEP-Bleo courses (eldisine 3 mg/m² d1, cyclophosphamide 750 mg/m² d2, farmorubicin 80 mg/m² d1, prednisone 50 mg/m²/d d1–7, bleomycine 10 mg d1 and 5, every 3 weeks) in older pts. Involved field radiotherapy (40 Gy) was performed for every patient. The median age was 46 years (17–69) and 70 years (65–75) respectively. Four patients between 60 and 69 with a good performance status (PS) were included in the 02 trial. In contrary to previous reports, the main localization were axial skeleton (20, 71%) including vertebrae (13), pelvis (5) and ribs (2) while skull and extremities were involved in both 4 patients (mandible 3, occiput 1, tibia 1, finger 1, humerus 2, one of them with including scapula involvement). Histological subtype included diffuse large cell lymphoma (68%), diffuse mixed cell lymphoma (14%), immunoblastic (10%), anaplastic Ki1+ (3%) and unclassified (3%). Immunophenotype were B (53.6%), T (3.6%), anaplastic (3.6%) or undone (39.3%). Ann Arbor classification included 23 stage I (82%) and 5 stage 2 (18%). Skin and subcutaneous tissues were involved by extension in 2 pts. Spinal compression, epidural involvement and paraplegia were observed in 8 pts. B symptoms were present in 5 pts (including 2 stage I). LDH were elevated in 5/23 pts. The IPI score was 0 for 18%, 1 for 39%, 2 for 14%, 3 for 10% and undetermined for 18%. PS >2 and bulk (≥ 5 cms) were observed in 43% and 39% of pts respectively. Besides age, VCAP and VCEP-Bleo groups were comparable for histological type, localization, Ann Arbor classification, B symptoms and LDH. All but one patient (96%) achieved CR. A 63 years old patient with costal localization, resistant to chemotherapy, died of progression after 15 months. Relapses occurred in 9/27 pts (33%, 3/8 for older pts, 6/20 for younger pts) at a median time of 2.3 years (0.4–6.5) from CR. Four of these relapses occurred before 2 years of CR, 4 between 2.1 and 5 years and 1 occurred 6.5 years after CR. Amongst 8 pts with spinal compression, 1 died in CR, 4 relapsed (1 alive in CR2) and 3 are in continuous CR. The relapse rate of pts without epidural involvement was 25% (5/20). With a median follow up of 8 years (1.2–17), OS, EFS and FFR were 62% (±12), 56% (±10) and 60% (±10), respectively. OS, EFS and FFR were 66%, 54%, 63% and 56%, 62%, 62% in VACP group and VCEP-Bleo group respectively. In univariate analysis, PS >2 significantly decreases OS, EFS and FFR (P = .036, .013 and .064). Epidural extension significantly decreases EFS (P = .009) but not OS. In multivariate analysis, poor PS but not epidural extension significantly decrease EFS and OS (P=.02 and P = .03 respectively for PS). The survival results of PBL are very similar to survival of 325 localized aggressive NHL treated in the 02-GOELAMS trial reported previously (Desablens ASH 2002). The poor prognostic value of PS and epidural extension of PBL should be underlined.

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Zolotukhin, D. S., I. V. Krochek, and S. V. Sergiyko. "Treatment of the pilonidal sinus in children using laser radiation." Laser Medicine 24, no. 4 (April 28, 2021): 32–36. http://dx.doi.org/10.37895/2071-8004-2020-24-4-32-36.

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The work carried out a comparative analysis of the results of surgical treatment of the epithelial-coccygeal course of ECC in 133 children aged 3 to 17 years, using laser-induced interstitial thermotherapy (LIT) and open excision. Comparative analysis was carried out according to the following criteria: duration of surgery, average time of hospital stay, duration of pain syndrome on a 10-point scale (VAS), the presence of complications in the early and late postoperative period. In the main group, the average time of hospital stay was 4.9 ± 0.3; the duration of surgical treatment was 17.2 ± 2.8 minutes. The duration of the pain syndrome was 5.3 ± 2.1 hours, and its severity was 2.7 ± 0.8 points. Average terms of epithelialization of fistulas are 3.1 ± 2.8 days. Recurrence of ECC was observed in 7 patients (11.7%), which required re-intervention. In 3 (5.0%) patients, LIT was used, and in 4 (6.7%), excision using plastics according to the Bascom method. In the comparison group, the duration of surgical treatment was 32.6 ± 5.4 minutes. The duration of inpatient treatment is 16.7 ± 1.4 days. Pain syndrome averaged 71.8 ± 11.9 hours, severity 6.5 ± 2.3 points. The number of relapses was 9 (12.3%), of which 5 (6.8%) children underwent laser treatment, and 4 (5.5%) repeated surgical excision with Bascom with recovery. This technique is an effective and minimally invasive method for treating ECC, which makes it possible to recommend this method for use in pediatric surgical practice.

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Beierwaltes, W. H. "Macula densa stimulation of renin is reversed by selective inhibition of neuronal nitric oxide synthase." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 5 (May 1, 1997): R1359—R1364. http://dx.doi.org/10.1152/ajpregu.1997.272.5.r1359.

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The neuronal isoform of nitric oxide synthase (nNOS) exists in the renal cortex predominantly in the macula densa, suggesting that nitric oxide (NO) derived from the macula densa plays a role in feedback regulation of renin in response to altered sodium metabolism. To determine if nNOS is a critical component in renin stimulation induced by dietary sodium restriction, rats received either normal sodium or a sodium-restricted diet (0.03%) for 7 days and subsequently were or were not treated with the selective inhibitor of nNOS 7-nitroindazole (7-NI) either acutely (50 mg/kg body wt ip) on the final day or chronically (20 mg/kg body wt ip 2 x/day) over the final 5 days. On the last day, rats were anesthetized with Inactin and fitted with arterial and renal venous catheters to collect blood and monitor blood pressure (BP) and a flow probe to measure renal blood flow (RBF). BP (105 vs. 108 mmHg) was similar in normal and low-sodium dietary groups, respectively, whereas RBF tended to be higher in the sodium-restricted group (6.5 +/- 0.3 vs. 7.6 +/- 0.4 ml.min-1.g kidney wt-1). Both renal venous renin (RR) and renin secretion rate (RSR) were elevated approximately fourfold by sodium restriction [RR = 5.8 +/- 0.8 vs. 20.5 +/- 2.7 ng angiotensin (ANG) I.ml-1.h-1; P < 0.001; RSR = 3.0 +/- 0.9 vs. 13.1 +/- 4.1 ng ANG I.h-1.min-1; P < 0.025]. Acute 7-NI did not change BP, RR, or RSR, but reduced RBF in sodium-restricted rats by 8% (P < 0.05). Chronic 7-NI had no effect on renin in rats on a normal diet, but reduced RR by one-half in the sodium-restricted group (to 9.9 +/- 1.6 ng ANG I-ml-1.h-1; P < 0.001) and reduced RSR to normal (diet) levels (to 3.9 +/- 1.4 ng ANG I.h-1.min-1; P < 0.05). Although selective NOS inhibition by 7-NI did not affect BP, RBF, or renin in control rats on a normal diet, chronic 7-NI reversed the stimulation of renin induced by dietary sodium restriction. These data suggest that nNOS-derived NO plays an important role in the macula densa during feedback stimulation of renin induced by dietary sodium restriction.

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Smiley, Shannon L., Theresa Hahn, Wei Tan, Gregory Wilding, Minoo Battiwalla, and Philip L. McCarthy. "BuCy Provides Equivalent Outcomes to VCyTBI as Conditioning Prior to Auto-SCT in Patients with Relapsed/Refractory NHL and Is a Valuable Option in Older (≥60 years) Patients." Blood 112, no. 11 (November 16, 2008): 2176. http://dx.doi.org/10.1182/blood.v112.11.2176.2176.

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Abstract Cyclophosphamide+total body irradiation +/− etoposide (CyTBI+/−V) is a standard conditioning regimen prior to auto-SCT for NHL patients. However, TBI-based dose intensive therapy is often contraindicated in older patients, or those with prior radiation. We performed a single-institution Phase II non-randomized prospective study of VCyTBI vs. Busulfan+Cy (BuCy) to determine if BuCy provides comparable disease control to standard dose intensive therapy with VCyTBI. BuCy was used in patients ≥60 years and when TBI was contraindicated. Seventy-five relapsed or refractory NHL patients underwent auto-SCT at Roswell Park Cancer Institute from 8/92 to 7/05. All patients were treated on a single IRB-approved protocol with standard eligibility criteria including age ≥18 and ≤70, adequate cardiac, pulmonary, hepatic and renal function and KPS ≥70. All patients signed informed consent and were followed prospectively. All data have been de-identified. Survival status for all patients was updated through 8/1/08. VCyTBI (N=47) consisted of V 1800 mg/m2 26-hour continuous iv infusion on day -5, Cy 60 mg/kg day -4 (12 patients received 180 mg/kg total dose), and TBI 200 cGy on days -3, -2, and -1 for total dose of 1000 cGy (8 patients received 1200 cGy). BuCy (N=28) consisted of iv Bu 0.8 mg/kg every 6 hours on days -7, -6, -5, -4 (total 12.8mg, one patient received oral Bu total dose 16 mg/kg) and Cy 60 mg/kg on days -3 and -2 (total 120 mg/kg, one patient received total dose 200 mg/kg). Eight patients received iv Bu without dose adjustment and 19 received iv Bu with dose adjusted to maintain a steady state level between 600– 900 ng/ml. Stem cells were re-infused on day 0. Patients received peripheral blood stem cells (n=53), bone marrow (n=14) or both (n=8). The median age was significantly higher in the BuCy compared to the VCyTBI group (61.5 vs 53 years, p=0.0002), and there were fewer patients with a KPS of 90–100 in the VCyTBI group (75% vs 93%, p=0.07). There were no significant differences on the following patient characteristics by BuCy vs VCyTBI: gender, disease risk, stem cell source, histology (diffuse, follicular, mantle, other), or remission status at SCT. Treatment-related mortality at day+100 post-auto SCT was very low in both groups: 0% in BuCy and 2% in VCyTBI. However, 3 patients in the VCyTBI group and none in the BuCy group developed AML at 1.3, 1.8 and 6.5 years post-auto-SCT. At a median follow-up of 4.6 years, the 5-year progression-free survival for BuCy and VCyTBI was 32% (95% CI 14–50%) and 24% (95% CI, 11–39%, P>0.8), respectively. The 5-year overall survival for BuCy and VCyTBI was 46% (95% CI 25– 64%) and 49% (95% CI 33–64%, P>0.7), respectively. Multivariate analysis controlling for age and KPS at BMT also demonstrated no significant difference between BuCy and VCyTBI for either progression-free (RR=0.9, 95% CI 0.5–1.8) or overall (RR=0.7, 95% CI 0.3–1.6) survival. This is the largest reported study evaluating the efficacy of BuCy as alternative conditioning for auto-SCT in relapsed/refractory NHL. BuCy provides equivalent survival outcomes to VCyTBI as conditioning for auto-SCT in NHL patients. Based on these results, our practice continues to use BuCy for NHL patients ≥60 years.

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Ennishi, Daisuke, Anja Mottok, Hennady Shulha, Pedro Farinha, Fong Chun Chan, Barbara Meissner, Merrill Boyle, et al. "Genetic Alterations of Gα13 Signaling Pathway with BCL2 over-Expression Confers Lymphoma Dissemination and Inferior Outcome in Germinal Center B Cell Diffuse Large B Cell Lymphoma." Blood 126, no. 23 (December 3, 2015): 111. http://dx.doi.org/10.1182/blood.v126.23.111.111.

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Abstract Background: Diffuse large B cell lymphoma (DLBCL) is divided into two distinct molecular subtypes, germinal center B cell (GCB) subtype and activated B cell (ABC) subtype. Genetic landscape studies of DLBCL have revealed several GCB-DLBCL specific mutations, including CREBBP, GNA13, EZH2, TNFRSF14, BCL2 and MEF2B. Functional studies have recently shown that the inactivation of Gα13 signaling pathway genes, including GNA13, together with BCL2 over-expression, allows GC B-cells to escape the germinal center niche and widely disseminate. Although these findings revealed a critical role of genetic alterations of Gα13 signaling pathway in GC-driven mouse models of lymphomagenesis, clinical correlation is lacking. Here we analyzed the clinical impact of genetic alterations of Gα13 signaling pathway in a large population-based DLBCL cohort. Methods: We analyzed 347 newly diagnosed de novo DLBCL cases that were uniformly treated with R-CHOP at the BC Cancer Agency. Comprehensive clinical annotation was available through the BCCA Lymphoid Cancer Database. Deep targeted re-sequencing of the coding exons of GNA13, P2RY8, ARHGEF1, S1PR2 and RHOA was performed using a Truseq Custom Amplicon assay (Illumina) and/or Fluidigm Access Array chips. High-resolution copy number analyses were performed using Affymetrix SNP 6.0 arrays. Immunohistochemical staining and break-apart FISH assays for MYC and BCL2 were performed on tissue microarrays (n=332). Cell-of-origin classification was available in 331 cases, according to gene expression profiling by the Lymph2Cx assay using the NanoString platform (Scott, Blood 2014; 123) in 299 patients and the Hans algorithm (Hans, Blood 2004; 103) in 32 cases with low tumor content (<40%). Results: Using next generation sequencing, 225 SNVs and 5 Indels were detected in GNA13 (16%), P2RY8 (18%), ARHGEF1 (6%), S1PR2 (3%) and RHOA (6%). SNP 6.0 microarrays revealed heterozygous deletions in GNA13 (2%), ARHGEF1 (1%), S1PR2 (4%) and RHOA (8%), but homozygous deletion was not found in any of these five loci. GNA13, P2RY8 and ARHGEF1 mutations were significantly more frequent in the GCB subtype than ABC subtype (26% vs. 6%; p<.0001, 25% vs 7%; p=.0002, and 8% vs. 5%; p=.008, respectively). 185 GCB-DLBCL cases were further analyzed for clinical correlations. In the cases with mutations of any of the five Gα13 signaling pathway genes, BCL2 over-expression (cut off; 50%) and translocation was associated with increasing stage (p=.018 and p=.005, respectively), but not in wt cases (p=.53 and p=.63, respectively). Specifically, in the cases with GNA13 and P2RY8 mutations individually, BCL2 over-expression was associated with advanced stage (stage III/IV, p=.018 and p=.037, respectively), but not in wild type (wt) cases. Importantly, BCL2 over-expression in the cases harboring Gα13 pathway mutations was not significantly associated with other poor risk features, including any other IPI factors or bone marrow involvement, indicating that genetic alterations in Gα13 signaling pathway accompanied by BCL2 over-expression might promote lymphoma dissemination into lymph nodes but not extranodal sites. With a median follow up of 6.5 years for living patients, there was no prognostic impact of harboring any isolated Gα13 pathway mutation in GCB-DLBCL patients. However, in cases with any Gα13 pathway mutations, BCL2 over-expression was significantly associated with an inferior 5y-time to progression (TTP; 90% vs 62%, p=.003) and disease-specific survival (DSS; 90% vs 71%, p=.042), but not in wt cases (Fig 1). In a Cox model of TTP including the IPI, BCL2 over-expression remained prognostic in the cases harboring any Gα13 pathway mutations (HR=4.13 [1.42-12.01], p=.009), but not in wt cases (HR=1.70 [0.62-4.68], p=.31). In cases with any Gα13 pathway alterations including copy number loss, BCL2 over-expression was also significantly associated with an inferior TTP (HR=3.64 [1.39-9.57], p=.009) independent of IPI, but not in the cases without genetic alterations (HR=1.75 [0.57-5.34], p=.33). Conclusions: Genetic alterations in Gα13 signaling pathway genes cooperate with BCL2 over-expression to promotes lymphoma dissemination to nodal sites and is associated with the poor outcome in GCB-DLBCL Figure 1. TTP and DSS according to BCL2 over-expression with/without Gα13 signaling pathway mutations in GCB-DLBCL patients (n=185) treated with R-CHOP Figure 1. TTP and DSS according to BCL2 over-expression with/without Gα13 signaling pathway mutations in GCB-DLBCL patients (n=185) treated with R-CHOP Disclosures Savage: Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Scott:Celgene: Consultancy, Honoraria; NanoString: Patents & Royalties: Inventor on a patent that NanoString has licensed.

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Patel, Manish R., James L. Gulley, Keun-Wook Lee, Jeffrey R. Infante, Juliane Manitz, Vijay Kasturi, Hao Zhang, Galit Rosen, and Andrea B. Apolo. "Avelumab treatment in metastatic urothelial carcinoma: Association between early response and durable outcomes in the phase Ib JAVELIN Solid Tumor Study." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 429. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.429.

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429 Background: Avelumab is a human anti‒PD-L1 IgG1 antibody approved in the US, Canada, and Israel for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) progressed after platinum chemotherapy. In the JAVELIN Solid Tumor study, avelumab treatment in post-platinum patients (pts) has shown promising and durable antitumor activity and favorable overall survival (OS) outcomes. Here, we report post hoc analyses to assess if early response to avelumab is associated with long-term treatment outcomes. Methods: Pts with mUC that had progressed after platinum-based therapy in the JAVELIN Solid Tumor study were analyzed. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). A Kaplan-Meier subgroup analysis has been performed for duration of response (DOR); response by week 7 (first tumor scan ± 5 days) define balanced subgroups. A landmark analysis was used to assess the association between time-to-response and OS. The landmark was 3 mo (second tumor assessment; 12 weeks ± 5 days). Results: 242 pts with platinum-treated mUC received avelumab and were followed up for ≥2 years (median, 2.7 years; data cutoff, Apr 2018). No difference in DOR was found between pts who had responded by the first tumor assessment (n=15) and those who responded later (n=25; HR, 0.8 [95% CI: 0.3-2.0]). In a landmark analysis for OS, the median OS was not reached (NR [95% CI: 18.9 mo-NR]) in pts who had responded within 3 mo (n=29) compared with 9.5 mo (95% CI: 6.5-14.4) in pts with late response or stable disease (n=74), and 4.3 mo (95% CI: 2.8-7.1) in other pts (progressive disease [PD] or not evaluable; n=70). Further sensitivity analyses found that survival did not vary between pts who continued treatment beyond investigator-confirmed PD (n=46) vs those that did not (n=24; median survival, 5.0 mo [95% CI: 2.8-8.8] vs 4.3 mo [95% CI: 0.9-8.3], respectively). Conclusions: Responses to avelumab have similar durability irrespective of time to response. Pts with an early response to avelumab tend to survive longer than pts with stable disease, and both groups have longer OS than nonresponders. Clinical trial information: NCT01772004.

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Mitrou, Panayota, Eleni Boutati, Vaia Lambadiari, Aikaterini Tsegka, Athanasios E. Raptis, Nikolaos Tountas, Theofanis Economopoulos, Sotirios A. Raptis, and George Dimitriadis. "Insulin resistance in hyperthyroidism: the role of IL6 and TNFα." European Journal of Endocrinology 162, no. 1 (January 2010): 121–26. http://dx.doi.org/10.1530/eje-09-0622.

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ObjectiveAlthough insulin resistance is a common finding in hyperthyroidism, the implicated mechanisms are obscure. The aim of this study was to investigate whether interleukin 6 (IL6) and tumour necrosis factor α (TNFα) are related to the development of insulin resistance in hyperthyroidism of nonautoimmune origin.Design and methodsA meal was given to ten hyperthyroid (HR) and ten euthyroid (EU) women. Plasma samples were taken for 360 min from the radial artery for measurements of glucose, insulin, and nonesterified fatty acids (NEFA). IL6 and TNFα were measured preprandially from the superficial epigastric vein and from the radial artery.Resultsi) In HR versus EU: (a) arterial glucose was similar (AUC0–3602087±57 vs 2010±43 mM×min), but insulin was increased (AUC0–36017 267±2447 vs 10 331±666 μU/ml×min,P=0.01), (b) homeostasis model assessment (HOMA) was increased (2.3±0.4 vs 1±0.1 kg/m2,P=0.007), (c) arterial NEFA were increased (AUC0–360136±18 vs 89±7 mmol/l×min,P=0.03), (d) arterial IL6 (2±0.3 vs 0.9±0.1 pg/ml,P=0.0009) and TNFα (4.2±0.8 vs 1.5±0.2 pg/ml,P=0.003) were increased, and (e) IL6 production from the subcutaneous adipose tissue (AT) was increased (18±6 vs 5±1 pg/min per 100 ml tissue,P=0.04). ii) (a) Subcutaneous venous IL6 was positively associated with HOMA (β-coefficient=1.7±0.7,P=0.049) and (b) although TNFα was not produced by the subcutaneous AT, arterial TNFα was positively associated with NEFA (AUC0–360;β-coefficient=0.045±0.01,P=0.005).ConclusionsIn hyperthyroidism: i) glucose and lipid metabolism are resistant to insulin, ii) subcutaneous AT releases IL6, which could then act as an endocrine mediator of insulin resistance, iii) although there is no net secretion of TNFα by the subcutaneous AT, increased systemic TNFα levels may be related to the development of insulin resistance in lipolysis.

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Hardy, Steven J., Kristina K. Hardy, Shane M. Wise, Katie J. Olson, Amanda L. Thompson, and Emily Riehm Meier. "Initial Results of a Randomized Controlled Trial of Computerized Working Memory Training in Pediatric Sickle Cell Disease." Blood 128, no. 22 (December 2, 2016): 247. http://dx.doi.org/10.1182/blood.v128.22.247.247.

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Abstract Introduction: Disease-related neurocognitive deficits are common in sickle cell disease (SCD), even in the absence of stroke. Working memory (WM) is among the domains most commonly affected, likely a result of the high frequency of disease-related cerebral insults localized to the prefrontal cortex. Computerized cognitive training programs have garnered support for their efficacy in improving working memory across multiple pediatric populations, but have not been thoroughly explored in SCD. We present initial findings from a randomized controlled trial of the feasibility and efficacy of a home-based, computerized WM training intervention (Cogmed) with children with SCD. Methods: Youth with SCD between the ages of 7 and 16 years old were recruited to complete a randomized (intervention or waitlist-control), dose-controlled, home-based computerized WM training program (Cogmed). After an initial neuropsychological assessment, participants with WM deficits were loaned an iPad on which they accessed Cogmed at home. Cogmedconsists of 12 increasingly challenging exercises that target skills involving visuo-spatial and verbal WM, practiced over 25 training sessions. At the end of the training period, participants completed a post-intervention neuropsychological assessment, including tests of auditory WM (Digit Span subtest, Wechsler Intelligence Scale for Children - Fifth Edition [WISC-V]) and visuo-spatial WM (Picture Span subtest, WISC-V; and Block Design-Forward and Block Design-Backward subtests, Wechsler Intelligence Scale for Children - Fourth Edition [WISC-IV]). Subtest scores are represented using scaled scores (M = 10; SD = 2). Scores on WISC-V WM subtests were used to calculate a composite Working Memory Index (WMI), represented by a standard score (M = 100; SD = 15). Results: To date, 59 participants (M = 10.45, SD = 2.90; 53% female) have enrolled and completed a baseline neuropsychological assessment. Forty-nine percent (n = 29) exhibited WM deficits and were randomized to either begin Cogmed immediately (n = 14) or wait 5-8 weeks before beginning Cogmed (n = 15). Among those who have received the intervention and reached the end of their training (n = 24), 12 participants (50%) completed at least 10 sessions and 7 participants (29%) completed at least 20 sessions. The mean number of Cogmed sessions completed was 11.83 (SD = 7.97). As expected, participants in the waitlist condition did not exhibit improvements in WM, as demonstrated by stable performance on the WMI (t[8] = -1.520, p = .167), and on the Digit Span (t[9] = -0.449, p = .664), Picture Span (t[9] = -0.708, p = .497), Spatial Span-Forward (t[9] = 0.261, p = .802), and Spatial Span-Backward (t[7] = -0.261, p = .802) subtests. Participants who exhibited WM deficits at baseline and were given Cogmed exhibited reliable improvements in WMI (Baseline M = 89.79, SD = 12.36; Post-test M = 96.83, SD = 14.97), Digit Span (Baseline M = 7.62, SD = 2.24; Post-test M = 8.61, SD = 3.07), Picture Span (Baseline M = 8.93, SD = 2.87; Post-test M = 10.39, SD = 3.01), Block Design-Forward (Baseline M = 8.39, SD = 2.50; Post-test M = 9.06, SD = 3.35), and Block Design-Backward (Baseline M = 7.61, SD = 1.95; Post-test M = 9.39, SD = 2.62). Paired Samples t-tests conducted with participants who completed at least half of the Cogmed program (i.e., 10 sessions), revealed significant improvements on the WMI (t[7] = -3.361, p = .012), and on the Digit Span (t[7] = -3.175, p = .016), Spatial Span-Forward (t[7] = -2.448, p = .044), and Spatial Span-Backward (t[7] = -4.233, p = .004) subtests. Partial correlations controlling for respective baseline scores, indicated that the number of Cogmed sessions completed was positively correlated with post-test scores on the WMI (r = .568, p = .017), and on the Digit Span (r = .623, p = .008), Spatial Span-Forward (r = .518, p = .033), and Spatial Span-Backward (r = .612, p = .009) subtests. Conclusions: Children with SCD exhibit significant neurocognitive deficits, particularly in WM. Initial results suggest that a home-based, computerized WM training program leads to significant improvements in WM. A dose-effect was observed, as participants who completed more Cogmed sessions evidenced the greatest improvements in WM. Home-based cognitive training programs may ameliorate SCD-related WM deficits but innovative approaches to motivating and supporting patients as they complete home-based interventions are needed to enhance adherence. Disclosures No relevant conflicts of interest to declare.

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Goodnough, Lawrence T., George Despotis, Peter K. Smith, Jerrold Levy, Robert Poston, Mary Short, Govinda Weerakkody, and LeRoy Lenarz. "Transfusion Requirements and Outcomes In the Cohort of Patients Undergoing Isolated CABG Treated with Prasugrel or Clopidogrel: TRITON-TIMI 38 Data Analysis." Blood 116, no. 21 (November 19, 2010): 1108. http://dx.doi.org/10.1182/blood.v116.21.1108.1108.

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Abstract Abstract 1108 Coronary artery bypass grafting (CABG)-related bleeding and associated transfusion support are concerns with dual antiplatelet therapy. The amount and the type of blood products transfused may be influenced by patient characteristics, procedural characteristics, acquired hemostatic defects, regional standard of care, and the amount of perioperative blood loss. Withdrawal of clopidogrel 5 days prior or prasugrel 7 days prior to CABG is suggested by the respective product labels to reduce the potential for CABG-related bleeding. Accordingly, a cohort of 422 patients undergoing isolated CABG in TRITON-TIMI 38 (PRASugrel n=208; CLOPidogrel n=214) was analyzed retrospectively to characterize the risk adjusted (using predicted risk of transfusion - Magovern, et al. Ann Thorac Surg 1996;61:27-32) difference in transfusion requirements between prasugrel and clopidogrel. Seventy-six patients who never received study drug or who received open label thienopyridine treatment prior to CABG were excluded. Packed red blood cells (PRBC) were the most frequently used blood product while platelet transfusions were relatively infrequent and regionally specific. No difference was noted in mean predicted transfusion risk score (TRS) between cohorts (PRAS 2.13 vs. CLOP 2.31; p=0.53; two-sided p value per ANOVA). TRS was associated with the number of units of PRBC transfused (p < 0.0001). Overall, there were significantly higher mean 12 hour chest tube loss (655 ±580 ml vs. 503± 378 ml; Kruskal-Wallis p=0.050) and platelet transfusion rates (18% vs. 9.8%; Pearson's chi-square p=.033) with PRAS. However, there were no statistically significant differences in PRBC transfusion units (mean 2.1±3.0 PRAS vs. 1.7±2.2 CLOP; Kruskal-Wallis p=0.44) or total donor exposure units (PRBC + whole blood + platelets + cryoprecipitate + fresh frozen plasma) (4.4±7.6 PRAS vs. 3.0±4.5 CLOP; Kruskal-Wallis p=0.46), although all of the analyses presented are underpowered. Total donor exposures were correlated with chest tube blood loss at 12 hours and the correlations were similar for both cohorts (PRAS, r=0.42; CLOP, r=0.45) (Figure). Transfusion requirements and blood loss by days from last dose categories are presented in the Table. Fifty-four (54)%, 22%, and 24% of patients went to CABG surgery ≤5 days, 6–7 days, and >7 days from the last dose of study drug, respectively (days from last dose to CABG unknown for 0.6% of patients). A significantly higher number of platelet units were used postoperatively in the PRAS patients going to surgery ≤5 days after withdrawal of drug. There is no suggestion of excess blood loss or excess of total units of blood transfusions after 7 days for PRAS or CLOP. In an analysis adjusted for the predicted risk of mortality (using Society of Thoracic Surgeons mortality score), total donor exposures were not associated with increased mortality risk [all-cause death within 30 days following CABG (odds ratio, 1.05 (0.97- 1.13) p=0.25; logistic regression analysis]. In addition, PRAS was independently associated with a reduction in mortality (PRAS, 1.2%; CLOP, 6.9%; p=0.027). In summary, the amount of blood products transfused is significantly influenced by patient and surgical characteristics, as well as by agents that can inhibit the hemostatic system. However, despite increased blood loss and use of greater numbers of platelets in a higher percentage of patients within the PRAS cohort, use of PRAS was associated with improved outcomes in the isolated CABG cohort of TRITON-TIMI 38. Disclosures: Goodnough: Eli Lilly and Company: Consultancy. Despotis:Eli Lilly Company: Consultancy. Levy:Eli Lilly Company: Consultancy, Research Funding. Short:Eli Lilly & Company: Employment, Equity Ownership. Weerakkody:Eli Lilly & Company: Employment, Equity Ownership. Lenarz:Eli Lilly & Company: Employment, Equity Ownership.

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Koreth, John, Haesook T. Kim, Paulina B. Lange, Philippe Armand, Corey S. Cutler, Vincent T. Ho, Brett Glotzbecker, et al. "Bortezomib-Based Versus Standard of Care Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation: A Phase II Randomized Controlled Trial." Blood 128, no. 22 (December 2, 2016): 508. http://dx.doi.org/10.1182/blood.v128.22.508.508.

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Abstract Background: We previously reported on a novel bortezomib (bort)/tacrolimus(tac)/methotrexate (mtx) regimen with low rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) and promising overall and progression-free survival (OS, PFS) in HLA-mismatched donor (MMD) reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT). To determine whether bort provided a meaningful improvement in outcomes, we undertook a prospective randomized controlled trial (RCT) of standard-of-care (SOC) tac/mtx versus 2 novel bortezomib-based GVHD regimens for RIC HSCT recipients lacking HLA-matched related donors (Clinical Trial ID: NCT01754389). Intervention: The open-label phase II 3-arm 1:1:1 RCT enrolled adult hematologic malignancy patients aged 18-75 years. Conditioning was IV busulfan (0.8 mg/kg BID) and fludarabine (30 mg/m2 QD) from d-5 to -2. 8/8 matched unrelated donor (MUD) or 7/8 MMD T-replete PBSC grafts (≥ 2x106 CD34+ cells/kg) were infused on d0. GVHD regimens were: tac/mtx (arm A, SOC); bort/tac/mtx (arm B); and bort /sirolimus (siro)/tac (arm C) dosed as: bort (1.3 mg/m2 IV d+1, +4, +7), mtx (10 mg/m2 IV d+1, 5 mg/m2 d+3, +6, +11), siro (target trough level 5-12 ng/ml) and/or tac (target trough level 5-10 ng/ml) from d-3 with taper from d+100 and complete by d+180, as applicable per treatment arm. Primary endpoint was grade II-IV acute GVHD incidence by d+180. Secondary endpoints included NRM, relapse, PFS, OS and chronic GVHD at 1 year. Patient and transplant variables: 138 evaluable patients with a median age of 64 years (range, 24-75), variable diagnoses (53 AML, 33 MDS, 20 NHL, 11 CLL, etc) and disease-risk indices (Low 14, Intermediate 96, High/Very High 28) were accrued between Jan 2013 and Nov 2015. They received 8/8 (98) MUD or 7/8 (40) MMD PBSC grafts. The treatment arms (A: 46; B: 45; C: 47) were balanced for pre-transplant variables, except for lower CMV seropositivity in arm C (78.3% vs. 77.8% vs. 53.2%, p=0.01). Median follow up in survivors was 15 months (range, 5.5-38). Outcomes: The regimens were well tolerated. No bort doses required omission or reduction. Grade 3-5 AE rates were similar across arms. TMA/HUS and VOD rates were not different (p=0.16, p=0.41, respectively). Median day +30 donor chimerism was ~96% (range, 42-100) across arms (p=0.84). The d+180 incidence of grade II-IV acute GVHD was similar overall across arms at 33% (A) vs. 31% (B) vs. 21% (C, p=0.65, Figure 1), but for the 8/8 MUD subgroup it was 33% (A) vs. 16% (B) vs. 19% (C) with a trend to significance for the bort-based regimens at 33% (A) vs. 17% (B+C, p=0.08). Across arms, the 1-year NRM incidence was 11% (A) vs. 15% (B) vs. 6.5% (C, p=0.43), and relapse was 24% (A) vs. 28% (B) vs. 36% (C, p=0.62). The 1-year incidence of extensive chronic GVHD was 39% (A) vs. 44% (B) vs. 48% (C, p=0.52). 1-year PFS was 64% (A) vs. 57% (B) vs. 57% (C, p=0.89, Figure 2), and OS was 72% (A) vs. 63% (B) vs. 70% (C, p=0.54). Conclusions: 1. For 7/8 MMD RIC HSCT, adding bort does not provide benefit to SOC tac/mtx, which offers outcomes better than historically anticipated. 2. For 8/8 MUD RIC HSCT, adding bort may offer grade II-IV acute GVHD benefit, but direct randomization with an appropriately powered sample size would be required for confirmation. Disclosures Koreth: kadmon corp: Membership on an entity's Board of Directors or advisory committees; takeda pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; prometheus labs inc: Research Funding; amgen inc: Consultancy; LLS: Research Funding; millennium pharmaceuticals: Research Funding. Armand:Roche: Research Funding; Pfizer: Research Funding; Merck: Consultancy, Research Funding; Sequenta Inc: Research Funding; Infinity Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees.

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Cummings, Joanna, Aloura Linfesty, and Diane Stadler. "Energy and Nutrient Concentrations of Water Buffalo Milk and Liquid and Dried Whey: Potential Dietary Supplement to Address Malnutrition in Lao PDR." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 746. http://dx.doi.org/10.1093/cdn/nzaa052_015.

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Abstract Objectives In Lao PDR, 33.5% of children <5 years are stunted, 26% are underweight and 8% are severely wasted. Nutritional rehabilitation of malnourished children often requires dietary protein (PRO) and energy supplementation. Water buffalo (WB) native to SE Asia produce milk with more fat and PRO than dairy cow (DC) milk. Although WB milk is not typically consumed in Lao, it is used to make cheese. Whey, a byproduct of cheese production and a source of PRO and energy, is currently discarded in Lao. We analyzed and compared energy and macronutrient concentrations of WB milk and liquid and dried acid whey to DC milk and acid whey data in the 2020 USDA nutrient database to determine potential as a locally-sourced protein supplement. Methods WB milk and whey samples were obtained from the Lao Buffalo Dairy in Lao PDR. Nutrient analysis was performed by Mahidol University, Bangkok, Thailand. Crude PRO and fat concentrations were measured by Kjeldahl and Soxtec™ technology, respectively; and carbohydrate (CHO) and energy concentrations were calculated by weight-difference and standard equations. Results WB milk contained 4.5 ± 0.0 g PRO, 7.6 ± 0.3 g fat, 5.2 ± 0.3 g CHO and 107 ± 3 kcals per 100 g milk. WB liquid acid whey contained 0.8 ± 0.3 g PRO, 0.6 ± 0.2 g fat, 5.4 ± 0.3 g CHO and 29.6 ± 2.1 kcals per 100 g whey. WB dried acid whey contained 9.4 ± 3.3 g PRO, 6.5 ± 1.8 g fat, 70 ± 4.9 g CHO and 376 ±13 kcals per 100 g dried whey. PRO (P < 0.01), fat (P < 0.01) and energy (P < 0.01) concentrations were higher in WB than DC milk. Energy (P < 0.01) and fat (P < 0.01) concentrations were higher in WB than DC liquid acid whey. Energy concentration (P < 0.01) was higher in WB than DC dried acid whey; PRO concentrations were not different (P > 0.14) but met USDA PRO powder criteria of 7 g PRO/100 g dried whey. Conclusions WB milk and liquid and dried acid whey contain sufficient amounts of PRO, fat and energy to develop a locally-sourced nutritional supplement to rehabilitate malnourished children. Funding Sources Funding for this research was supported by the OHSU Foundation, OHSU Graduate Programs in Human Nutrition, Vejdusit Foundation, and Bangkok Dusit Medical Services. WB milk and whey samples were generously donated by the Lao Water Buffalo Dairy in Luang Prabang, Lao PDR.

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Hall, Emily A., Andrea K. Chomistek, Jackie J. Kingma, and Carrie L. Docherty. "Balance- and Strength-Training Protocols to Improve Chronic Ankle Instability Deficits, Part II: Assessing Patient-Reported Outcome Measures." Journal of Athletic Training 53, no. 6 (June 1, 2018): 578–83. http://dx.doi.org/10.4085/1062-6050-387-16.

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Context: Assessing global, regional, and fear-of-reinjury outcomes in individuals with chronic ankle instability (CAI) is critical to understanding the effectiveness of clinical interventions. Objective: To determine the improvement of patient-reported outcomes after balance- and strength-training and control protocols among participants with CAI. Design: Randomized controlled clinical trial. Setting: Athletic training research laboratory. Patients or Other Participants: Thirty-nine volunteers with CAI who scored 11 or greater on the Identification of Functional Ankle Instability questionnaire were randomly assigned to 1 of 3 groups: balance-training protocol (7 males, 6 females; age = 23.5 ± 6.5 years, height = 175.0 ± 8.5 cm, mass = 72.8 ± 10.9 kg), strength-training protocol (8 males, 5 females; age = 24.6 ± 7.7 years, height = 173.2 ± 9.0 cm, mass = 76.0 ± 16.2 kg), or control (6 males, 7 females; age = 24.8 ± 9.0 years, height = 175.5 ± 8.4 cm, mass = 79.1 ± 16.8 kg). Intervention(s): Each group met for 20 minutes, 3 times each week, for 6 weeks. The control group completed a mild to moderately strenuous bicycle workout. Main Outcome Measure(s): Global patient-reported outcomes, regional ankle function, and perceived instability were measured using the Disablement in the Physically Active Scale, the Fear-Avoidance Beliefs Questionnaire, the Foot and Ankle Ability Measure, and a visual analog scale for perceived instability. Participants completed the questionnaires at pretest and 6 weeks posttest. A multivariate repeated-measures analysis of variance with follow-up univariate analysis was conducted. The α level was set a priori at .05. Results: No time-by-group interaction was found (P = .78, η2 = 0.09). However, we observed a main effect for time (P = .001, η2 = 0.49). Follow-up univariate analyses revealed differences between the pretest and posttest for the Disablement in the Physically Active Scale (P = .02, η2 = 0.15), Fear-Avoidance Beliefs Questionnaire (P = .001, η2 = 0.27), Foot and Ankle Ability Measure–Activities of Daily Living subscale (P = .003, η2 = 0.22), Foot and Ankle Ability Measure–Sport subscale (P = .001, η2 = 0.36), and visual analog scale (P = .008, η2 = 0.18). Conclusions: Statistically, after the 6-week intervention, all groups improved in global and regional health-related quality of life. Clinicians should compare patient-reported outcomes with clinical measures to have a better understanding of progression during rehabilitation.

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Belli, Carolina, Ronald Feitosa Pinheiro, Maria Gabriela Flores, Silvia M. M. Magalhaes, Laura Kornblihtt, Alicia Enrico, Juliana Cordeiro, et al. "Clinical Characteristics and Prognosis in South-American Patients with Myelodysplastic Syndrome: A Multicenter Study." Blood 124, no. 21 (December 6, 2014): 4651. http://dx.doi.org/10.1182/blood.v124.21.4651.4651.

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Abstract There are previous reported data describing differences between European and Asian patients with Myelodysplastic Syndromes (MDS), and little is known about South-American (SA) patients. Our aim was to describe clinical characteristic of SA MDS population, to compare our series with diverse ethnicity, to evaluate scoring systems and prognostic factors. We retrospectively analysed a series of 1080 patients with de novo MDS (1981-2014) from Argentine (Ar-635), Brazil (Br-345), and Chile (Ch-100). Patients were classified following FAB and WHO criteria, excluding patients with bone marrow (BM) blasts >30% and CMML with white blood cells count >12x109/L. Patients undergoing hematopoietic stem cell transplantation (5%) or hypomethylating therapy (12%) were censored at treatment initiation. Chilean patients were younger (mean age: 59 vs 66-Ar, p<.001 and vs 65 years old-Br, p=.003), with a female preponderance (ratio M/F: 0.8-Ch, 1.3-Ar, 1.3-Br, p=.061). Since Ch did not include patients with CMML, distributions among FAB and WHO categories were different (p<.001). Br series showed a higher predominance of RARS (17% vs 9%-Ar vs 1%-Ch), and a lower percentage of RCMD (38% vs 43%-Ar vs 49%-Ch), while the frequency of the other subtypes were comparable. BM blast categories according to IPSS and IPSS-R were similar (p=.626 and =.508). Hemoglobin (Hb) level was significantly higher in Ar series (9.6g/dL vs 8.6g/dL-Ch, p<.001, and vs 8.7g/dL-Br, p=.002), with no differences in ANC and platelets (p=.842 and .763). There were no differences in the distribution of cytogenetic groups of risk (CGR) according to IPSS (p=.157). With respect to IPSS-R CGR distribution, Ar series showed a higher frequency of Very Good and Intermediate findings (4% and 19%, vs 2% and 15%–Br, 0% and 9%-Ch, respectively, p=.037). The distribution among IPSS categories was similar with a higher predominance of the high risk group in Ch (17%, 9%-Ar, 9%-Br, p=.056). IPSS-R distribution confirmed a higher frequency of very high risk in Ch series (20%, 13%-Br, 10%-Ar) and a lower predominance of very low risk (5%, 15%-Br and 22%-Ar) (p<.001). We also evaluated different prognostic factors in each MDS population and in the whole population (table). Overall survival (OS) was lower in Ch patients, consistent with the higher prevalence of higher risk group categories (36 months vs 56m-Ar; 63m-Br, p=.026). Hb, BM blast, CGR, IPSS and IPSS-R were useful to predict survival in the three series and in the overall SA MDS population. Age was not useful for Br patients and showed a borderline influence for the whole SA series. The ANC was neither a predictive variable for Br nor for Ch patients, and platelets count was not useful in Ch series. Epidemiological and clinical characteristics, distribution among prognostic subgroups and OS were similar for Ar and Br compared to Ch MDS series. This will need further analysis in a larger group of patients. Nevertheless, the IPSS-R system and its variables showed a good reproducibility to predict clinical outcome for the whole SA population. Abstract 4651. Table 1 Argentine Brazil ChileWhole SASurvival (50%, m)pSurvivalpSurvivalpSurvivalpAll patients56633655.026Gender M/F42/66<.00140/87=.00117/49ns41/70<.001Age ≤/>60 years77/50=.01944/68ns74/31=.00264/49=.052Hb ≥10/8-<10/<8g/dL98/50/31<.001135/44/36<.001NR/15/13=.002121/43/30<.001ANC ≥/<800/µL58/37=.03668/36=.06535/NRns57/37=.046Platelets ≥100/50-<100/<50 x103/µL71/44/40<.00170/47/40=.02941/36/17ns63/44/29<.001BM Blast ≤2/>2-<5/5-10/>10%80/63/21/17<.00175/70/36/11<.00148/36/15/7<.00177/60/25/13<.001CGR VG-G/I/P/VP66/35/20/12<.00170/20/9/16<.00174/13/4/7<.00168/32/16/12<.001IPSS121/44/19/14<.001116/55/13/9<.00150/49/6/7<.001116/49/18/10<.001IPSS-R136/64/34/18/14<.001135/70/32/17/11<.001NR/50/NR/13/6<.001135/70/41/18/11<.001 Disclosures No relevant conflicts of interest to declare.

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Walz, Lars, Gian M. Salzmann, Thomas Fabbro, Stefan Eichhorn, and Andreas B. Imhoff. "The Anatomic Reconstruction of Acromioclavicular Joint Dislocations Using 2 TightRope Devices." American Journal of Sports Medicine 36, no. 12 (September 2, 2008): 2398–406. http://dx.doi.org/10.1177/0363546508322524.

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Background For the reconstruction of acromioclavicular (AC) joint separation, several operative procedures have been described; however, the anatomic reconstruction of both coracoclavicular ligaments has rarely been reported. Purpose The aim of this biomechanical study is to describe a new procedure for anatomic reconstruction of the AC joint. Study Design Controlled laboratory study. Materials and Methods Forty fresh-frozen cadaveric shoulders were tested. Cyclic loading and a load-to-failure protocol was performed in vertical (native, n = 10; reconstructed, n = 10) and anterior directions (native, n = 10; reconstructed, n = 10) on 20 AC joints and repeated after anatomic reconstruction. Reconstruction of conoid and trapezoid ligaments was achieved by 2 TightRope devices (Arthrex, Naples, Florida). Dynamic, cyclic, and static loading until failure in vertical (n = 5) and horizontal (n = 5) directions were tested in native as well as reconstructed joints in a standardized setting. Results The native coracoclavicular ligaments in static load for vertical force measured 598 N (range, 409–687), elongation 10 mm (range, 6–14), and stiffness 99 N/mm (range, 67–130); static load for anterior force was 338 N (range, 186–561), elongation 4 mm (range, 3–7), and stiffness 140 N/mm (range, 70–210). The mean maximum static load until failure in reconstruction for vertical force was 982 N (range, 584–1330) ( P = .001), elongation 4 mm (range, 3–6) ( P < .001), and stiffness 80 N/mm (range, 66.6–105) ( P = .091); and for anterior static force 627 N (range, 364–973) ( P < .001), elongation 6.5 mm (range, 4–10) ( P = .023), and stiffness 78 N/mm (range, 46–120) ( P = .009). During dynamic testing of the native coracoclavicular ligaments, the mean amount of repetitions (100 repetitions per stage, stage 0–100 N, 100–200 N, 200–300 N, etc, and a frequency of 1.5 Hz) in native vertical direction was 593 repetitions (range, 426–683) and an average of 552 N (range, 452–683) load until failure. In vertical reconstructed testing, there were 742 repetitions (range, 488–893) ( P = .222; with a load until failure of 768 N (range, 486–900) ( P = .095). In the anterior direction load, the native ligament failed after an average of 365 repetitions (range, 330–475) and an average load of 360 N (range, 307–411), while reconstructed joints ended in 549 repetitions (range, 498–566) (P = .008J with a load until failure of 547 N (range, 490–585) ( P = .008). In all testing procedures, a preload of 5 N was performed. Conclusion The anatomic reconstruction of the AC joint using TightRope is a stable and functional anatomic reconstruction procedure. The reconstruction technique led to favorable in vitro results with equal or even higher forces than native ligaments. Clinical Relevance Through anatomic repair, stable function of the AC joint can be achieved in an anatomic manner.

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Abdellatif, A., L. Zhao, P. M. Peloso, K. Cherny, B. Marder, J. Scandling, and K. Saag. "POS1122 PRELIMINARY FINDINGS OF THE PROTECT CLINICAL TRIAL: PEGLOTICASE EFFICACY AND SAFETY IN KIDNEY TRANSPLANT RECIPIENTS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 840.2–840. http://dx.doi.org/10.1136/annrheumdis-2021-eular.97.

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Background:The prevalence of gout is high in kidney transplant (KT) recipients (up to 13%), largely because of decreased kidney function and calcineurin inhibitor use.1 Residual chronic kidney disease (CKD) leading to decreased urate lowering therapy clearance and drug interactions make managing gout in KT recipients challenging. Studies show that successful treatment with pegloticase, a pegylated uricase, leads to marked reductions in serum uric acid (sUA)2 and a subsequent decrease in overall urate load and tophi burden.3 However, pegloticase use in solid organ transplant recipients has not been systematically studied or well-characterized in the literature.4,5Objectives:To examine the safety and efficacy of pegloticase in KT recipients with uncontrolled gout.Methods:This ongoing multicenter, open-label, efficacy and safety study of pegloticase in KT recipients (NCT04087720) included patients with uncontrolled gout sUA ≥7 mg/dL, urate lowering therapy [ULT] contraindication/inefficacy, and with either visible tophi, chronic gouty arthritis, or ≥2 flares in past year, who were KT recipients (KT >1 year prior), had a functioning graft (estimated glomerular filtration rate [eGFR] ≥15 ml/min/1.73m2), and were on a stable immunosuppressant regimen. Pegloticase (8 mg infusion) was administered biweekly for 24 weeks (12 infusions) followed by a safety visit 30 days after the last infusion and 3-month post-treatment follow up visit. The primary endpoint was proportion of patients who were serum uric acid responders during Month 6 (sUA <6 mg/dL for ≥80% of time). Change from baseline (CFB) at 24 weeks was also evaluated for sUA, renal function, and health assessment questionnaire (HAQ) disability index (DI, maximum = 3) and pain (maximum = 100).Results:Preliminary findings of this study included 15 patients (12 male, 53.5±11.0 years of age) with uncontrolled gout (6.2±6.0 years since diagnosis) who had received a donor kidney 15.1±6.6 years earlier. At the time of analysis, 5 patients had completed the 24-week treatment period and 8 remained on therapy (last visit sUA <0.1 mg/dL in 6 patients, 1 had sUA of 7.4 mg/dL, 1 only received first infusion), and 2 had discontinued treatment (sUA rise [n=1], COVID-19 concerns [n=1]). Of the 5 patients who completed 24 weeks of therapy, all met response criteria and sUA was below detection limits (CFB: -10.2±1.3 mg/dL, baseline [BL]: 10.2±1.3 mg/dL). Patients also had less pain (HAQ-pain CFB: -33.6±22.2, BL: 35.9±22.0; n=5) and disability (HAQ-DI CFB: -0.3±0.6, BL: 0.7±0.8; n=5) at 24 weeks compared to BL. eGFR remained stable during 24 week treatment (eGFR CFB: -0.2±6.3 ml/min/1.73 m2, BL: 40.9±14.4 ml/min/1.73 m2; n=5). Urine albumin-to-creatinine ratio showed improvement at 24 weeks (CFB: -223±405 mg/g, BL: 664±870 mg/g; n=5). 80% of patients experienced an AE, and 4 SAEs (duodenal ulcer, cellulitis, dyspnea, skin bacterial infection) deemed unrelated to pegloticase were reported. AEs that occurred in >1 patient included gout flare, pyrexia, arthralgia, and nasal congestion. No anaphylaxis or infusion reactions occurred.Conclusion:Initial findings suggest that pegloticase therapy is effective at reducing sUA in most KT recipients while preserving renal function. Results suggest that in the setting of profound urate lowering with pegloticase in KT patients, eGFR remains stable and patients experience clinically beneficial reductions in pain and disability with an absence of unexpected safety findings.References:[1]Clive DM. J Am Soc Nephrol 2000;May11(5):974-9.[2]Sundy JS, et al. JAMA 2011;306:711-720.[3]Mandell BF, et al. Arthritis Res Ther 2018;20:286.[4]Freyne B. Transplant Proc 2018;50:4099-101.[5]Hershfield MS, et al. Arthritis Res Ther 2014;16:R63.Disclosure of Interests:Abdul Abdellatif Speakers bureau: Horizon Therapeutics plc, Consultant of: Horizon Therapeutics plc, Lin Zhao Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Paul M. Peloso Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Katya Cherny Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, Brad Marder Shareholder of: Horizon Therapeutics plc, Employee of: Horizon Therapeutics plc, John Scandling Consultant of: Horizon Therapeutics plc, Kenneth Saag Consultant of: Arthrosi, Atom Bioscience, Horizon, LG Pharma, Mallinkrodt, SOBI, Takeda, Grant/research support from: Horizon, SOBI, Shanton.

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Rodeghiero, Francesco, Andrew Provan, Michael Steurer, Bertrand Godeau, Nancy Carpenter, and Georg Kreuzbauer. "Pooled Analysis of Safety and Efficacy of Romiplostim in Splenectomized and Nonsplenectomized Patients (pts) with Immune Thrombocytopenia (ITP)." Blood 124, no. 21 (December 6, 2014): 4199. http://dx.doi.org/10.1182/blood.v124.21.4199.4199.

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Abstract Introduction: Romiplostim is a thrombopoietin receptor agonist approved for use in adult pts with ITP. Pooled analyses of combined pt data from romiplostim ITP clinical studies have previously been reported. Here we report updated safety and efficacy data according to baseline splenectomy status. Methods: Data from adult pts in 13 completed ITP studies with romiplostim were analysed up to June 2014. Pts received romiplostim, placebo or medical standard of care (SOC) and data from the placebo/SOC arms were pooled. All 13 studies were included in analyses of baseline pt characteristics and safety endpoints; 4 early dose-finding studies were excluded from analyses of efficacy endpoints as they do not reflect the current dosing of romiplostim. Adverse events were adjusted for time spent on study and reported as rates per 100 pt-years. For pts who started their parent study in the placebo/SOC group and then went on to receive romiplostim in an extension study, all data from the first dose of romiplostim were included in the romiplostim group. A platelet response was defined as a platelet count ≥50x109/L without rescue medication in the previous 8 weeks; a platelet response for 9 out of any 12 consecutive weeks on-study was considered a sustained platelet response. All analyses were descriptive and no statistical testing was performed. Results: Data from 1,111 pts were analysed, 395 splenectomized and 716 nonsplenectomized. The splenectomized and nonsplenectomized groups were similar in age (median 52 vs 53 years) and sex (female 64% vs 60%), but in the splenectomized group median baseline platelet counts were slightly lower (14 vs 19x109/L) and a higher proportion of pts were known to have received >3 prior ITP treatments (38% vs 12%) than the nonsplenectomized group. Rates of AEs, serious AEs, fatal AEs, treatment-related AEs, thrombotic events, and hemorrhages were lower in nonsplenectomized than splenectomized pts and were in general lower in romiplostim than placebo/SOC-treated pts in both groups. Bone marrow reticulin occurred in 17 romiplostim-treated pts and one placebo-treated pt, at a slightly increased rate in splenectomized vs nonsplenectomized pts. Bone marrow collagen was reported in one romiplostim-treated nonsplenectomised pt. Data from 1,024 pts were analysed for efficacy (376 splenectomized, 648 nonsplenectomized). The median (Q1, Q3) most frequent weekly dose was 4 µg/kg (2, 9) in splenectomized and 3 µg/kg (2, 7) in nonsplenectomized pts. A platelet response was achieved in 82% of splenectomized and 91% of nonsplenectomized pts and a sustained platelet response in 66% and 79%, respectively. The median time to first response was 2.1 weeks for splenectomized and 2.0 weeks for nonsplenectomized pts. Platelet responses were maintained in those who responded: after the first response the median (Q1, Q3) proportion of time with a response was 97% (79%, 100%) for splenectomized and 100% (91%, 100%) for nonsplenectomized pts. Conclusions: A relatively large number of nonsplenectomized pts have received romiplostim in clinical studies. Safety of romiplostim was comparable in splenectomized and nonsplenectomized patients with no new safety signals observed, and platelet response rates were high and of sustained duration in both groups. Abstract 4199. Table Number of events (rate per 100 pt-years) Splenectomized Nonsplenectomized Placebo/SOC N=27 Pt-yr=11.2 Romiplostim N=391 Pt-yr=702.0 Placebo/SOC N=106 Pt-yr=97.7 Romiplostim N=655 Pt-yr=1129.7 All AE 208 (1861.1) 8609 (1226.3) 1028 (1052.6) 9624 (851.9) Serious AE 15 (134.2) 478 (68.1) 92 (94.2) 498 (44.1) Fatal AE 3 (26.8) 11 (1.6) 5 (5.1) 31 (2.7) Treatment-related AE 15 (134.2) 864 (123.1) 152 (155.6) 928 (82.1) Treatment-related serious AE 0 (0) 65 (9.3) 18 (18.4) 59 (5.2) Treatment-related fatal AE 0 (0) 2 (0.3) 0 (0) 3 (0.3) Thrombotic events 1 (8.9) 44 (6.3) 5 (5.1) 52 (4.6) Hemorrhage events 54 (483.2) 1868 (266.1) 233 (238.6) 1591 (140.8) Fatal hemorrhage events 1 (3.7) 0 (0) 0 (0) 5 (0.8) Bone marrow reticulin /collagen events* 1 (8.9) 11 (2.0) 0 (0) 7 (0.8) Hematologic malignancies/MDS 0 (0) 6 (0.9) 4 (4.1) 8 (0.7) Any malignancies 0 (0) 24 (3.4) 9 (9.2) 43 (3.8) * Bone marrow collagen reported in one romiplostim-treated nonsplenectomized pt. Excludes study NCT00907478 as bone marrow evaluations were collected differently than in other studies; in the romiplostim arms the N/pt-yrs were 331/560.6 for splenectomised and 546/866.7 for nonsplenectomised pts. Disclosures Rodeghiero: GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Suppremol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Steurer:Amgen: Honoraria. Godeau:Amgen: Consultancy. Carpenter:Amgen: Employment, Equity Ownership. Kreuzbauer:Amgen: Employment, Equity Ownership.

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Dorfman, Todd A., Benjamin D. Levine, Tommy Tillery, Ronald M. Peshock, Jeff L. Hastings, Suzanne M. Schneider, Brandon R. Macias, Gianni Biolo, and Alan R. Hargens. "Cardiac atrophy in women following bed rest." Journal of Applied Physiology 103, no. 1 (July 2007): 8–16. http://dx.doi.org/10.1152/japplphysiol.01162.2006.

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Both chronic microgravity exposure and long-duration bed rest induce cardiac atrophy, which leads to reduced standing stroke volume and orthostatic intolerance. However, despite the fact that women appear to be more susceptible to postspaceflight presyncope and orthostatic hypotension than male astronauts, most previous high-resolution studies of cardiac morphology following microgravity have been performed only in men. Because female athletes have less physiological hypertrophy than male athletes, we reasoned that they also might have altered physiological cardiac atrophy after bed rest. Magnetic resonance imaging was performed in 24 healthy young women (32.1 ± 4 yr) to measure left ventricular (LV) and right ventricular (RV) mass, volumes, and morphology accurately before and after 60 days of 6° head-down tilt (HDT) bed rest. Subjects were matched and then randomly assigned to sedentary bed rest (controls, n = 8) or two treatment groups consisting of 1) exercise training using supine treadmill running within lower body negative pressure plus resistive training ( n = 8), or 2) protein (0.45 g·kg−1·day−1 increase) plus branched-chain amino acid (BCAA) (7.2 g/day) supplementation ( n = 8). After sedentary bed rest without nutritional supplementation, there were significant reductions in LV (96 ± 26 to 77 ± 25 ml; P = 0.03) and RV volumes (104 ± 33 to 86 ± 25 ml; P = 0.02), LV (2.2 ± 0.2 to 2.0 ± 0.2 g/kg; P = 0.003) and RV masses (0.8 ± 0.1 to 0.6 ± 0.1 g/kg; P < 0.001), and the length of the major axis of the LV (90 ± 6 to 84 ± 7 mm. P < 0.001), similar to what has been observed previously in men (8.0%; Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist Zerwekh JE, Peshock RM, Weatherall PT, Levine BD. J Appl Physiol 91: 645–653, 2001). In contrast, there were no significant reductions in LV or RV volumes in the exercise-trained group, and the length of the major axis was preserved. Moreover, there were significant increases in LV (1.9 ± 0.4 to 2.3 ± 0.3 g/kg; P < 0.001) and RV masses (0.7 ± 0.1 to 0.8 ± 0.2 g/kg; P = 0.002), as well as mean wall thickness (9 ± 2 to 11 ± 1 mm; P = 0.02). The interaction between sedentary and exercise LV and RV masses was highly significant ( P < 0.0001). Protein and BCAA supplementation led to an intermediate phenotype with no change in LV or RV mass after bed rest, but there remained a significant reduction in LV volume (103 ± 14 to 80 ± 16 ml; P = 0.02) and major-axis length (91 ± 5 to 88 ± 7 mm; P = 0.003). All subjects lost an equivalent amount of body mass (3.4 ± 0.2 kg control; 3.1 ± 0.04 kg exercise; 2.8 ± 0.1 kg protein). Cardiac atrophy occurs in women similar to men following sedentary 60 days HDT bed rest. However, exercise training and, to a lesser extent, protein supplementation may be potential countermeasures to the cardiac atrophy associated with chronic unloading conditions such as in spaceflight and prolonged bed rest.

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Кузнецов, Сергей Викторович, Алексей Сергеевич Низамутдинов, Эдуард Ильдарович Мадиров, Василий Андреевич Конюшкин, Андрей Николаевич Накладов, Валерий Вениаминович Воронов, Алексей Дмитриевич Япрынцев, Владимир Константинович Иванов, Вадим Владимирович Семашко, and Павел Павлович Фёдоров. "Исследование люминесценции твердых растворов на основе фторида иттрия, легированных иттербием и европием для фотоники." Kondensirovannye sredy i mezhfaznye granitsy = Condensed Matter and Interphases 22, no. 2 (June 25, 2020): 225–31. http://dx.doi.org/10.17308/kcmf.2020.22/2834.

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Подавляющая часть мирового рынка солнечных фотоэлектрических устройств основывается на кремниевых технологиях. Актуальной задачей является повышение эффективности их работы за счет использования люминесцентных покрытий, в том числе преобразующих излучение из УФ-синей области спектра в ближний инфракрасный диапазон, где кремний поглощает излучение с наибольшей эффективностью (стоксовая, или даун-конверсионная люминесценция) или из инфракрасной области спектра в ближний инфракрасный диапазон (ап-конверсионная люминесценция). Целью данного исследования были синтез и исследование спектрально-кинетических характеристик однофазных твердых растворов Y1–x–yEuxYbyF3 и определение квантового выхода даун-конверсионной люминесценции.Методом высокотемпературного сплавления были синтезированы однофазные образцы твердых растворов Y1–x–yEuxYbyF3 ромбической сингонии. Для серий образцов с различным соотношением Eu3+/Yb3+ при двойном допировании этими ионами было подтверждено образование соответствующих твердых растворов с кристаллической решеткой фазы b-YF3. Химический состав установлен энергодисперсионным анализом и было определено, что он соответствует номинальному. Показано, что при возбуждении на длинах волн 266 и 296 нм наблюдается люминесценция как ионов Eu3+, так и ионов Yb3+, что свидетельствует об перспективе их использования в качествесенсибилизаторов УФ излучения. При этом при возбуждении на длине волны 266 нм регистрируется люминесценция ионов Eu2+. Максимальные квантовые выходы даун-конверсионной люминесценции иттербия в ближнем инфракрасном диапазоне длин волн со значением 2.2 % при возбуждении на длине волны 266 нм были зарегистрированы для YF3:Eu:Yb при соотношениях Eu3+:Yb3+ 0.1:10.0 и 0.05:5.00. ЛИТЕРАТУРА 1. Weber E. R. Photovoltaics moving into the terawatt age. In: Proc. SPIE 10368, Next GenerationTechnologies for Solar Energy Conversion VIII. 2017;10368: 1036803. DOI: https://doi.org/10.1117/12.22779782. Seibt M., Kveder V. Gettering Processes and the Role of Extended Defects. In: Advanced Silicon Materialsfor Photovoltaic Applications. John Wiley & Sons, Ltd; 2012. pp. 127–188. DOI: https://doi.org/10.1002/9781118312193.ch43. Turkevych I., et al. Strategic advantages of reactive polyiodide melts for scalable perovskite photovoltaics.Nature Nanotechnology. 2019:14(1): 57–63. DOI: https://doi.org/10.1038/s41565-018-0304-y4. Abdollahi Nejand B., et al. Vacuum-assisted growth of low-bandgap thin fi lms (FA 0.8 MA 0.2 Sn0.5 Pb 0.5 I 3) for all-perovskite tandem solar cells. Advanced Energy Materials. 2020;10(5): 1902583. DOI:https://doi.org/10.1002/aenm.2019025835. Im J. H., et al. 6.5% effi cient perovskite quantumdot- sensitized solar cell. Nanoscale. 2011;3(10):4088–4093. DOI: https://doi.org/10.1039/C1NR10867K6. Huang X., Sanyang H., Wei H., Xiaogang L. Enhancing solar cell efficiency: the search forluminescent materials as spectral converters. Chemical Society Reviews. 2013;42(1): 173–201. DOI: https://doi.org/10.1039/C2CS35288E7. Trupke T., Green M. A., Würfel P. Improving solar cell effi ciencies by down-conversion of high-energyphotons. Journal of Applied Physics. 2002;92(3): 1668–1674. DOI: https://doi.org/10.1063/1.14920218. Yao H., Shen H., Tang Q. Highly luminescent up/down conversion thin fi lms prepared by a roomtemperature process. Thin Solid Films. 2019;683: 1–7. DOI: https://doi.org/10.1016/j.tsf.2019.05.0109. Loiko P. A., Khaidukov N. M., Mendez-Ramos J., Vilejshikova E. V., Skoptsov N. A., Yumashev K. V. Upanddown-conversion emissions from Er3+ doped K2YF5 and K2YbF5 crystals. Journal of Luminescence. 2016;170:1 – 7. DOI: https://doi.org/10.1016/j.jlumin.2015.10.01610. Li L., Lou C., Cao H., Diao H., Karunakaran S. K. Enhancing concentrator monocrystalline Si solarcells by down conversion Ce3+-Yb3+ co-doped YAG phosphors. Applied Physics Letters. 2018;113(10):101905. DOI: https://doi.org/10.1063/1.504322111. Serrano D., Braud A., Doualan J.-L., Camy P., Benayad A., Menard V., Moncorge R. Ytterbiumsensitization in KY3F10: Pr3+, Yb3+ for silicon solar cells effi ciency enhancement. Optical Materials. 2011;33(7): 1028–1031. DOI: https://doi.org/10.1016/j.optmat.2010.07.02312. Fischer S., Ivaturi A., Jakob P., Krämer K. W., Martin-Rodriguez R., Meijerink A., Goldschmidt J. C.Upconversion solar cell measurements under real sunlight. Optical Materials. 2018;84: 389–395. DOI:https://doi.org/10.1016/j.optmat.2018.05.07213. Kuznetsov S., Ermakova Y., Voronov V., Fedorov P., Busko D., Howard I. A., Turshatov A. Up-conversionquantum yields of SrF2:Yb3+, Er3+ sub-micron particles prepared by precipitation from aqueous solution.Journal of Materials Chemistry C. 2018;6(3): 598–604. DOI: https://doi.org/10.1039/C7TC04913G14. Fischer S., Ivaturi A., Jakob P., Krдmer K. W., Martin-Rodriguez R., Meijerink A., Richards B., GoldschmidtJ. C. Upconversion solar cell measurements under real sunlight. Optical Materials. 2018;84: 389–395. DOI: https://doi.org/10.1016/j.optmat.2018.05.07215. Lyapin A. A., Gushchin S. V., Kuznetsov S. V., Ryabochkina P. A., Ermakov A. S., V Proydakova. Yu.,Voronov V. V., Fedorov P. P., Artemov S. A., Yapryntsev A. D., Ivanov V. K. Infrared-to-visible upconversionluminescence in SrF2:Er powders upon excitation of the 4I13/2 level. Optical Materials Express.2018;8(7): 1863–1869. DOI: https://doi.org/10.1364/OME.8.00186316. Рожнова Ю. А., Кузнецов С. В., Воронов В. В., Федоров П. П. Синтез ап-конверсионных люминонофоров на основе фторида стронция, легированного Ho3+ и Er3+, для визуализаторов двухмикронного излучения. Конденсированные среды и межфазные границы, 2016;18(3): 408–413. Режим доступа: https://journals.vsu.ru/kcmf/article/view/150/10717. Александров А. А., Маякова М. Н., Воронов В. В., Поминова Д. В., Кузнецов С. В., Баранчиков А. Е., Иванов В. К., Лысакова Е. И., Фёдоров П. П. Синтез ап-конверсионных люминофоров на основе фторида кальция. Конденсированные среды и межфазные границы. 2020;22(1): 3–10. DOI: https://doi.org/10.17308/kcmf.2020.22/252418. Van Der Ende B. M., Aarts L., Meijerink A. Nearinfrared quantum cutting for photovoltaics. AdvancedMaterials. 2009;21(30): 3073–3077. DOI: https://doi.org/10.1002/adma.20080222019. Piper W. W., DeLuca J. A., Ham F. S. Cascade fl uorescent decay in Pr3+-doped fl uorides: Achievementof a quantum yield greater than unity for emission of visible light. Journal of Luminescence. 1974;8(4):344–348. DOI: https://doi.org/10.1016/0022-2313(74)90007-620. Yasyrkina D. S., Kuznetsov S. V., Ryabova A. V., Pominova D. V., Voronov V. V., Ermakov R. P., FedorovP. P. Dependence of quatum yield of up-conversion luminescence on the composition of fl uorite-typesolid solution NaY1-x-yYbxEryF4. Nanosystems: Physics, Chemistry, Mathematics. 2013;4(5): 648–656. Availableat: http://nanojournal.ifmo.ru/en/articles-2/volume4/4-5/physics/paper07/21. Ding M., Lu C., Cao L., Song J., Ni Y., Xu Z. Facile synthesis of b-NaYF4:Ln3+ (Ln = Eu, Tb, Yb/Er,Yb/Tm) microcrystals with down- and up-conversion luminescence. Journal of Materials Science. 2013;48(14):4989–4998. DOI: https://doi.org/10.1007/s10853-013-7285-x22. Tao F., Wang Z., Yao L., Weili C., Li X. Synthesis and photoluminescence properties of truncatedoctahedral Eu-Doped YF3 submicrocrystals or nanocrystals. The Journal of Physical Chemistry C.2007;111(8): 3241–3245. DOI: https://doi.org/10.1021/jp065905z23. Свешников Б. Я., Широков В. В. О зависимости измерений средней длительности и выходалюминесценции в процессе тушения от закона взаимодействия молекул. Оптика и спектроскопия.1962;12(5): 576–581.24. Кузнецов С. В., Низамутдинов А. С., Пройдакова В. Ю., Мадиров Э. И., Воронов В. В., Япрынцев А. Д., Иванов В. К., Гориева В. Г., Марисов М. А., Семашко В. В., Федоров П. П. Cинтез и исследованиелюминесценции твердых растворов Sr1–x–yYbxEuyF2+x+y для фотоники. Неорганические материалы.2019;55(10): 1092–1100. DOI: https://doi.org/10.1134/S0002337X19100087

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Escamilla, Virginia, Jose Falantes, Cristina Calderon, Jose Gonzalez Campos, Rosario Morales Camacho, Isabel Montero, Rocio Parody, Ricardo Bernal, Ildefonso Espigado, and Jose A. Perez-Simón. "Prognostic Impact of Adverse Karyotype and Treatment in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 5241. http://dx.doi.org/10.1182/blood.v126.23.5241.5241.

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Abstract INTRODUCTION Karyotype is a key prognostic factor in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Adverse karyotype (AK) significantly influences on response to treatment, prognosis and survival in older MDS and AML patients(pts)1,2. AIMS Evaluate the frequency of adverse karyotype over the total number of patients (pts) diagnosed with MDS and AML in our institution, demographic features, treatment received and overall survival (OS) estimates. Second, to analyze prognostic factors associated to OS in this cohort of pts. PATIENTS AND METHODS A retrospective and observational analysis was performed including all consecutive cases of MDS and AML with adverse karyotype. Period of analysis was from 2008-2015 for AML and from 1990-2015 for MDS pts. Adverse karyotype was defined as categories Intermediate-II and adverse from European LeukemiaNet recommendations in AML3, whereas IPSS4 was used for MDS pts. Complex and monosomal karyotype (CK/MK) were defined by the presence of ≥3karyotypic abnormalities in the absence of recurrent cytogenetic alterations based on the WHO classification, and the presence of ≥2 distinct autosomal monosomies or a single autosomal monosomy associated with at least 1 structural abnormality; respectively. Patients were stratified based on type of treatment received: active [intensive chemotherapy(IC)/azacitidine (AZA) followed or not by allogeneic transplant) vs supportive care (SC; including pts not candidates to active treatment due to comorbidity, poor ECOG status or advanced age >70). RESULTS A total of 98 pts were identified (N=49 cases of MDS and AML each). Median age at diagnosis was 65 years (range: 14-89). Demographic and baseline characteristics are described in table 1. The frequency of AK from the global cohort of MDS and AML from our institution was 20% and 19% respectively. Ten out of 49 (21%) pts with AML displayed recurrent cytogenetic alteration according to WHO classification [t(9;11) and other alterations in MLL, t(6;9), inv(3) or t(3;3)] and 28/49 (57%) and 18/49 (38%) had a CK or MK, respectively. In the MDS cohort, 25/49 pts (51%) had a chromosome 7 abnormality and 30/49 (61%) presented with a MK. Globally (AML and MDS), almost half of pts (49.8%) had a MK. Most pts <65y received active treatment (as previously stated) as compared to pts >65y (69% vs 37%; p<0.001). After 49 months median follow-up (range: 1-100), 22% pts (22/98) are alive with a median OS of 9 months for the global series (95% CI, 5.6-12.3). Median OS for pts treated with intensive chemotherapy, azacitidine or SC was 11 (CI 95%; 3.2-20.7), 14 (IC 95%; 10-17) and 5 months (IC 95%; 2-7); respectively (p=0.001). No difference in OS was observed between AML or MDS cases. Age >65y, KC, MK and treatment received (SC) had a negative impact on OS (p<0.05 all cases). In multivariate analysis, only the presence of MK [HR: 1.7, 95% IC (1.06-2.7); p=0.02] and receiving active treatment [HR: 0.49, 95% IC (0.3-0.8), p=0.006] remained statistical significant for OS. DISCUSSION Adverse, and particularly MK predict poor survival in AML/MDS. Both IC and AZA offer significant survival advantage over SC. References 1. Grimwade D, et al. Blood . 1998;92(7):2322-33 2. Dombret H, et al. Blood. 2015. 16;123(3):291-9 3. Döhner H, et al. Blood. 2010 Jan 21;115(3):453-74 4. Greenberg P, et al. Blood. 1997; 89:2079-88 Table 1. Baseline characteristics MDS patients (N=49) Parameter N (%) Age (median, range) 65 (17-83) Sex M:F 28:22 (56/44) BM blasts (%) 6.5 (0-29) WHO RA RCMD RAEB-1 RAEB-2 CMML MDS-U 4 (9) 11 (26) 7 (16) 17 (40) 3 (7) 1 (2) IPSS Int-1 Int-2 High risk 3 (6) 22 (45) 24 (49) Karyotype CK/MK Alt chrom 7 25 (51)/30 (61) 25 (51) AML patients (N=49) Age (median, range) 67 (14-75) Sex M:F 24:25 (49:51) BM blasts MO (%) 50 (16-97) Karyotype Recurrent abn - 5 or del(5q) -7 del(20) CK/MK 10 (20%) 4 (8) 8 (16) 1 (2) 28 (57)/18 (37) Disclosures No relevant conflicts of interest to declare.

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Hosing, Chitra, Rima M. Saliba, Martin Korbling, Sandra Acholonu, Safa Karandish, Sergio Giralt, Jo Lauppe, et al. "Effect of High-Dose Rituximab on Peripheral Blood Stem Cell Mobilization in Intermediate Grade Non-Hodgkin’s Lymphomas." Blood 104, no. 11 (November 16, 2004): 2877. http://dx.doi.org/10.1182/blood.v104.11.2877.2877.

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Abstract High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is considered to be standard therapy for patients with intermediate grade NHL (IGNHL) in chemosensitive relapse. In recent years rituximab has been widely used for in vivo purging of lymphoma cells from apheresis products, however its impact on kinetics of stem cell mobilization and engraftment are not well characterized. We studied 69 patients with IGNHL who were mobilized using rituximab plus chemotherapy or with chemotherapy alone. 31 patients (No-R group) were mobilized with ifosfamide (10 g/m2), and etoposide (150 mg/m2 every 12 hours for 6 doses) followed by G-CSF (12 mcg/kg/day). 38 patients (R group) also received 2 doses of rituximab (375 mg/m2 and 1000 mg/m2) on days 1 and 10. Patients underwent HDT following successful stem cell collection. HDT was standard BEAM (+ rituximab for patients in the R group) regimen in most patients. 15 patients received a cycle of CVP (cyclophosphamide, cisplatin, etoposide) prior to BEAM because of failure to achieve at least a PR following mobilization chemotherapy (all in the No-R arm). RESULTS: The baseline characteristics of the 2 groups are summarized in Table 1. Patients in the No-R group were more likely to have stage III/IV disease, and were more likely to have BM involvement with lymphoma, but had received fewer number of chemotherapy regimens received prior to mobilization. Failure to mobilize was defined as failure to reach a circulating CD34 count of 10/mcl. The target cell dose was a minimum of 4 x 106 CD34+ cells/kg. The apheresis data is summarized in Table 2. All 31 patients in the No-R group mobilized the target cell dose (NA-1). In the R group 7.9% did not reach the target cell dose (P=NS). Median time to neutrophil engraftment after ASCT was 10 (8–17) and 11 (9–37) days in the No-R and R groups respectively (P=0.01). The OS and DFS at 2 years were 45% (27–61) and 39% (22–55) and 78% (51–92) and 63% (38–51) respectively in the No-R and R group (P=0.001 and 0.01). CONCLUSION: High dose rituximab added to the mobilization regimen does not affect the ability to collect adequate number of stem cells for ASCT. Incidence of bacteremic episodes was higher in the rituximab group. The OS and DFS were significantly longer in patients receiving rituximab. Table 2. Apheresis Data Rituximab group (N=38) No rituximab group (N=31) P=value Median days of apheresis (range) 2 (1–5) 2 (1–7) NS Failure to mobilize 1 0 NS Failure to collect 4 x 106CD34+cells/kg 3 0 NS Median CD 34+cells/kg (range) 6.5 (0–31.15) x 106 13.7 (4.8–148) x 106 <.0001 PRBC transfusions median (range) 1 (0–5) 0 (0–8) .01 Platelet transfusions median (range) 2 (0–6) 1 (1–3) .008 No. of patients with infections 13 8 0.45 Infectious episodes 26 (22 bacterial) 11 (6 bacterial) 0.01 Time to ANC > 500/mm3 after mobilization median (range) 13 (11–18) 14 (6–24) NA 3 0.7 Table 1: Baseline characteristics Rituximab group No rituximab group P value N=38 N=31 Age years (range) 49.9 (19–70 ) 48 (26–59 0.68 Stage III/IV (%) 9 (23.7%) 13 (43.3%) .003 No. of prior chemoregimens (median, range) 2 (1–5) 1 (1–3) .001 IPI score (median, range) 0 (0–2) 1 (0–2) NA 5 .03 LDH ≥ normal (%) 8 (21%) 8 (30.7%) 0.78 BM involvement (%) 0 (0) 8 (25.8)

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Goedde, Martin, Thomas Sitter, Helmut Schiffl, Ulrike Bechtel, Wolfgang Schramm, and Michael Spannagl. "Coagulation and Fibrinolysis-Related Antigens in Plasma and Dialysate of Capd Patients." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 17, no. 2 (March 1997): 162–66. http://dx.doi.org/10.1177/089686089701700211.

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Objective The present study is aimed at gaining insight into coagulation and fibrinolysis in the peritoneal cavity of patients on continuous ambulatory peritoneal dialysis (CAPD). For this purpose we measured coagulation and fibrinolysis-related antigens in plasma and dialysate, comparing patients with and without peritonitis. Design Markers of activated coagulation and fibrinolysis in plasma and dialysate of CAPD patients were determined at different time points (0 hr, 2 hr, 4 hr) after infusion of the dialysis solution in the peritoneal cavity. Prothrombin fragment (F1 +2), thrombin-antithrombin III complex (TAT), and fibrin monomer (FM) were chosen as parameters of activated coagulation. Fibrin degradation products (FbDP), D-dimer (DD), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor type 1 (PAI-1) were measured as parameters for ongoing fibrinolysis. Beta2-microglobulin, albumin, and IgG were used as marker proteins for the diffusion of proteins of intravascular origin into the peritoneal cavity. Patients Eleven clinically stable CAPD patients, who had not suffered from peritonitis during the last six months, and 5 CAPD patients with an acute episode of bacterial peritonitis were studied. Results In the dialysate of stable CAPD patients (n = 11) the concentration of activation markers of coagulation and fibrinolysis increased continuously with dwell time. After four hours we found remarkably high levels of the coagulation markers F1 +2 (0.4± 0.1 nmoIIL), TAT (6.5 ± 1.0 ng/mL), and FM (24.5 ± 7. 1 μglmL), and the fibrinolysis markers DD (851 ± 26 nglmL), FbDP (1.0 ± 0.3 μglmL), t-PA (3.3 ± 0.8 ngl mL), and PAI-1 (2.6± 1.2 ng/mL). The dialysate-to-plasma (DIP) ratios of all of these antigens were significantly higher compared to the DIP ratios of proteins with similar molecular weight, which are not produced intraperitoneally (β2microglobulin, albumin, and IgG). These findings point to a local, thrombin-induced intraperitoneal fibrin generation during regular CAPD. Compared with clinically stable CAPD patients, the patients with bacterial peritonitis (n = 5) had significantly higher levels of F1+2 (5.3 ± 1.6 nmol/L), TAT (57.8± 10.7 nglmL), FM (972 ± 302 μg/mL), FbDP (16.4 ± 2.9 μg/mL), and PAI-1 (7.3± 2.4 ng/mL) in the dialysate (4-hr dwell time), and a 2.4-times higher ratio between FM and FbDP. These results can be interpreted as an intraperitoneal imbalance between coagulation and fibrinolysis during peritonitis. Conclusion Our study demonstrates a high intraperitoneal fibrin formation, not only during peritonitis but also in clinically stable CAPD patients. The remarkably high levels of coagulation (F1+2, TAT, FM) and fibrinolysis (FbDP, DD, t -PA, PAI-1) related antigens in the dialysate of patients without peritonitis cannot be explained by transport from plasma into the peritoneal cavity and may reflect a high rate of intraperitoneal fibrin turnover. The balance between peritoneal generation and degradation of fibrin is obviously disturbed in CAPD patients with peritonitis, who had significantly higher levels of coagulation markers in the dialysate and a higher ratio between FM and FbDP.

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van Rood, Jon J., Cladd E. Stevens, Jacqueline Smits, Carmelita Carrier, Carol Carpenter, and Andromachi Scaradavou. "Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse." Blood 114, no. 22 (November 20, 2009): 661. http://dx.doi.org/10.1182/blood.v114.22.661.661.

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Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 Disclosures: No relevant conflicts of interest to declare.

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Cortes, Jorge E., Neil P. Shah, Charles A. Schiffer, Philipp D. LeCoutre, Giuseppe Saglio, Alfonso Quintás-Cardama, Hagop Kantarjian, et al. "Significance of ELN Provisional Response Definitions In Predicting Long-Term Outcomes of Patients with CP-CML Treated with Dasatinib After Imatinib Failure." Blood 116, no. 21 (November 19, 2010): 3439. http://dx.doi.org/10.1182/blood.v116.21.3439.3439.

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Abstract Abstract 3439 Introduction: The European LeukemiaNet (ELN) recommendations for the management of chronic phase chronic myeloid leukemia (CP-CML) have provisionally defined criteria for suboptimal and failure to second-generation tyrosine kinase inhibitors (TKIs) (Baccarani et al., J Clin Oncol. 27 (35):6041-51, 2009). We tested the significance of these definitions in 3 studies of dasatinib after imatinib failure. Methods: Data from 1150 treated patients (pts) included in the 3 studies [CA180-013 (n=387); dasatinib only arm of CA180-017 (n=101); CA180-034 (n=662)] were analyzed. For the purpose of this analysis, we modified the 2009 ELN recommendations to add an optimal response category as shown in Table 1. Background: The median age of the pts included in this analysis was 56 yrs (range, 18–85) and the median duration of CML in these pts was 58 months (range, 0.9–250.8). Thirty-eight percent of the pts had received imatinib at a dose > 600mg/day and 45% had been on imatinib therapy >3 yrs. Twenty-four percent of pts included in this analysis had demonstrated imatinib-intolerance. Thirty-five percent of pts had mutations before the start of dasatinib therapy (5% had T315l). Results: Rates of optimal response at 3, 6 and 12 months were 51%, 44% and 36%. Rates of suboptimal response at 3, 6 and 12 months were 7%, 16% and 27%. Rates of failure response at 3, 6 and 12 months were 29%, 34% and 37%. Rates of warning response at 3 and 6 months were 12% and 6%. The starting dose of dasatinib did not influence these response rates. The group defined as suboptimal at 12 months (of whom 52% had already achieved CCyR) had a higher probability of achieving CCyR within 2 yr (83%) compared to the groups defined as suboptimal at 6 months (69%) or 3 months (51%). This suboptimal group at 12 months also had a higher 2 yr progression-free survival (PFS) (92%) compared to the suboptimal groups at 6 months (82%) and 3 months (80%). The probability of achieving an MMR within 2 yr was slightly higher in pts defined as optimal at 6 months (80%) vs. those at 3 months (71%). However, the probability of achieving an MMR within 2 yr showed minimal change for the suboptimal (31-35%) or the failure (5%) response groups defined at 3, 6 and 12 months. The pts with a warnings response had a profile that was intermediate between suboptimal and failure response. Table 2 summarizes 2 yr outcomes based on response. Conclusions: These results suggest that the 2009 ELN provisional response definitions may be helpful in predicting long term outcomes in pts receiving second-line dasatinib therapy. In this cohort of pts, optimal responders identified themselves rapidly as did pts with failure. However, the outcome of pts defined as suboptimal at 12 months appeared more favorable than that of pts defined as suboptimal at 3 and 6 months. This, in addition to the higher proportion of pts classified as suboptimal at 12 months, compared to those classified as suboptimal at 3 and 6 months, may suggest that the ELN defined cut-off between optimal vs. suboptimal at 12 months (i.e. MMR) may need to be modified in order to make the prognosis for suboptimal response more consistent across different time points. Pts classified in the warnings category at 3 and 6 months had an outcome intermediate between those with suboptimal and failure response. Disclosures: Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Shah:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. LeCoutre:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Kantarjian:Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Bahceci:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Lambert:Bristol-Myers Squibb: Employment. Guilhot:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.

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Sagatys, Elizabeth, Lynn Moscinski, Sophie Dessureault, Eduardo Sotomayor, and Hernani Cualing. "Analysis of T-Cell Subpopulations in the Lymph Nodes of Patients with Mantle Cell Lymphoma." Blood 110, no. 11 (November 16, 2007): 1580. http://dx.doi.org/10.1182/blood.v110.11.1580.1580.

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Abstract Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell NHL characterized by a high relapse rate. Novel treatments capable of providing and/or sustaining more durable responses in MCL patients are clearly needed. Manipulation of the immune system to unleash its protective effect might induce durable responses in MCL. To effectively harness the immune system against MCL, it is important to understand how T-cells interact with malignant B-cells that reside where immune responses are normally initiated. In the present study, we evaluated the number and phenotype of T-cells present in the lymph nodes of 14 patients with MCL. Given the increasingly important role of T regulatory cells (Tregs) and the paucity of information regarding their role in MCL, we also evaluated if T-cells infiltrating the lymph node of MCL patients co-express CD4 and FoxP3. Our patients consisted of 1 woman and 13 men, age range from 49–78 (mean age 65), 6 previously treated with chemotherapy, and 8 de novo. There was heterogeneity in the CD3+ T cell populations in our patients (range 2.7–55% [mean 15.8%]). Double staining with CD4/FoxP3 (range 0.2–3.4% [mean 1.7%]) and CD8/FoxP3 (range 0–3.2% [mean 1.4%]) showed significant heterogeneity in both populations (Table 1). A significant portion of FoxP3 positive, CD4/CD8 negative cells were seen in several cases (range 0–16% [mean 4.9%]). Flow cytometry was run on all 14 cases to evaluate the T cell populations. Spearman non-Gaussian regression analysis (using GraphPad™ software) comparing the CD4/FoxP3+ and CD8/FoxP3+ cells to the total CD8 cells showed a negative correlation by both immunohistochemical and flow, confirming that as the Treg population increases the CD8 population decreases (Table 2). Correlating CD4 Treg with CD8 by flow cytometry and IHC indicated an inverse correlation in 7 of 14 cases. Only 1 case had a positive correlation. The remaining cases had no correlation. These findings suggest increasing FoxP3 populations in MCL could result in a decrease in CD8+ T cell immune response against the malignant cells. Future studies including the characterization of the non-CD4/CD8 FoxP3+ cells may help clarify the role of Tregs in MCL. Table 1: MCL T cell Populations CD3+ FLOW (%) Total FoxP3 IHC (%) CD4/FoxP3+ IHC (%) CD8/FoxP3+ IHC (%) CD4+ IHC (%) CD8+ IHC (%) CD4+ FLOW (%) CD8+ FLOW (%) 6.5 3.2 1.8 0.4 6.4 7.8 2 4 43 12.8 0.6 1 10.6 19.2 16 27 16 4.4 0.2 0.8 8.8 15.4 5 11 11 3.6 1.4 0 6.2 1.8 8 3 8.4 3.4 0.8 1.4 17.6 11.2 1.6 3.9 10 7.8 1.8 0.6 13.6 9.2 7.5 2.5 26 12.4 3.4 2.4 15.8 16.8 20 0.1 6.3 8.2 2.2 3.2 11.6 11 1.7 3.7 55 8.6 3.4 1 21 21.6 30 25 12 10.8 2.4 2 16.8 17 5.1 6 8.4 4.6 1.6 1.2 17.6 18 5.1 3.2 5.4 9.6 1.8 1.8 13.6 16 3.6 0.3 2.7 2.2 0.8 1.4 3.8 3.4 0.8 1.9 11 19 1.2 1.8 22 8.6 7.6 3.6 Table 2: Spearman Rank Correlation Group Spearman Rank Correlation 95% Confidence Interval CD4/FoxP3+ vs. CD8 (IHC) 0.2788 −0.3115 to 0.7138 CD4/FoxP3+ vs. CD8 (FLOW) −0.2614 −0.7045 to 0.3284 CD8/FoxP3+ vs. CD8 (IHC) 0.2558 −0.3337 to 0.7105 CD8/FoxP3+ vs. CD8 (FLOW) −0.2196 −0.6815 to 0.3673 CD4/FoxP3+ vs. CD4 (IHC) 0.3448 −0.2440 to 0.7479 CD4/FoxP3+ vs. CD4 (FLOW) 0.3636 −0.2237 to 0.7572 CD8/FoxP3+ vs. CD4 (IHC) 0.4044 −0.1777 to 0.7769 CD8/FoxP3+ vs. CD4 (FLOW) −0.2243 −0.6841 to 0.3630

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Kelaidi, C., Aspasia Stamatoullas, Odile Beyne-Rauzy, Francois Dreyfus, Bruno Quesnel, Agnes Guerci, E. Raffoux, et al. "Myelodysplastic Syndrome (MDS) in France: Results of a One-Week Cross-Sectional Survey on Daily Practice Management in 919 Patients by the GFM." Blood 112, no. 11 (November 16, 2008): 2672. http://dx.doi.org/10.1182/blood.v112.11.2672.2672.

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Abstract Background: Epidemiological data on MDS is scarce in France, and registries from other countries do not provide data on the daily practice management of MDS in 2008. Methods: GFM centers were asked to collect characteristics of ongoing or recent treatments in all MDS patients (pts) seen at their clinic (as in or outpatients) during the Jan 28th–Feb 3rd, 2008 period (one week).Results: 919 pts from 74 centers were included, 57% males, mean age (+/− SD), 73 (±11) years, with 2.8%, 19% and 28% of pts aged <50, <65 and >80 years, respectively (resp).13% of pts were hospitalized >24h (4.5% for infections or bleeding and 8.5 % for “active” treatments), 46% were seen in the day care facility (40% for transfusions), and 41% as consultations (for staging, follow up or ambulatory treatment). 93% of patients had PS ≤2. Median interval from diagnosis to survey was 29.2 months. FAB at time of survey was: 35.1% RA, 18.5% RARS, 39.1% RAEB, 7.4% CMML; WHO was: 17.4% RA, 13.3% RARS, 14% RCMD, 4.5% RCMD-RS, 18.5% RAEB-1, 15.9% RAEB-2, 7.7% CMML, 4.9% 5q-syndrome and 3.9% unclassifiable. Cytogenetic analysis had been performed at least once in 77.4 % pts: favorable (498 pts), intermediate (88 pts), unfavorable (96 pts). IPSS (determined in 75.4% of pts) was: 41.6% low, 33.3% Int-1, 16.4% Int-2 and 8.7% high. Significant differences between pts <65 years and >65 years were, respectively, % of unfav karyotype (25.8% vs. 12.7%, p=0.0004), of isolated +8 (5.1% vs. 2.1%, p=0.04), of isolated −7 (6.2% vs. 1.1%, p=0.0003), and, with borderline significance, of CMML (4.5% vs. 9.5%, p=0.06), of 5q-syndrome (1.5% vs. 5%, p=0.07). EPO level, assessed in 359 (39.1%) of pts at diagnosis and 252 (27.4%) of pts at time of survey) was >200UI/l in 24.5% and 26.6% resp, and >500U/l in 13.5% and 14.7% pts resp and was significantly correlated with interval from diagnosis. At the time of survey, treatment received in the last 6 months (IPSS: high-int 2 vs low–int1) included: no active treatment 66.5% (IPSS: 42% vs. 72.9%), chemotherapy 12.8% (IPSS: 22.6% vs. 9.1%) including 2.7% intensive and 0.7% LD AraC, allogeneic SCT 1.7% (IPSS: 3.8% vs. 2.6 %) including 0.3% classical and 1.4% NMA, azacytidine 6.5%, (IPSS: 21.6% vs. 2.3%), decitabine 0.8%, lenalidomide 4%, thalidomide 0.5%, ATG 0.2 %, androgens 2.2% while 64.8% pts required RBC transfusions (IPSS: 81% vs. 61%) and 39.7% pts received an Erythropoiesis-Stimulating Agent (ESA) (IPSS: 40.3% vs. 37.2%), alone in 314 pts (epoetin alfa or beta in 92 pts, darbepoetin in 222 pts), and with G-CSF (61 pts). Response rates to ESAs were 58.6% and 33.8% in low int-1 and int-2-high risk MDS, resp (p=0.0009). Iron chelation therapy was administered in 17.6% pts (5.8% desferroxamine, 11% deferasirox) including 22.1% and 13.6% low-int-1 and int-2-high risk MDS, resp (p=0.009). Conclusions: Our survey provides a better knowledge of the characteristics and of the daily management of MDS in France. Of particular note are the more frequent unfavorable karyotypes in MDS pts <65 years and the generally low EPO levels that may increase the indications for ESAs in low and int 1 risk MDS with anemia. Apart from ESAs, active treatments of MDS still only reach a minority of pts, and transfusions account for as many as 40 % of the hospital visits/stays for MDS.

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Leitch, Heather A., Hatoon Ezzat, Meaghan D. Rollins, Dominic H. C. Wong, Chantal S. Leger, Khaled M. Ramadan, Michael J. Barnett, and Linda M. Vickars. "Transfusion Dependence in Patients with Primary Myelofibrosis Has a Negative Impact on Survival Independent of Decreased Myelopoiesis." Blood 110, no. 11 (November 16, 2007): 4653. http://dx.doi.org/10.1182/blood.v110.11.4653.4653.

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Abstract Primary myelofibrosis (PMF) is a myeloproliferative disorder characterized by progressive bone marrow failure, extramedullary hematopoiesis and risk of progression to blast phase (BP). Many PMF patients (pts) require red blood cell (RBC) transfusions, risking iron overload (IOL)-related organ dysfunction. Pts with myelodysplastic syndrome and RBC transfusion dependence (TD) have worse overall survival (OS), which may be improved by iron chelation therapy (ICT). To assess the effect of TD and ICT on survival in PMF, we reviewed 30 pts seen from 1985 to 2007 with a marrow biopsy confirmed diagnosis. 21 pts were male and 9 female and median age at Dx was 66.5 (range 43–84) years (y). ECOG Performance Status; 0, n=13; 1, n=9; 2, n=7; 3, n=1. WBC count was <4.0 or >30x109/L at diagnosis in 5 pts, and hemoglobin (Hb) <100G/L in 14. Karyotype in 13 pts: normal, n=11; del (6)(q25), n=1; complex, n=1. Lille Prognostic Score was: 0, n=10; 1, n=11; 2, n=4. 20 pts were RBC-TD with total units (U) transfused: 1–20, n=6; 21–50, n=3; >50, n=11. Initial PMF treatment was: supportive care, n=21; low-dose chemotherapy, n=4; immunomodulatory, n=3; splenectomy, n=2. Clinical evidence of IOL, n=14 total: CHF, n=4; liver disease, n=3; endocrine, n=3; ferritin ≥1000 ug/L at Dx, n=6. Baseline features that differed between transfusion-independent (TI) and TD and between non-ICT-TD and ICT pts: total RBCU transfused (p=0.0001 and p=0.03) and evidence of IOL (p=0.003 and p=0.06), respectively. 5 pts received ICT for a median of 75.7 (range 2.9–117) months (mo); 4 received desferrioxamine (DFO) 0.5–3g by subcutaneous infusion 12 h/d, 5 d/wk and 2 received deferasirox (1 switched from DFO). At a median follow-up (FU) of 58.8 (0.1–243.7) mo, 2 non-ICT pts and 1 ICT pt progressed to PMF-BP; 2 received chemotherapy and all 3 died of progressive BP within weeks. Median OS for all pts, TI, TD and ICT pts was: 102.1 (14.4–243.7) mo; not reached at 204.9 mo; 60.8 (14.4–243.7) mo and 83.6 (60.8–202.9) mo and 5y OS was 67%; 100%; 55% and 66% respectively (p=0.014 for TD vs. TI). Factors significant for OS were: RBC-TD (p=0.014, hazard ratio [HR] 43.6, confidence intervals [CI] 41–46.2); increasing RBC transfusion requirement (TR; 2 fold change in RBCU/4wk; p=0.018, HR 5.0 [4.3–5.7]); Hb<100G/L (p=0.03, HR 3.8, [3.2–4.4]); total RBCU transfused (p=0.0001, HR 1.3 [1.0–1.6]). 12 TD pts (60%) died: cardiac, n=3; infection, n=3; bleeding, n=2 (1 ICT pt); PMF-BP, n=3; unknown, n=1. Initial/pre-ICT mean ± standard error (se) ferritin was 2337±1038ug/L in ICT pts and 506±466ug/L in non-ICT pts, and FU ferritin decreased in ICT pts to 1902±428ug/L (p=0.03) and was 824±445ug/L in non-ICT pts (p=NS). Initial and FU neutrophil counts (NC) in ICT pts were a mean ±se of 4.7±1.6 and 5.0±1.7 vs. 7.2±1.5 and 20.6±7.7 x109/L in non-ICT pts; platelet counts (PLTC) were 432±89; 527±208; 293±50; and 203±36 x109/L respectively and RBCU transfused/4 wk were 2.3±0.6; 3.3±0.8; 1.3±0.3; 1.8±0.4 (p=NS for all and for TI vs. TD NC and PLTC). In conclusion, 67% of pts with PMF developed RBC-transfusion dependence, which portended worse OS. However, there was no significant decrease in neutrophil or platelet counts or increase in RBC transfusion requirements. This suggests the effect of TD on OS was not from impaired myelopoiesis alone, and that there may be an impact of IOL secondary to TD on outcome. Prospective studies of ICT in PMF pts are warranted.

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Morales, L., R. Chavez, ME Ayala, and R. Dominguez. "Effects of unilateral or bilateral superior ovarian nerve section in prepubertal rats on the ovulatory response to gonadotrophin administration." Journal of Endocrinology 158, no. 2 (August 1, 1998): 213–19. http://dx.doi.org/10.1677/joe.0.1580213.

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The modulating effects of ovarian innervation reaching the ovary through the suspensory ovarian nerve on the reactivity of the ovaries to gonadotrophins were analysed. Juvenile rats (32 days old), with or without unilateral or bilateral section of the superior ovarian nerve, were injected with 8 iu of pregnant mare serum gonadotrophin (PMSG), 10 iu of human chorionic gonadotrophin (hCG) or with 8 iu of PMSG followed 56 h later with 10 iu of hCG. Treatments were given immediately after surgery or 4 days later, and the rats were killed on the day of first vaginal oestrus. In rats with unilateral section, treatment with PMSG did not induce full ovulatory response by the denervated ovary whether the treatment was applied immediately or 4 days after surgery (0/11 rats treated immediately ovulated vs 5/5 (sham) and 11/12 (control, P < 0.05 Fisher's exact probability test), and 4/19 did when treatment was done 4 days after surgery vs 8/10 (sham) and 11/12 (control, P < 0.05). The rats with bilateral section receiving the same hormonal treatment, PMSG administration, ovulated. The number of ova shed by the left ovary was similar to those of the control, while the right ovary released fewer ova. Stimulation with hCG immediately after unilateral section did not induce ovulation in normal or denervated ovary. When the treatment was applied 4 days after surgery, ovulation was observed only in the innervated ovary. In the rats with bilateral section, hCG injection induced ovulation in both ovaries. In those rats with unilateral section of the superior ovarian nerve, the treatment with PMSG + hCG given immediately after surgery resulted in a compensatory ovulation by the innervated ovary (the number of ova shed/ovulating animal was significantly higher than those released by control or sham-operated animals: left section, number of ova shed by the right ovary 7.6 +/- 0.3 vs 5.5 +/- 0.8 and 4.9 +/- 1 respectively, P < 0.05; right section, number of ova shed by the left ovary 10.2 +/- 0.6 vs 4.4 +/- 1.1 and 7.0 +/- 0.9, P < 0.05), while the denervated one showed a lower ovulation rate as well as a smaller number of ova shed than those by the control animals. When the hormonal replacement was given 4 days after surgery, such compensatory ovulation was observed in the left ovary of those rats with a section of the right nerve (14.3 +/- 2.6 vs 4.4 +/- 1.1 and 6.5 +/- 1.1, P < 0.05). When the PMSG + hCG treatment was applied to animals with bilateral section of the superior ovarian nerve, the ovulation rate by the right ovary was significantly lower than in control and sham-operated treated animals (2/10 vs 11/11 and 6/7, P < 0.05). Because the ovaries receive innervation through the superior ovarian nerve, the ovarian plexus and the vagus nerve, the results obtained in unilateral denervated animals suggest that the innervation of the ovary via the superior ovarian nerve regulates in a stimulatory way the effects of gonadotrophin resulting in ovulation. The ovulation induced by hormonal treatment of rats with bilateral section of the superior ovarian nerve suggests that the effects of bilateral section on ovulation are not the addition of the effects of left and right denervation, implying the existence of a modulatory effect in gonadotrophin action on ovulation via other neural pathways.

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Rogers, Kimberly Papay, Victoria G. Morris, Melissa F. Miller, and Thomas W. LeBlanc. "The Relationship between Depression, Anxiety, and Clinical Trial Perceptions Among Patients with Hematologic Cancer." Blood 138, Supplement 1 (November 5, 2021): 1901. http://dx.doi.org/10.1182/blood-2021-148010.

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Abstract Introduction. Despite the fact that thousands of cancer clinical trials (CCTs) are available today, engagement remains low, with only 2-7% of patients with cancer participating in CCTs. Research has shown that this may partially be due to fear-based perceptions around CCTs. Unfortunately, depression and anxiety, two psychological factors that are highly prevalent in the cancer space, are known to bias attention in ways that alter perceptions and are specifically known to amplify fear-based perceptions. Thus, the purpose of this exploratory study was to examine the relationship between depression, anxiety, and perceptions of clinical trials among patients with hematologic cancer. Method: In this observational, cross-sectional study, 625 patients with hematologic cancer (46.4% multiple myeloma; 19.5% CLL; 11.4% non-Hodgkin lymphoma; 4.0% AML; 3.5% Hodgkin lymphoma; 3.2% CML; 1.6% ALL; 1.3% MPN; 7.4% other lymphoma; 1.8% other leukemia) completed the Cancer Support Community's online survey, the Cancer Experience Registry®. Participants provided sociodemographic and clinical history information, rated their level of agreement (0 = strongly disagree to 4 = strongly agree) with 8 statements related to beliefs about CCTs, and completed the Anxiety and Depression subscales (4 items each rated 1 = never to 5 = always) from the Patient-Reported Outcomes Measurement Information System (PROMIS-29v2.0). Responses to these 8 PROMIS items were averaged to compute a combined depression and anxiety score on a 5-point Likert scale. To understand the impact of depression and anxiety on perceptions of CCTs, 8 hierarchical regression models were examined; the dependent variable for each model was one of the CCT perception variables. Clinical history (cancer diagnosis, time since diagnosis, type of cancer care facility) and sociodemographic variables (age, gender identity, income, educational attainment, race, ethnicity, geographic area) were controlled for. Results: The sample was 54.9% female, 86.7% Non-Hispanic White, 60.1 years old on average (SD=10.8) and had an average time since diagnosis of 5.3 years (SD=5.3; Median = 3.0 years; IQR = 6 years). 67.7% had a college degree, 20.5% had a gross annual household income of $100,000 or above, 41.4% received cancer treatment at an academic or comprehensive cancer center, and 45.6% lived in a suburban area. Participants' average anxiety and depression score was 1.91 (SD=.93). Hierarchical regression analyses demonstrate that depression and anxiety had a significant effect on 7 of the 8 CCT perceptions assessed, when controlling for sociodemographic and cancer characteristics. Specifically, depression and anxiety were significant predictors of participants' perceptions that, "I would be unable to fulfill trial requirements due to logistical barriers" (ΔR 2=.019, b=.19, p=.003), "I don't trust the medical establishment and fear I will be used as a 'guinea pig'" (ΔR 2=.017, b=.17, p=.006), "I am uncomfortable with being randomly assigned" (ΔR 2=.016, b=.19, p=.01), "I fear receiving a placebo (for example, a sugar pill) in a clinical trial" (ΔR 2=.012, b=.18, p=.024), "I don't understand what clinical trials are" (ΔR 2=.011, b=.13, p=.021), "There are no clinical trials available in my community" (ΔR 2=.010, b=.14, p=.030), and "I fear side effects that might come with treatment on a clinical trial" (ΔR 2=.009, b=.13, p=.047). Thus, depression and anxiety accounted for significant amounts of variance in each of these clinical trial perceptions above and beyond the controls. Depression and anxiety did not have a significant impact on participants' perceptions that their health insurance would not cover a CCT (ΔR 2=.002, b=.05, p=.370). Conclusion. Our findings demonstrate small but significant relationships between depression, anxiety, and perceptions of CCTs among patients with hematologic cancer. While common attempts to alter CCT perceptions often focus on information dissemination, the present study indicates that psychological factors may also need to be considered. While this study is an important first step in considering the relationship between mental health and perceptions of CCT, further longitudinal research is needed to better elucidate these findings. For example, differential analyses should explore if and how these relationships differ among patients with pre-existing clinically-significant levels of depression and anxiety. Disclosures LeBlanc: AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Flatiron: Consultancy, Other: Advisory board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; UpToDate: Patents & Royalties; Pfizer: Consultancy, Other: Advisory Board; CareVive: Consultancy, Other, Research Funding; NINR/NIH: Research Funding; Helsinn: Consultancy, Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Astellas: Consultancy, Honoraria, Other: Advisory board; Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; Jazz Pharmaceuticals: Research Funding; Otsuka: Consultancy, Honoraria, Other; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Other: travel; Heron: Consultancy, Honoraria, Other: advisory board; American Cancer Society: Research Funding; Duke University: Research Funding.

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Bai, Q. R., X. Y. Jiang, J. Gao, and Y. Li. "Target Spot on Menispermum dauricum Caused by Streptobotrys (≡Streptotinia) caulophylli, a New Disease in China." Plant Disease 98, no. 12 (December 2014): 1743. http://dx.doi.org/10.1094/pdis-06-14-0565-pdn.

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Menispermum dauricum (moonseed) (family Menispermaceae), a perennial twining vine, is an ornamental plant traditionally used in Chinese medicine. M. dauricum is distributed mostly in northeastern, northern, and eastern China, Japan, Korea, and southern Siberia (4). Rhizoma menispermi is the dry root of M. dauricum, which has detoxifying and dehumidifying effects, and is mainly used for the treatment of sore throat, enteritis, diarrhea, and rheumatism. From June to September in 2012 and 2013, target spots were observed on moonseed plants, with an incidence above 30% in the medicinal herb garden of the Institute of Special Animal and Plant Sciences at the Chinese Academy of Agricultural Science (44°02′ N, 126°05′ E) in Jilin Province. Lesions on the leaves were roughly circular, forming concentric rings of alternating light and dark brown bands with yellow halos at the margins, and up to 50 mm in diameter. Lesions coalesced to a large area capable of destroying the leaf. Under humid conditions, the lesions enlarged rapidly. Occasionally, grayish-white mycelia appeared on the lesions. Subsequently, grayish-brown conidiophores arose, singly or in dense groups, up to 700 μm high, with large loose conidial heads. Side branches and branchlets were tightly twisted, brown and 7 to 11 μm in width. Conidiogenous cells were inflated at the apex of the branches and delimited by a septum. Conidia were globose to subglobose, pale brown, unicellular, minutely echinulate, and rounding to 7.8 to 16.9 μm in diameter. Four isolates were obtained from necrotic tissue from leaf spots and cultured on potato dextrose agar (PDA) at 25°C. Mycelia grown on PDA were sparse, whitish-gray, and produced small black sclerotia within 3 to 5 days. Sclerotia were round or oval to oblong and 0.3 to 1.7 × 0.8 to 1.7 mm. No conidiophores or conidia were produced on PDA. The similar species Streptobotrys streptothrix had smooth conidia and small sclerotia. So, all isolates were identified as S. caulophylli based on their morphological and cultural characteristics (2,3). The internal transcribed spacer (ITS) region was amplified by using the primers ITS4 and ITS5 (1). The ITS sequences (529 bp) were identical in these four isolates (Accession No. HG918042). Pathogenicity tests were performed on healthy 2-year-old moonseed plants. Ten leaves were inoculated with a 0.6-cm diameter mycelial plug from 3-day-old PDA cultures for each isolate, and the inoculation sites covered with moistened sterile absorbent cotton. Another 10 leaves were inoculated with sterile PDA plugs as controls. All plants in the experiments were covered with plastic bags and maintained in a greenhouse at 20 to 25°C for 24 h. After 3 days, dark brown spots were observed on all leaves inoculated with these isolates. After 7 days, the classical symptoms were evident, while control plants remained healthy. The re-isolated pathogen was identified as S. caulophylli based on morphological analysis. The pathogenicity test was repeated with similar results. Currently, the economic importance of this disease is limited, but it may become a more significant problem with the cultivation area of M. dauricum increasing. To our knowledge, this is the first report of S. caulophylli causing target spot on M. dauricum in China. References: (1) D. E. L. Cooke et al. Mycol. Res. 101:667, 1997. (2) M. E. Elliott, Can. J. Bot. 40:1197, 1962. (3) S. K. Hong et al. Plant Pathol. J. 20:192, 2004. (4) Y. H. Liu. Page 39 in: Flora Republicae Popularis Sinicae, vol. 30. Sciences Press, Beijing, 1996.

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Rumiantceva, D., E. Agafonova, M. Urumova, and S. Erdes. "AB0470 EXPERIENCE WITH THE USE OF INTERLEUKIN 6 INHIBITOR IN SEVERE ANKYLOSING SPONDYLITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1262.1–1262. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1740.

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Background:Inhibitors of interleukin 6 (IL6) have been found to be ineffective in ankylosing spondylitis (AS) based on the results of randomized clinical trials (RCTs) on tocilizumab (TCZ) and sarilimumab [1, 2]. However, there is evidence that IL6 is actively involved in the pathogenesis of the disease [3]. In addition, the efficacy of IL6 inhibitors has been shown in patients with secondary AA amyloidosis [4].Objectives:to analyze the effectiveness of IL6 inhibitor - TCZ in patients with AS with high disease activity and secondary AA-amyloidosis.Methods:The analysis included 10 patients with AS receiving TCZ therapy, of which 8 (80%) men, 2 (20%) women, and 100% HLA B27 positive. The average age of the patients was 40 ± 8.6 years, the average age of disease onset was 13.4 ± 7.5 years, the average duration of AS was 25.6 ± 6.5 years. 9 patients had histologically confirmed secondary AA-amyloidosis: 100% had kidney amyloidosis, 6 (66.6%) patients also had gastrointestinal amyloidosis and 3 (33.4%) patients had heart amyloidosis. All patients had arthritis and coxitis.Results:As the first biological drug, TCZ was prescribed to 2 patients due to the presence of manifestations of secondary AA-amyloidosis, and 8 patients had previous experience of treatment with one or more inhibitors of tumor necrosis factor-α (TNF-α). The average duration of TCZ treatment was 22.0 months [1.0; 36.0]. 8 (80%) patients continue to take TCZ therapy to date, and 2 (20%) - are transferred to TNF-α inhibitors. Table 1 shows the main clinical and laboratory characteristics of patients at the initiation of TCZ therapy and during the last hospitalization at the V.A. Nasonova Research Institute of Rheumatology. As you can see, against the background of TCZ therapy, both the level of CRP, proteinuria and the indices of AS activity (BASDAI, ASDAS CRP) significantly decreased. The number of patients with inflammatory back pain (IBP), arthritis and coxitis also decreased significantly.Table 1.The main clinical and laboratory characteristics of patients at the initiation and after of TCZ therapy.Before TCZAfter TCZрCRP, Ме [25‰; 75‰], mg/l95.2 [52.2; 189.0]10,8 [0.8; 8.0]р<0,05Proteinuria, Ме [25‰; 75‰], g/day.1,6 [1,0; 2,1]0,08 [0; 0,3]р<0,05BASDAI, Мean (SD)6,1 (1,6)3,3 (0,9)р<0,05ASDAS CRP, Мean (SD)4,3 (1,1)2,2 (0,7)р<0,05IBP, N (%)10 (100%)2 (20%)р<0,05Arthritis, N (%)10 (100%)2 (20%)р<0,05Cocxitis, N (%)10 (100%)5 (50%)р<0,05Enthesitis, N (%)7 (70%)6 (60%)р>0,05Conclusion:The above data showed that the method of treating AS with IL6 inhibitors, in certain clinical situations, primarily such as ineffectiveness of TNF-α inhibitors, high CRP level and the development of secondary AA-amyloidosis, can be highly effective. Therefore, it is advisable to continue the set of clinical observations on the treatment of especially severe patients with AS treated with non-standard methods.References:[1]Sieper J, Porter-Brown B, Thompson L, et al. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trialsAnn Rheum Dis 2014; 73: 95–100. doi:10.1136/annrheumdis-2013-203559.[2]Sieper J, Braun J, Kay J, et al. Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis. 2015; 74: 1051–1057. doi:10.1136/annrheumdis-2013-204963.[3]Londono J, Romero-Sanchez MC, Torres VG, et al. The association between serum levels of potential biomarkers with the presence of factors related to the clinical activity and poor prognosis in spondyloarthritis. Rev Bras Reumatol 2012; 52: 536-44.[4]Yilmaz S, Tekgöz E, Çinar M. Recurrence of proteinuria after cessation of tocilizumab in patients with AA amyloidosis secondary to FMF. Eur J Rheumatol. 2018; 5: 278-80. DOI: 10.5152/eurjrheum.2018.17183.Disclosure of Interests:None declared.

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Thwaites, Guy E., Matthew Scarborough, Alexander Szubert, Pedro Saramago Goncalves, Marta Soares, Jennifer Bostock, Emmanuel Nsutebu, et al. "Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT." Health Technology Assessment 22, no. 59 (October 2018): 1–148. http://dx.doi.org/10.3310/hta22590.

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Background Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. Objectives To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. Design Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. Setting UK NHS trust hospitals. Participants Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. Interventions Adjunctive rifampicin (600–900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). Main outcome measures The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Results Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50–76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18–45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference –1.4%, 95% confidence interval (CI) –7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). Conclusions Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. Future work Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. Trial registrations Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.

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Buller, Harry Roger. "Oral Rivaroxaban for the Acute and Continued Treatment of Symptomatic Venous Thromboembolism. the Einstein-DVT and Einstein-Extension Study." Blood 116, no. 21 (November 19, 2010): 187. http://dx.doi.org/10.1182/blood.v116.21.187.187.

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Abstract Abstract 187 Background New oral anticoagulants hold the promise of simple fixed-dose regimens without the need for monitoring and could make extended use more attractive. Current guidelines advise indefinite therapy in a substantial proportion of DVT patients. The Einstein-DVT study was designed to compare rivaroxaban, a direct oral factor Xa inhibitor, to enoxaparin followed by oral vitamin K antagonist (VKA) treatment in patients with acute DVT for either 3, 6, or 12 months. In Einstein-Extension, patients who had completed 6 to 12 months of anticoagulant treatment for either DVT or PE were randomized to receive rivaroxaban or placebo for an additional 6 or 12 months. Study Design Einstein-DVT was an open label, event-driven (target 88 confirmed recurrent VTEs) non-inferiority study. Subjects with a confirmed acute symptomatic DVT without symptomatic PE were randomized to receive either oral rivaroxaban 15 mg twice-daily for 3 weeks followed by 20 mg once-daily or initial treatment with enoxaparin (1 mg/kg twice daily) followed by oral VKA treatment (warfarin or acenocoumarol, target INR 2.5, range 2.0 to 3.0). Einstein-Extension was a randomized, double-blind, event-driven (target 30 confirmed recurrent VTEs), placebo-controlled, superiority study that evaluated rivaroxaban 20 mg once-daily for an additional 6 or 12 months. The primary efficacy outcome for both studies was recurrent non-fatal or fatal symptomatic venous thromboembolism (VTE). The principal safety outcome was clinically relevant bleeding (major or clinically relevant non-major bleeding) in Einstein-DVT and major bleeding only in Einstein-Extension. All study outcomes were adjudicated by a central and blinded committee. Results Einstein-DVT: the ITT-population consisted of 1,731 rivaroxaban and 1,718 enoxaparin/VKA recipients and rivaroxaban demonstrated non-inferior efficacy to enoxaparin/VKA for the primary outcome (rivaroxaban 36 events (2.1%), enoxaparin/VKA 51 events (3.0%), hazard ratio (HR), 0.68; 95% CI 0.44 –1.04, p <0.0001 for non-inferiority, 0.076 for superiority). Major and non-major clinically relevant bleeding occurred in 8.1% of subjects in both treatment groups (HR 0.97; 95% CI 0.76 –1.22, p =0.77) and major bleedings occurred in 14 (0.8%, 1 fatal) and 20 (1.2%, 5 fatal) of the rivaroxaban and enoxaparin/VKA recipients, respectively (HR 0.65; 95% CI 0.33 –1.28, p =0.21). The net clinical benefit defined as the primary efficacy outcome plus major bleeding showed a HR of 0.67 (95% CI 0.47 – 0.95; p=0.027). In the rivaroxaban group, 38 (2.2%) subjects died versus 49 (2.9%) in the enoxaparin/VKA group (HR 0.67; 95% CI 0.44 – 1.02). The time spent in the therapeutic INR range during VKA treatment was 58%. Einstein-Extension: the ITT population consisted of 602 rivaroxaban and 594 placebo subjects and rivaroxaban demonstrated superiority to placebo for the primary outcome (rivaroxaban 8 events (1.3%), placebo 42 events (7.1%), HR 0.18; 95% CI, 0.09 – 0.39; p<0.0001; number needed to treat: 15) over a mean study treatment period of approximately 6.5 months. Major bleeding did not occur in placebo subjects and was observed in 4 (0.7%, none were fatal) rivaroxaban subjects (p=0.11). Clinically relevant non-major bleeding was noted in 7 (1.2%) and 32 (5.4%) of the placebo and rivaroxaban recipients, respectively (p<0.0001). Two (0.3%) patients in the placebo group died versus 1 (0.2%) in the rivaroxaban group. Efficacy and safety results were consistent across all pre-specified subgroups in both studies. Conclusions Against a background of prolonging anticoagulant treatment for many months to years, this study indicates that oral rivaroxaban, 15 mg twice-daily for 3 weeks followed by 20 mg once-daily, could provide clinicians and patients with a simple, single-drug approach for the acute and continued treatment of DVT that potentially improves the benefit–risk profile of anticoagulation. Disclosures: Buller: Bayer Schering Pharma: Consultancy, Research Funding.

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Yada, Koji, Keiji Nogami, Arisa Takenaka, Takeshi Kawamura, and Midori Shima. "A New Classification of Mild/Moderate Hemophilia Α Based on a Multi-Dimensional FVIII(a) Functions Evaluated By a Plasma-Based Factor Xa Generation." Blood 128, no. 22 (December 2, 2016): 1392. http://dx.doi.org/10.1182/blood.v128.22.1392.1392.

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Abstract In mild/moderate hemophilia A (MHA), the real hemostatic potential of their innate factor (F) VIII(a) may not be evaluated by FVIII activity (FVIII:C) obtained in a one-stage clotting assay. We often experience the discrepancies between clinical phenotype and FVIII:C in MHA patients. In order to elucidate the hemostatic potentials of the innate FVIII in MHA patients with a simple method, we here have established a plasma-based FXa generation assay (PB-XaG) to clarify the multi-dimensional functions of FVIII(a) in MHA determined by the interaction with the components of tenase complex consisting of FIXa, FX, and phospholipid (PL). XaG was evaluated in the patients' plasmas and in the control plasma dilutions consisting of FVIII-deficient plasma and serial dilutions of recombinant FVIII (1-100 IU/dL) by a chromogenic substrate S-2765 together with human plasma-derived (pd)FIXa (0-20 nM), pdFX (0-200 nM), and PL vesicles (0-114 µM) initiated by thrombin (0.01 nM). The interaction between FVIIIa and each component of tenase complex was evaluated by Michaelis-Menten's kinetic parameters, Vmax and apparent Km (Kmapp). We investigated the PB-XaG in the plasmas obtained from 17 MHA patients, carrying F8 mutations and FVIII:C as shown in the table. The PB-XaG showed that the group A, consisting of the case 1, 2, 3 and 4 with mutations at the residue(s) essential to formation of the inter-domain surface in the FVIII molecule, possessed ~1.8-7.1-fold increases in Kmapp for FIXa (10±0.9, 49±17, 31±6 and 9±3 nM, respectively) compared to FVIII:C-matched control (6.5±1.3 nM), whilst Kmapp for FX and PL in this group were of little difference from that in control, indicative of the reduced affinity for FIXa. The group B, including the case 5, 6, 7, 8 with mutations at the A2 or A3 domain remote from the PL-binding region on the C2 domain (residue 2303-2332) and the case 9 with the mutation at the PL-binding region, demonstrated ~1.7-4.8-fold increases in Kmapp for PL (4.3±2.4, 5.0±1.0, 6.5±1.3, 12±4.0 and 3.0±0.6 µM, respectively) compared to control (2.0±0.4 µM), whilst Kmapp for FIXa and FX in this group were similar to that in control, indicative of the reduced affinity to PL. Noteworthy, the apparent catalytic efficiencies defined as Vmax/Kmapp were 0.033 min-1 for the case 6 and 0.019 min-1 for the case 8 with mutations at the A3 domain, 0.3 or 0.1-fold lower than that for the case 9 (0.19 min-1) with mutation at the PL-binding region. The PB-XaG showed that the group C consisting of the case 10, 11, 12, 13, 14 and 15 demonstrated ~1.6-7.5-fold increases in Kmapp for FX (22±9, 23±9, 24±9, 10±4, 4.6±1.6 and 5.8±3.0 nM, respectively) compared to control (4.5±0.8 nM), whilst Kmapp for FIXa and PL in this group were similar to that in control, indicative of the reduced affinity to FX. Interestingly, the case 16 classified in the group C' showed enhancing affinity with FX represented by a half decrease of Kmapp for FX compared to FVIII:C-matched control (2.0±0.9 and 4.8±1.5 nM, respectively). By contrast, the case 17 with mutation at the thrombin cleavage site categorized in the group D demonstrated any little XaG initiated by thrombin for all axes of FIXa, FX and PL. Taken together, the function of FVIII(a) in MHA could be evaluated multi-dimensionally and clearly classified into the some types of interaction with FIXa, FX, PL and thrombin by the PB-XaG. Our plasma-based XaG assay would be a useful tool for functional analyses of FVIII(a) to clarify the mechanism(s) of hemostatic heterogeneity in mild/moderate HA. Disclosures Nogami: Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; F. Hoffmann-La Roche Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sysmex Corporation: Patents & Royalties, Research Funding. Shima:F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sysmex Corporation: Patents & Royalties, Research Funding; Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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Fitria Budi Utami. "The Implementation of Eating Healthy Program in Early Childhood." JPUD - Jurnal Pendidikan Usia Dini 14, no. 1 (April 30, 2020): 125–40. http://dx.doi.org/10.21009/141.09.

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Eating habits develop during the first years of a child's life, children learn what, when, and how much to eat through direct experience with food and by observing the eating habits of others. The aim of this study is to get a clear picture of the Eating program Healthy, starting from the planning, implementation, supervision, and evaluation as a case study of nutrition education; to get information about the advantages, disadvantages and effects of implementing a healthy eating program for children. This research was conducted through a case study with qualitative data analysed using Miles and Huberman techniques. Sample of children in Ananda Islāmic School Kindergarten. The results showed the Healthy Eating program could be implemented well, the diet was quite varied and could be considered a healthy and nutritious food. The visible impact is the emotion of pleasure experienced by children, children become fond of eating vegetables, and make children disciplined and responsible. Inadequate results were found due to the limitations of an adequate kitchen for cooking healthy food, such as cooking activities still carried out by the cook himself at the Foundation's house which is located not far from the school place; use of melamine and plastic cutlery for food; the spoon and fork used already uses aluminium material but still does not match its size; does not involve nutritionists. Keywords: Early Childhood, Eating Healthy Program References: Bandura, A. (1977). Social learning theory. Englewood Cliffs: Prentice-Hall. Bandura, Albert. (2004). Health promotion by social cognitive means. Health Education and Behavior, 31(2), 143–164. https://doi.org/10.1177/1090198104263660 Battjes-Fries, M. C. E., Haveman-Nies, A., Renes, R. J., Meester, H. J., & Van’T Veer, P. (2015). Effect of the Dutch school-based education programme “Taste Lessons” on behavioural determinants of taste acceptance and healthy eating: A quasi-experimental study. 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