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Pellegrini de la Viuda, Tomás Rafael. "Salas Astrain, Ricardo, ed. 2020. Luchas sociales, justicia contextual y dignidad de los pueblos. 330 páginas. Santiago de Chile: Ariadna Ediciones. ISBN: 978-956-8416-92-8". Revista Española de Antropología Americana 51 (7.05.2021): 263–65. http://dx.doi.org/10.5209/reaa.75968.
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Rastegaeva, M. G., i A. L. Syrkin. "Electrical characteristics of tungsten-contacts to 6HSiC at temperatures between 300 and 950 K". Sensors and Actuators A: Physical 33, nr 1-2 (maj 1992): 95–96. http://dx.doi.org/10.1016/0924-4247(92)80234-t.
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Di Biagio, Claudia, Paola Formenti, Lionel Doppler, Cécile Gaimoz, Noel Grand, Gerard Ancellet, Jean-Luc Attié i in. "Continental pollution in the Western Mediterranean basin: large variability of the aerosol single scattering albedo and influence on the direct shortwave radiative effect". Atmospheric Chemistry and Physics 16, nr 16 (25.08.2016): 10591–607. http://dx.doi.org/10.5194/acp-16-10591-2016.
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Abstract. Pollution aerosols strongly influence the composition of the Western Mediterranean basin, but at present little is known on their optical properties. We report in this study in situ observations of the single scattering albedo (ω) of pollution aerosol plumes measured over the Western Mediterranean basin during the TRAQA (TRansport and Air QuAlity) airborne campaign in summer 2012. Cases of pollution export from different source regions around the basin and at different altitudes between ∼ 160 and 3500 m above sea level were sampled during the flights. Data from this study show a large variability of ω, with values between 0.84–0.98 at 370 nm and 0.70–0.99 at 950 nm. The single scattering albedo generally decreases with the wavelength, with some exception associated to the mixing of pollution with sea spray or dust particles over the sea surface. The lowest values of ω (0.84–0.70 between 370 and 950 nm) are measured in correspondence of a fresh plume possibly linked to ship emissions over the basin. The range of variability of ω observed in this study seems to be independent of the source region around the basin, as well as of the altitude and aging time of the plumes. The observed variability of ω reflects in a large variability for the complex refractive index of pollution aerosols, which is estimated to span in the large range 1.41–1.77 and 0.002–0.097 for the real and the imaginary parts, respectively, between 370 and 950 nm. Radiative calculations in clear-sky conditions were performed with the GAME radiative transfer model to test the sensitivity of the aerosol shortwave Direct Radiative Effect (DRE) to the variability of ω as observed in this study. Results from the calculations suggest up to a 50 and 30 % change of the forcing efficiency (FE), i.e. the DRE per unit of optical depth, at the surface (−160/−235 W m−2 τ−1 at 60° solar zenith angle) and at the Top-Of-Atmosphere (−137/−92 W m−2 τ−1) for ω varying between its maximum and minimum value. This induces a change of up to an order of magnitude (+23/+143 W m−2 τ−1) for the radiative effect within the atmosphere.
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Lisamy, Sisilia E. A., Charles P. H. Simanjuntak, Ayu Ervinia, Taufiq A. Romdoni, Arif Munandar, Seplina Nurfaiqah i Donna M. Guarte. "Reproductive aspects of the Japanese threadfin bream, Nemipterus japonicus (Bloch, 1791) in the Southern Java waters (FMA-RI 573)". E3S Web of Conferences 442 (2023): 01025. http://dx.doi.org/10.1051/e3sconf/202344201025.
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This study describes the reproductive biology of the Japanese threadfin bream, Nemipterus japonicus (Bloch, 1791) captured from the Southern Java Waters (FMA-RI 573). Fish monthly sampling collection was conducted from July to December 2022 at three fish landing ports: PPI Ciwaru, PPN Palabuhanratu, and PPI Binuangeun. Overall, 951 individuals consisting of 469 males (49.32%) and 482 females (50.68%), with a size range of 92-300 mm and a weight range of 10–344 g were collected. The sex ratio is balanced (1:1.10), with fecundity ranging from 10,079 to 82,650 eggs. The length at first maturity is 146 mm for males and 141 mm for females. The Japanese threadfin bream is a total spawner. Spawning occurs throughout the sampling period, with a peak in October-November. The length-based spawning potential ratio (LBSPR) measures the sustainability of fish stocks, indicating that Japanese threadfin bream in southern Java is in an overexploited condition.
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Guex, J. J., B. Hiltbrand, J. M. Bayon, F. Henri, F. A. Allaert i M. Perrin. "Anatomical Patterns in Varicose Vein Disease: A Duplex Scanning Study". Phlebology: The Journal of Venous Disease 10, nr 3 (wrzesień 1995): 94–97. http://dx.doi.org/10.1177/026835559501000303.
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Objectives: To determine symptomatology, clinical class, and topographic patterns of varicose veins in a consecutive series of patients with venous complaints. Methods: We performed clinical examination and duplex scanning of 498 lower limbs in 317 patients with obvious varicose veins for whom no previous treatment had been undertaken. Results: Classes of chronic venous insufficiency (CVI) in 498 legs: grade 0: 117 (23.5%); gr 1: 310 (62.2%); gr 2: 47 (9.4%); gr 3: 24 (4.8%). Duplex-detected venous reflux was found in the greater saphenous vein territory (junction or trunk or related perforator or main tributary) in 423 limbs (85.3%) the sapheno-femoral junction was incompetent in only 342 legs (68.7%). Reflux was found in the lesser saphenous vein territory in 100 limbs (20.1%) and in sapheno-popliteal junction in 92 (18.5%). Strictly non saphenous origin of varicosities was found in 31 limbs (6.2%). Deep venous incompetence was found in 48 legs (9.6%). Conclusions: These findings yield data on the distribution and occurence of lower limbs venous lesions in patients with varicose disease.
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Bajwa, Asif Azeem, Sikandar Ali, Junaid Tahir, Tashfeen Bin Nazir i Abdullah Asif. "Internet Gaming among Medical Students: Its Impact on Quality of Life". Life and Science 5, nr 4 (22.11.2024): 07. http://dx.doi.org/10.37185/lns.1.1.790.
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Objective: To determine the frequency of Internet gaming disorder among medical students and its impact onQuality of life on these students.Study Design: Cross-sectional study.Place and Duration of Study: This study was conducted in a tertiary care Mental Health Facility Armed ForcesInstitute of Mental Health (AFIMH) Rawalpindi, Pakistan from 1st January 2021 to 30th June 2022.Methods: Basic demographic data including age, gender, medical college and year of study amongconsecutively sampled 950 participants was recorded. Each participant was given internet gaming Disorderscore (IGD) and world health organization quality of life assessment score (WHO-QoL) to ascertain level ofinvolvement in internet gaming and quality of life respectively. Students were to fill both forms within twentyfour hours.Results: Out of total 950 participants 30 (3.2%) students scored severe, 92 (9.7%) scored moderate, 320 (33.7%)students scored for mild levels while 508 (53.5%) attained normal or no internet gaming disorder scores.Assessment of quality of life revealed that 500 (52.6%) enjoyed good quality of life, 361 (38%) experiencedaverage quality of life while 89 (9.4%) of students experienced below average quality of life. IGD scores showhigher level of significance with quality of life among medical students (P < 0.05).Conclusion: Indulgence in internet gaming negatively affects quality of life. How to cite this: Bajwa AA, Ali S, Tahir J, Nazir T, Asif A. Internet Gaming Among Medical Students: Its Impact On Quality Of Life. Life and Science. 2024; 5(4): 504-510. doi: http://doi.org/10.37185/LnS.1.1.790
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Łukaszewicz, Grzegorz, Michał Tacikowski, Michał Kulka, Krzysztof Chmielarz, Monika Węsierska-Hinca i Wiesław A. Świątnicki. "Effect of Prior Boriding on Microstructure and Mechanical Properties of Nanobainitic X37CrMoV5-1 Hot-Work Tool Steel". Materials 16, nr 12 (7.06.2023): 4237. http://dx.doi.org/10.3390/ma16124237.
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The influence of prior pack boriding on the microstructure and properties of nanobainitised X37CrMoV5-1 hot-work tool steel was investigated in the present work. Pack boriding was conducted at 950 °C for 4 h. Nanobainitising consisted of two-step isothermal quenching at 320 °C for 1 h, followed by annealing at 260 °C for 18 h. A combination of boriding with nanobainitising constituted a new hybrid treatment. The obtained material exhibited a hard borided layer (up to 1822 ± 226 HV0.05) and a strong (rupture strength 1233 ± 41 MPa) nanobainitic core. However, the presence of a borided layer decreased mechanical properties under tensile and impact load conditions (total elongation decreased by 95% and impact toughness by 92%). Compared with borided and conventionally quenched and tempered steel, the hybrid–treated material retained higher plasticity (total elongation higher by 80%) and higher impact toughness (higher by 21%). It was found that the boriding led to the redistribution of carbon and silicon atoms between the borided layer and substrate, which could influence bainitic transformation in the transition zone. Furthermore, the thermal cycle in the boriding process also influenced the phase transformations during subsequent nanobainitising.
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Singh, Suresh Kumar, Narsingh Verma, Shraddha Singh, M. L. Patel i Anupam Mittal. "Effect of magnesium and zinc supplementation in the patients of essential hypertension". International Journal of Research in Medical Sciences 12, nr 11 (30.10.2024): 4136–41. http://dx.doi.org/10.18203/2320-6012.ijrms20243361.
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Background: Primary hypertension is the most common (almost 95%) and it can easily be controlled through lifestyle modification by regular exercise and controlled diet plan. Magnesium and zinc supplementation can alleviate essential hypertension. Methods: 73 hypertensive patients were recruited. Thrice in a row with interval of 5 minutes, twice a day for 7 days high BP monitoring was done and ensured daily intake of Mg (300 mg) and Zn (10 mg) for 4 weeks. Thereafter again 4th week home Blood pressure monitoring was done. Study was done from 25 April 2023 to 24 April 2024. Secondary hypertension was excluded after proper radiological and pathological investigations. Results: Decrease in SBP by 6.9 mmHg, pre SBP 141±11.3 SD and post SBP 134±9.6 SD and DBP by 4.8 mmHg, pre DBP 91±7.8SD and Post DBP 86±73, observed after 4 weeks supplementation. In 30 medicated patients, antihypertensive showed decrease in SBP by 4.6 mmHg, pre SBP 137±11.5 SD and post SBP 132±9.6 SD with and DBP by 4.7 mmHg, Pre DBP 89.6±9.2SD and post DBP 84.9±8.7. Whereas, in a group of 43, without any medicine exhibited decline in SBP by 8 mmHg (Pre SBP 144±10 SD and Post SBP 136±9.5 and DBP by 5 mmHg, pre DBP 92±6.8 SD and post DBP 87±0.6.3 SD. Value of p<0.001 in the study group. Conclusions: Supplementation reduced blood pressure in all pre and post groups. The effect of supplementation had slighter edge on who were not taking antihypertensive medicine than were taking single medication or combined therapy.
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Rozhmina, T. A., A. A. Zhuchenko Jr., N. V. Melnikova i A. D. Smirnova. "Resistance of flax gene pool samples to edaphic stress caused by low acidity". Agricultural Science Euro-North-East 21, nr 2 (22.04.2020): 133–40. http://dx.doi.org/10.30766/2072-9081.2020.21.2.133-140.
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In conditions of vegetative trial carried out against selective backgrounds in 2017-2019 the response of 27 flax samples to a decrease in soil acidity to neutral pHKCl was studied. The scheme of the experiment was as follows: variant I (control) − pHKCl 5.3-5.5, P2O5 − 320-340 mg/kg, K2O − 81-92 mg/kg; variant II − pHKCl 6.2, P2O5 − 312-345 mg/kg, K2O − 84-98 mg/kg. It has been shown that during the «herringbone» phase in the majority of studied flax genotypes against the background of pH 6.2, the symptoms of “physiological oppression” of flax were observed: small spots developed on the upper leaves, the plants stopped growing, the stems thickened, and the tops of severely affected plants died off. As a result, at the beginning of the growing season at plant height of 7-10 cm, most of the samples were severely affected (from 69 to 100 %). The exceptions were varieties of fibre-flax Hermes (France), Vega 2 (Lithuania), Atlant (Russia) and linseed genotypes No. 3896 (Russia) and Norlin (Canada), which had a weak and medium degree of affection (8.3-45.5 %). Moreover, these genotypes showed a high level of both biological (75-90 %) and agronomic (77.3-85.6 %) resistance in the phase of "early yellow ripeness". The identified flax collection samples can be used as sources of resistance to flax «physiological oppression» caused by stressful edaphic factors in a neutral environment. On the basis of the analysis of the main elements of fiber productivity in studied flax genotypes, it has been established that against the background of pH 6.2 the reduce in plant height was from 11.4 to 52.1 % relative to the control, weight of the technical part of the stem − from 7.2 to 83.4 % , fiber mass − from 9.6 to 85.1 %. For the first time, on the basis of hybridological analysis, an assumption was done as to the pres-ence of a strong dominant gene, controlling the resistance to high soil pH values in the Hermes (France) flax variety and the linseed line No. 3896 (Russia).
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Wahlbrink, Daiane, Claudete Rempel, Claudete Moreschi, Carmen Neri Fernández Pombo, Daniel Silveira da Silva i Franciele Dietrich. "PERFIL DE PESSOAS COM HEMOCROMATOSE ATENDIDAS EM UM CENTRO HEMOTERÁPICO DO VALE DO TAQUARI/RS, DE 2008 A 2012". Hygeia - Revista Brasileira de Geografia Médica e da Saúde 13, nr 24 (22.06.2017): 189–98. http://dx.doi.org/10.14393/hygeia1330192.
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Estudo transversal, retrospectivo que verifica o perfil de pessoas com hemocromatose registradas no Centro Hemoterápico do Vale do Taquari (Hemovale), RS/Brasil atendidas de 2008 a 2012. Foram coletadas, através de registros documentais as variáveis: prevalência de hemocromatose (PH) sexo, idade, peso, pressão arterial (PA), frequência cardíaca (FC), temperatura axilar (TA), volume de sangue retirado para flebotomia e hematócrito. A PH foi de 285 casos. Os homens correspondem a 92% das pessoas atendidas no hemocentro. A faixa etária variou de 24 a 81 anos, sendo que a média de idade foi de 53,37 (10,79). O peso variou entre 54 e 158 Kg. Referente aos sinais vitais, houve variação da PA sistólica de 100 a 180 mmHg, e PA diastólica de 60 e 100 mmHg. Após o tratamento houve uma redução média da PA para 130,69 (15,41) e 82,26 (9,56) respectivamente. Em relação à FC houve diminuição da média de 77,54 (9,59) para 76,72 (8,78) e da TA de 36,11 (0,42) para 35,94 (2,06). O volume sanguíneo retirado variou de 300 a 500 mL. O hematócrito variou de 33% a 57%. Conclui-se que nessa região homens são mais acometidos com hemocromatose, sendo a média de idade maior no sexo feminino.
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Atoma, Charity Nwamaka, Elizabeth Chidinma Mube-William i Olufemi Martins Adesope. "Perceived soft skills needs of agriculture students in public universities in Niger Delta, Nigeria". Journal of Agricultural Extension 27, nr 4 (20.10.2023): 13–19. http://dx.doi.org/10.4314/jae.v27i4.2.
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The study investigated the perceived soft skills needs of agriculture students in public universities in the Niger Delta area of Nigeria. The population of the study is 11,283 agriculture undergraduate students in the 12 public universities in states in the Niger Delta geo-political zone. The sample size was 300 agriculture undergraduate students. Multistage sampling procedure was used to select the sample. The instrument for data collection was a questionnaire. Percentage and mean were used for analysis. Results revealed that the majority of the respondents (97.2%) could communicate effectively; 96% had a good sense of humour; 95.6% possessed the ability to cope with new changes; 92% possessed the ability to meet responsibilities on time; 89.6% possessed problem-solving skills. The results also revealed that agriculture students need many soft skills; some of which are creative thinking skills (x̄ =3.51), teamwork skills (x̄ =3.50); problem-solving/decision-making skills (x̄ =3.48); and leadership/management skills (x̄ ==3.47) among others. The universities should establish 6-month to 1-year student internship programmes, which will enable agriculture students to fully understand professional soft skills such as teamwork, creative thinking skills, and time management, among others that are relevant to the establishment and sustainability of agro-based enterprises.
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Pentheroudakis, George E., Anna Batistatou, Urania Dafni, Mattheos Bobos, Eleftheria Tsolaki, Vassiliki Kotoula, Eleftherios Kampletsas i in. "ESR1 gene amplification and protein expression in 946 patients with resected breast cancer: A Hellenic Cooperative Oncology Group (HeCOG) translational research study." Journal of Clinical Oncology 30, nr 15_suppl (20.05.2012): 592. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.592.
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592 Background: Discrepant data have been reported on the incidence of ESR1 gene amplification in breast cancer, its correlation to clinicopathologic characteristics and its impact on prognosis. Methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 946 patients participating in two adjuvant chemotherapy phase III trials (HE10/97 and HE10/00) were centrally assessed in tissue microarrays by immunohistochemistry (IHC) for estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2). FISH was also performed for HER2, TOP2A and ESR1 using commercially available dual (for ESR1) and triple (for HER2 and TOP2A) hybridization probes. Results: The majority of patients had >T2 (69%), node-positive, ER-positive (>1% stained cells, 73%) tumors managed with resection, chemotherapy and hormonotherapy (76%). Only 38 tumors (4.0%) had ESR1 gene amplification (ESR1/CEN6 ratio >2) and 514 (54.3%) ESR1 gene gain (1<ratio<2). The number of ESR1 gene copies was 3-4 in 251 (26.5%) and 5-10 in 42 (4.4%) of cases. HER2 and TOP2A gene amplification was seen in 234 (25.3%) and 101 (10.9%) of tumors, respectively. We studied the immunohistochemical expression of ER protein by evaluating the percentage of stained cells, the Allred score (0-2, 26.8%; 3-6, 62.5%; 7-8, 10.7% of tumors) and the semiquantitative H-Score (50-100, 13.8%; 101-200, 36.8%; 201-300, 15% of tumors). ESR1 gene amplification was significantly associated with taxane therapy, age >50, postmenopausal status, grade III-IV, absence of HER2 amplification and ER protein expression (p<0.05). At a median follow-up of 92 months, univariate Cox regression analysis showed that ER protein expression, but not ESR1 gene status, was a predictor of favorable outcome. In multivariate analysis, tumor size >5 cm, >4 involved nodes and negative/low ER protein expression by Allred score were independent adverse prognostic factors. Conclusions: Our data showed a rather low incidence of ESR1 gene amplification and failed to confirm its prognostic/predictive utility. ESR1 mRNA expression data will be presented at the meeting.
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Wang, Jinghong, Yeqiang Shu, Dongxiao Wang, Ju Chen, Yang Yang, Weiqiang Wang, Binbin Guo, Ke Huang i Yunkai He. "Observed 10–20-Day Deep-Current Variability at 5°N, 90.5°E in the Eastern Indian Ocean". Journal of Physical Oceanography 54, nr 2 (luty 2024): 521–36. http://dx.doi.org/10.1175/jpo-d-23-0082.1.
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Abstract In the eastern off-equatorial Indian Ocean, deep current intraseasonal variability within a typical period of 10–20 days was revealed by a mooring at 5°N, 90.5°E, accounting for over 50% of the total bottom subtidal velocity variability. The 10–20-day oscillations were more energetic in the cross-isobathic direction (STD = 3.02 cm s−1) than those in the along-isobathic direction (STD = 1.50 cm s−1). The oscillations were interpreted as topographic Rossby waves (TRWs) because they satisfied the TRWs dispersion relation that considered the smaller Coriolis parameter and stronger β effect at low latitude. Further analysis indicated significant vertical coupling between the deep cross-slope oscillations and cross-isobathic 10–20-day perturbations at the depth of 300–950 m. The 10–20-day TRWs were generated by cross-isobathic motions under the potential vorticity conservation adjustment. The Mercator Ocean output reproduced the generation of kinetic energy (KE) of deep current variability. The associated diagnostic analysis of multiscale energetics showed that the KE of TRWs was mainly supplied by vertical pressure work. In the seamount region (2°–10°N, 89°–92°E), vertical and horizontal pressure works were identified to be the dominant energy source (contributing to 94% of the total KE source) and sink (contributing to 98% of the total KE sink) of the deep current variability, transporting energy downward and redistributing energy horizontally, respectively.
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Shah, Binay K., Krishna B. Ghimire i Dinesh Pendharkar. "Survival Trends Among Very Elderly Patients with Advanced Diffuse Large B-Cell Lymphoma - a Population Based Study". Blood 124, nr 21 (6.12.2014): 2640. http://dx.doi.org/10.1182/blood.v124.21.2640.2640.
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Abstract Background Rituximab became commercially available in Novermber 1997. It was FDA approved in February 2006 for the first line treatment of patients with advanced diffuse large B cell lymphoma (DLBCL). The incidence of diffuse large B cell lymphoma increases with age, with >100 cases per 100000 persons aged >80 years. There is a limited data on survival very elderly patients with DLBCL. This study was conducted to evaluate survival trends of very elderly (≥80 years) patients with advanced DLBCL in the United States. Methods We selected very elderly patients (age ≥80 years) diagnosed with Stage III and IV DLBCL from the Surveillance, Epidemiology, and End Results (SEER) 18 database. We calculated 1- and 2- year relative survival rates of the patients during 1992-1997 (Pre-rituximab era) and 1998-2009 (post –rituximab era). We also analyzed survival rates of patients diagnosed before (1998 – 2005) and after (2006-2009) FDA approval of rituximab for the first line treatment of DLBCL. We used SEER Stat software to calculate relative survival (RS) rates. Results There were 2709 advanced DLBCL patients reported during 1992-2009. Overall median survival of the group was 6±0.240 months. The 1- and 2- year relative survival rates of the patients improved significantly from pre-rituximab era to post-rituximab era (1 year RS: 30±2.0 vs 38.9±1.2; Z value 4.16 and 2 year RS: 19.7±1.8 vs 32.8±1.2; Z 5.16). The survival rates were higher in the post-rituximab era for all the cohorts except the Blacks and Others. However, there was no difference in the survival rates of the patients diagnosed during 2006-2009 compared to those diagnosed during 1998-2005 (Table). Conclusion Our population based study showed that the survival rates of very elderly patients with advanced DLBCL have improved in the post-rituximab era for all groups except the Blacks and Others. There is no significant improvement in survival of patients before- and after approval of rituximab in the post-rituximab era. Abstract 2640. Table: Advanced DLBCL relative survival rates in elderly (age ≥ 80 years) Cohorts Survival 1992-1997 1998-2009 1998-2005 2006-2009 Z value (92-97 vs 98-09) Zvalue (98-05 vs 06-09) N RS ± SE% N RS ± SE% N RS ±SE % N RS ± SE% Male & Female 12 mo 633 30±2.0 2,076 38.9±1.2 1,274 38.1±1.5 802 40.1±1.9 4.159 0.796 24 mo 19.7±1.8 2,076 32.8±1.2 31.2±1.5 35.3±1.9 5.162 1.166 Male 12 mo 263 30.6±3.1 950 39.7±1.7 583 38.3±2.2 367 41.0±2.8 2.798 0.632 24 mo 18.6±2.7 950 33.7±1.8 30.6±2.2 38.4±3.0 3.750 1.304 Female 12 mo 370 29.5±2.5 1,126 38.2±1.5 691 37.4±2.0 435 39.4±2.5 3.036 0.478 24 mo 20.4±2.3 1,126 32.1±1.6 31.7±2.0 32.7±2.5 3.620 0.335 White 12 mo 572 29.8±2.0 1,786 39.8±1.3 1,101 38.5±1.6 685 41.8±2.0 4.145 1.106 24 mo 19.9±1.9 1,786 33.7±1.3 32.0±1.6 36.4±2.1 5.029 1.266 Black 12 mo 20 21.0±9.4 77 27.0±5.4 46 30.9±7.3 31 21.2±7.8 1.499 -1.030 24 mo 17.3±9.2 77 23.6±5.5 25.1±7.0 19.5±8.0 1.476 -0.894 Other 12 mo 41 36.1±7.8 211 35.4±3.5 126 36.3±4.5 85 34.1±5.4 0.349 0.029 24 mo 16.7±6.3 211 28.1±3.4 25.4±4.1 31.7±5.4 1.114 0.631 N: Number of patients Disclosures No relevant conflicts of interest to declare.
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Mailankody, Sham, Andrzej J. Jakubowiak, Myo Htut, Luciano J. Costa, Kelvin Lee, Siddhartha Ganguly, Jonathan L. Kaufman i in. "Orvacabtagene autoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): update of the phase 1/2 EVOLVE study (NCT03430011)." Journal of Clinical Oncology 38, nr 15_suppl (20.05.2020): 8504. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.8504.
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8504 Background: Orva-cel is an investigational, BCMA-directed CAR T cell product with a fully human binder. Over 100 pts have been treated in the EVOLVE phase 1 study. Pts treated at 50 and 150 × 106 CAR+ T cells were previously reported (Mailankody ASH 2018 #957). We now report results of the higher dose levels (DLs) in 51 pts who received orva-cel manufactured using the process intended to support commercial use. Methods: Pts with RRMM who had ≥3 prior regimens, a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody (mAb), received orva-cel at 300, 450, and 600 × 106 CAR+ T cells after lymphodepletion with fludarabine/cyclophosphamide. Results: Median pt age was 61 (range, 33–77) y; median time from diagnosis was 7.0 (range, 1.7–23.6) y, with a median of 6 (range, 3–18) prior regimens. Overall, 92% of pts were penta-exposed (2 IMiDs, 2 PIs, and an mAb); 61% of pts received bridging therapy (77% were refractory to bridging therapy). Two pts had dose-limiting toxicities: grade 3 neurological event (NE) for >7 d at 300 × 106 CAR+ T cells and grade 4 neutropenia for >28 d at 450 × 106 CAR+ T cells. Key efficacy and safety outcomes are shown in the Table. Cytokine release syndrome (CRS)/NEs were managed with tocilizumab and/or steroids (78%), anakinra (14%), and/or vasopressors (6%). Grade ≥3 anemia, neutropenia, and thrombocytopenia at 29 d occurred in 21%, 55%, and 44% of pts (median time to resolution to grade ≤2 of any cytopenia, ≤2.1 mo). Grade ≥3 infections occurred in 14%. After a median follow-up (F/U) of 5.9 mo, median progression-free survival was not reached. Conclusions: Orva-cel at 300, 450, and 600 × 106 CAR+ T cells demonstrated manageable safety (CRS grade ≥3: 2%; NE grade ≥3: 4%) and compelling efficacy in heavily pretreated pts with RRMM, with a 91% objective response rate (ORR) and 39% complete response (CR)/stringent CR (sCR) rate. Updated results will be presented, including minimal residual disease, durability of response, and recommended phase 2 dose. Clinical trial information: NCT03430011 . [Table: see text]
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Dokic, Ljubisa, Dragan Delic, Olga Dulovic, Milos Korac, Branko Milosevic i Lidija Lavadinovic. "The frequency of pathological ultrasonographic findings of the gallbladder in patients with infectious diseases". Medical review 60, nr 1-2 (2007): 89–92. http://dx.doi.org/10.2298/mpns0702089d.
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Introduction The objective of our study was to establish, through retrospective analysis of sonographic findings obtained by portable ultrasound devices, the frequency of pathological findings of the gallbladder and common bile duct in a randomized group of patients with infectious diseases. Material and methods During five years (January 1, 2000 - December 31, 2004), gallbladder and common bile duct were examined by ultrasonography in 2691 adult patients (1440 males and 1251 females), mean age 48?17 years, ranging from 17 to 92 years at the Institute of Infectious and Tropical Diseases in Belgrade. The examination included the measurement of size and shape of the gallbladder, its wall and lumen, as well as measurement of caliber and content of the common bile duct. Conventional portable ultrasound devices, ALOKA SSD-500 and SSD-1000 (B-mod) with convex 3.5 and 5 MHz probes were used. Results The cholecyst was normal in size (<120x50 mm) in 2164 (80.4%), and enlarged in 65 (2.4%) patients. The gallbladder was surgically removed in 163 (6.1%) patients, it was pseudoseptal in 141 (5.2%) and invisible in 44 (1.6%) patients. The gallbladder wall was normal in 2031 (75.5%), thickened in 259 (9.6%) and edematous in 173 (6.4%). Gallbladder calculosis was present in 310 (11.5%), and choledocholithiasis in 13 (0.5%) patients. Conclusion Development of morphological abnormalities of the gallbladder and common bile duct was frequent in non-selected patients with infectious diseases. The majority of them may be detected by portable ultrasound devices, which makes them rather applicable for large clinical-epidemiological studies.
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Ahmed, Md Shakeel, Imranul Mawa, Ayesha Ahmed Khan i Md Abdullah al Mamun. "Bacteriological Profile and Antibiotic Susceptibility Pattern of Isolates from Suspected Neonatal Septicemia Patients in Different Hospitals of Chattogram". IAHS Medical Journal 7, nr 1 (13.11.2024): 68–73. http://dx.doi.org/10.3329/iahsmj.v7i1.77576.
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Background: Bacterial blood stream infection is an important cause of morbidity and mortality in neonates. This study was undertaken to identify the bacterial isolates from suspected neonatal septicemia patients and to understand their antimicrobial susceptibility pattern in Chattogram. Materials and methods: A cross-sectional descriptive type of study was done for a period of two years from January 2022 to December 2023. Blood samples from 340 neonates with clinically suspected septicemia were taken for automated culture and susceptibility test was conducted in Bacteriology Laboratory of IbneSina, Chattogram. The samples were collected and processed following standard microbiological techniques and an antibiotic susceptibility test was done on pure culture isolates using disc-diffusion method for the commonly used antibiotics. The data were analyzed by using SPSS version 20 and the results were summarized by using tables and graphs. Results: Out of 340 blood culture done, 62 (18.24%) were positive. Among them 61.3% were of early onset sepsis. The predominant bacteria isolated was Klebsiella spp. 27 (43.6%) followed by Coagulase negative staphylococci 12(19.4%), Salmonella typhi 10 (16.1%), E. coli 6 (9.6%) and Pseudomonas 5 (8.0%). Antibiotic susceptibility tests showed that the most sensitive antibiotics to Gram-negative organisms wereImipenem (81-100%), Tazobactam-Piperacillin (74-100%), Amikacin (67-90%), Ceftriaxone (60-100%) and Levofloxacin (63-80%). Maximum resistance among Gram-negative organisms were seen in Ampicillin (60-100%), Cotrimoxazole (60-100%) and Cefixime (30-80%). Among Gram-positive organisms, all strains (100%) were sensitive to Linezolid and Vancomycin. Other alternates with good sensitivity were Amikacin (92%), Imipenem (83%), Ceftriaxone (83%) and Levofloxacin (75%). While maximum resistance was seen to Ampicillin (83%), Amoxiclav (75%), Cefixime (75%) and Ciprofloxacin (75%). Conclusions: In the present study, most of the pathogens isolated from blood cultures were Gram negative and they showed high resistance to commonly used antibiotics. Therefore, rational use of antibiotics after sensitivity testing should be practiced. IAHS Medical Journal Vol 7(1), June 2024; 68-73
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Mbopi-Kéou, François-Xavier, Stefano Mion, Bertrand Sagnia i Laurent Bélec. "Validation of a Single-Platform, Volumetric, CD45-Assisted PanLeucogating Auto40 Flow Cytometer To Determine the Absolute Number and Percentages of CD4 T Cells in Resource-Constrained Settings Using Cameroonian Patients' Samples". Clinical and Vaccine Immunology 19, nr 4 (15.02.2012): 609–15. http://dx.doi.org/10.1128/cvi.00023-12.
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ABSTRACTThe study evaluated the single-platform, volumetric, CD45-assisted PanLeucogating Auto40 flow cytometer (Apogee Flow Systems Ltd., Hemel Hempstead, United Kingdom) for CD4 T cell numeration, compared to the reference FACSCalibur flow cytometer. Results of absolute counts and percentages of CD4 T cells by Auto40 and FACSCalibur of 234 tripotassium EDTA (K3-EDTA)-blood samples from 146 adults and 88 children (aged from 18 months to 5 years), living in Yaoundé, Cameroon, were highly correlated (r2= 0.97 andr2= 0.98, respectively). The mean absolute bias and relative bias between Apogee Auto40 and FACSCalibur absolute CD4 T cell counts were +9.6 cells/μl, with limits of agreement from −251 to 270 cells/μl, and +4.1%, with limits of agreement from −16.1 to 24.4%, respectively. The mean absolute bias and relative bias between Apogee Auto40 and FACSCalibur CD4 T cell results expressed as percentages were +0.05% CD4 (95% confidence interval [CI], −0.03 to 0.41), with limits of agreement from −6.0 to 5.9% CD4, and +1.0%, with limits of agreement from −32.3 to 34.4%, respectively. The Auto40 counting allowed identification of the majority of adults with CD4 T cell counts below 200 cells/μl (sensitivity, 87%; specificity, 98%) or below 350 cells/μl (sensitivity, 92%; specificity, 98%) and of children with CD4 T cell counts below 750 cells/μl (sensitivity, 82%; specificity, 98%) or below 25% CD4+(sensitivity, 96%; specificity, 99%). The Auto40 analyzer is a reliable alternative flow cytometer for CD4 T lymphocyte enumeration to be used in routine immunological monitoring according to the WHO recommendations for HIV-infected adults as well as children living in resource-constrained settings.
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RIBEIRO, Rebeca Sadigursky, Glícia Estevam de ABREU, Eneida Regis DOURADO, Maria Luiza VEIGA, Victoria Andrade LOBO i Ubirajara BARROSO JR. "BLADDER AND BOWEL DYSFUNCTION IN MOTHERS AND CHILDREN: A POPULATION-BASED CROSS-SECTIONAL STUDY". Arquivos de Gastroenterologia 57, nr 2 (czerwiec 2020): 126–30. http://dx.doi.org/10.1590/s0004-2803.202000000-23.
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ABSTRACT BACKGROUND: Recently it was shown an association between lower urinary tract symptoms in mothers and their children. However, the role of functional constipation in this binomial is unclear. OBJECTIVE: To evaluate bladder and bowel dysfunction between mothers and children. METHODS: A population-based cross-sectional study. Mothers and their children responded a self-administrated questionnaire composed by Rome IV criteria, International Consultation on Incontinence Questionnaire - Overactive Bladder, Dysfunctional Voiding Scoring System and demographic questions. RESULTS: A total of 441 mother-child pairs was obtained. Children’s mean age was 9.1±2.7 years, with 249 (56.5%) female. Mothers’ mean age was 35.7±6.1 years. Isolated constipation was present at 35 (7.9%) children and 74 (16.8%) mothers. Isolated lower urinary tract symptoms were present in 139 (31.5%) children and 92 (20.9%) mothers and bladder bowel dysfunction occurred in 51 (11.6%) children and 78 (17.7%) mothers. There wasn’t any association between isolated lower urinary tract symptoms in children and isolated lower urinary tract symptoms in mothers (P=0.31). In univariate analysis there were an association between bladder bowel dysfunction in children and bladder bowel dysfunction in mothers (OR=4.8 IC 95% 2.6-9.6, P<0.001) and isolated constipation in children and isolated constipation in mothers (OR=3.0 IC 95% 1.4-6.4, P=0.003). In multivariate analysis mothers with bladder bowel dysfunction was the only independent factor associated with bladder bowel dysfunction in children (OR=5.4 IC 95% 2.5-11.6, P<0.001). CONCLUSION: Mothers with bladder bowel dysfunction are more likely to have a child with bladder bowel dysfunction. Association between these two dysfunctions plays an important role in this familiar presentation.
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Richardson, P. G., A. Chanan-Khan, S. Lonial, A. Krishnan, M. Carroll, G. F. Cropp, M. Albitar, R. G. Johnson, A. Hannah i K. Anderson. "Tanespimycin (T) + bortezomib (BZ) in multiple myeloma (MM): Pharmacology, safety and activity in relapsed/refractory (rel/ref) patients (Pts)". Journal of Clinical Oncology 25, nr 18_suppl (20.06.2007): 3532. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3532.
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3532 Background: Tanespimycin (17-AAG/KOS 953) disrupts Hsp90, a molecular chaperone of MM client proteins including IL-6 and IGF-1R that are key to MM growth, survival and drug resistance. Single agent T was well tolerated with modest anti- MM activity. Preclinical studies suggest potential synergy with BZ. Methods: Pts received BZ as IVB followed by 1-hr infusion of T on D1,4,8,11 q 21d. Results: 49 pts were enrolled in 7 cohorts (T 100- 340 mg/m2; BZ 0.7 - 1.3 mg/m2). PK of T was similar with or without BZ. Inhibition of 20S proteasome with T+BZ was not different vs. historical BZ single agent data. PBLs showed induction of Hsp70 4h post-infusion with maintenance of induction prior to T infusion across the dosing interval; pAKT plus total AKT were also reduced 4 and 72h following infusion. CD138 but not CD4 or CD8 cells from serial BM aspirates showed induction of apoptosis by flow cytometry. In addition, ↓expression of IGR-1R and IL-6R client proteins was seen after treatment. Safety: In Cohort 7, 19 pts received T 340 / BZ 1.3 mg/m2. Common all-grade (G) drug-related toxicity (n=19) included diarrhea (42%), nausea (32%), vomiting (26%), ↑ AST/ALT/Alk Phos (26%/21%/21%), myalgias (16%), and dizziness (16%). G3 thrombocytopenia was noted in 16% with no other G3 toxicity observed in more than 1 pt. DLT was seen in 2 pts: G3 myalgias/cramps and dehydration (reversible in both). G1–2 only treatment-emergent peripheral neuropathy was recorded in 15%. Activity: Responses have been seen across dose levels in BZ-naïve, pre-treated and ref pts (“ref” defined as no response to or disease progression within 60d of last dose of BZ-containing regimen). Specifically, 1 BZ-ref pt with 3 prior regimens had confirmed PR after 2 cycles and continues in Cycle 9 (M-spike ↓92%); a 2nd pt with 2 prior regimens achieved PR after 2 cycles and continues in Cycle 7; a 3rd pt with 7 prior regimens with confirmed PR after 3 cycles continues in Cycle 6. Conclusions: Treatment with T 340/ BZ 1.3 combination had generally manageable toxicity. Durable Hsp90 inhibition and similar proteasome inhibition (vs single-agent BZ) was seen. Importantly, anti-MM activity in BZ-ref pts was observed and further investigation of this combination in rel/ref MM is therefore warranted. No significant financial relationships to disclose.
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Family, Leila, Su-Jau Yang, Zandra Klippel, Yanli Li, John H. Page, Roberto Rodriguez i Chun Chao. "Risk of Febrile Neutropenia (FN) in Select Myelosuppressive Chemotherapy Regimens". Blood 126, nr 23 (3.12.2015): 3257. http://dx.doi.org/10.1182/blood.v126.23.3257.3257.
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Abstract Introduction Febrile neutropenia (FN) is a serious adverse effect of myelosuppressive chemotherapy, which often results in hospitalization and chemotherapy dose modification. FN risk depends on patient characteristics and chemotherapy regimen risk. Understanding the FN risk associated with individual chemotherapy regimens can help guide the use of prophylactic granulocyte colony-stimulating factor (G-CSF) and patient monitoring. To this end, the NCCN has classified regimens into high (≥20%), intermediate (10%-20%), or low (<10%) FN risk based primarily on clinical trial data. However, even for the same regimen, the FN risk is often higher in clinical practice than in clinical trials. In this study, we assessed the FN risk associated with several regimens for which FN risk has not been determined or has shown substantial variability outside of a clinical trial setting, using data from Kaiser Permanente Southern California (KPSC), a large, community-based practice. Methods Included were patients diagnosed with incident non-Hodgkin's lymphoma (NHL), breast cancer (BC), or multiple myeloma (MM) between 2008 and 2013 at KPSC who initiated the following chemotherapy regimens: bendamustine ± rituximab for NHL; docetaxel, carboplatin, and trastuzumab (TCH) or docetaxel and cyclophosphamide (TC) for BC; or Q4W lenalidomide 25 mg/dexamethasone for MM. Bendamustine ± rituximab, TCH, and lenalidomide are not classified by NCCN; TC is classified as intermediate FN risk but has shown considerable variability of FN incidence when used in clinical practice. Data on cancer diagnosis, chemotherapy use, G-CSF use, neutrophil count, and infections were obtained from KPSC's electronic medical records to estimate the incidence proportions of FN and grade 3 and 4 neutropenia. FN was defined as (1) hospitalization with absolute neutrophil count (ANC) <1000/µL or (2) hospitalization with primary or secondary diagnosis codes of neutropenia (ICD-9 288.0x) and fever (ICD-9 780.6), diagnosis code for bacterial/fungal infection, or antibiotic use. Grade 3 neutropenia was defined as ANC ≥500/µL to <1000/µL; grade 4 neutropenia as ANC <500/µL. Patients who received prophylactic G-CSF within 5 days of chemotherapy initiation were excluded from analysis. Results Overall, 40 (12%) NHL patients; 149 (24%) and 340 (28%) BC patients who received TCH and TC, respectively; and 0 (0%) MM patients were excluded due to prophylactic G-CSF. Over the first 6 cycles of bendamustine (median 338.4 mg/m2) ± rituximab for NHL patients (n = 307), 7.2% experienced FN, 4.2% grade 3 neutropenia, and 17.6% grade 4 neutropenia. Over the first 6 cycles of TCH for BC patients (n = 462), 24.2% experienced FN, 10.6% grade 3 neutropenia, and 44.6% grade 4 neutropenia. Over the first 6 cycles of TC for BC patients (n = 859), 20.5% experienced FN, 9.5% grade 3 neutropenia, and 37.5% grade 4 neutropenia. Over the first 4 cycles of lenalidomide/dexamethasone for MM patients (n = 186), 3.8% experienced FN, 5.9% grade 3 neutropenia, and 18.3% grade 4 neutropenia (Table 1). Conclusions Using NCCN criteria, bendamustine ± rituximab for NHL and lenalidomide/dexamethasone for MM would be classified as low-FN-risk regimens (<10%). By contrast, BC regimens TCH and TC would be classified as high-FN-risk regimens (>20%) based on our data. These results could help inform prophylactic G-CSF use for the selected regimens in clinical practice. Table 1. Number and Incidence Proportion of Neutropenic Outcomes Overall and by Cycle Cancer: Regimen Cycle Patients n FN Events n (%) Grade 3 Neutropenia Events n (%) Grade 4 Neutropenia Events n (%) NHL: Bendamustine ± rituximab Overall 307 22 (7.2) 13 (4.2) 54 (17.6) 1 307 12 (3.9) 5 (1.6) 28 (9.1) 2 225 3 (1.3) 4 (1.8) 21 (9.3) 3 173 2 (1.2) 4 (2.3) 15 (8.7) 4 130 2 (1.5) 4 (3.1) 10 (7.7) 5 92 4 (4.4) 4 (4.4) 8 (8.7) 6 69 2 (2.9) 2 (2.9) 0 (0) BC: TCH Overall 462 112 (24.2) 49 (10.6) 206 (44.6) 1 462 70 (15.2) 39 (8.4) 138 (29.9) 2 326 13 (4.0) 15 (4.6) 42 (12.9) 3 282 17 (6.0) 9 (3.2) 39 (13.8) 4 247 6 (2.4) 8 (3.2) 31 (12.6) 5 199 4 (2.0) 6 (3.0) 25 (12.6) 6 169 8 (4.7) 3 (1.8) 12 (7.1) BC: TC Overall 859 176 (20.5) 82 (9.5) 322 (37.5) 1 859 126 (14.7) 51 (5.9) 266 (30.9) 2 649 21 (3.2) 42 (6.5) 82 (12.6) 3 571 19 (3.3) 23 (4.0) 62 (10.9) 4 511 14 (2.7) 22 (4.3) 45 (8.8) 5 94 1 (1.1) 3 (3.2) 9 (9.6) 6 84 2 (2.4) 1 (1.2) 2 (2.4) MM: Lenalidomide / dexamethasone Overall 186 7 (3.8) 11 (5.9) 34 (18.3) 1 186 2 (1.1) 8 (4.3) 17 (9.1) 2 101 3 (3.0) 5 (5.0) 14 (13.9) 3 63 2 (3.2) 2 (3.2) 8 (12.7) 4 37 0 (0) 0 (0) 4 (10.8) Disclosures Family: Amgen Inc.: Research Funding. Klippel:Amgen Inc.: Employment, Equity Ownership. Li:Amgen Inc.: Employment, Equity Ownership. Page:Amgen Inc.: Employment, Equity Ownership.
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Safarova, К. N., E. A. Fedotov i A. P. Rebrov. "Serum concentrations of interleukin-6 and tumor necrosis factor alpha in patients with spondyloarthritis: a relationship between systemic inflammation and anemia". Bulletin of Siberian Medicine 21, nr 2 (17.07.2022): 115–21. http://dx.doi.org/10.20538/1682-0363-2022-2-115-121.
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Aim. To assess the relationship between the activity of systemic inflammation and the hemoglobin level in patients with spondyloarthritis (SpA).Materials and methods. We examined 92 patients with SpA aged 42.9 ± 11.6 years (SpA duration – 14.8 ± 9.6 years, 55 (60%) men). We calculated the BASDAI and ASDAS-CRP scores, performed complete blood count, evaluated erythrocyte sedimentation rate (ESR), ferrokinetic parameters, C-reactive protein (CRP) level, and serum concentrations of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6).Results. Anemia was found in 52 (57%) patients: 13 (25%) patients were diagnosed with anemia of inflammation (AI), 39 (75%) individuals had a combination of AI and iron deficiency anemia. A significant increase in CRP (17.8 vs. 9.0 mg / l, respectively; p = 0.001) and ESR (23 vs. 10 mm / h, p < 0.001), a tendency toward an increase in IL-6 levels (5.4 vs. 4.1 pg / ml, p = 0.051), and no difference in TNF-α levels (3.4 vs. 3.0 pg / ml, p = 0.245) were revealed in patients with anemia compared with patients with normal hemoglobin level. The hemoglobin concentration was negatively correlated with the CRP level (r = –0.327, p = 0.001) and ESR (r = –0.527, p < 0.001). IL-6 was positively correlated with the levels of TNF-a, CRP, and ESR (r = 0.431, r = 0.361, r = 0.369; all p < 0.001). With the IL-6 concentration >10 pg / ml, the odds for anemia were 5.3 times higher (95% confidence interval: 1.4–19.9, p = 0.009).Conclusion. The relationship between the activity of systemic inflammation and anemia in patients with SpA was confirmed. Taking into account the pathogenesis of AI, the aim of antianemic treatment is to achieve remission or minimal activity of SpA. Additional studies are required to determine the effect of anti-inflammatory therapy on the development and course of anemia in patients with SpA.
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Philip, T., R. Ghalie, R. Pinkerton, J. M. Zucker, J. L. Bernard, G. Leverger i O. Hartmann. "A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Société Française d'Oncologie Pédiatrique." Journal of Clinical Oncology 5, nr 6 (czerwiec 1987): 941–50. http://dx.doi.org/10.1200/jco.1987.5.6.941.
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Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.
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Latagliata, Roberto, Dario Ferrero, Francesco Cavazzini, Malgorzata Monika Trawinska, Massimo Breccia, Mario Annunziata, Fabio Stagno i in. "Imatinib In Very Elderly CML Patients: What Can We Achieve?." Blood 116, nr 21 (19.11.2010): 1229. http://dx.doi.org/10.1182/blood.v116.21.1229.1229.
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Abstract Abstract 1229 In the “real world” of clinical practice, many very elderly CML patients have been treated with imatinib (IM), but there are few data on the results and the best initial dosage in such patients. To highlight peculiar aspects of toxicity and efficacy of IM in this subset which accounts for at least 10–15% of all CML cases, we retrospectively revised 156 CML patients in chronic phase treated with IM when aged > 75 years from 23 haematological Institutions in Italy; there were 85 males and 71 females, median age at IM start was 78.4 years (IR 76.1 – 81.4), Sokal Risk at diagnosis was low in 2 patients, intermediate in 90, high in 50 and not evaluable in 14. One or more concomitant diseases requiring specific treatments were present in 144/156 patients (92.3%), with 94 patients (60.2%) assuming 3 or more concomitant drugs. Thirty patients (19.2%) were in late chronic phase (≥ 12 months from diagnosis) and pretreated (25 with HU and 5 with IFN) before starting IM; on the whole, median time from diagnosis to IM was 1.2 months (IR 0.5 – 3.6). Starting dose of IM was 400 mg/day in 117 patients (75.0%) and 300 mg/day or less in 39 patients (25.0%); overall, 59 patients (37.8%) (52/117 at 400 mg starting dose and 7/39 at 3 300 mg starting dose) needed a dose reduction and 18 (11.5%) discontinued IM for toxicity (early toxicity in 13 and late toxicity in 5). Excluding the 13 patients who discontinued IM due to early toxicity, maximum tolerated daily dose during treatment was 400 mg in 63 patients, 300 mg in 51 patients and < 300 mg in 29 patients. According to CTC-AE, grade 3 – 4 hematological and extra-hematological toxicities were observed in 34 (21.7%) and 34 (21.7%) patients, respectively; 5 patients (3.2%) presented a pleural effusion during IM treatment. After a median treatment period of 29.4 months (IR 7.9 – 54.4), 8 patients (5.1%) are still too early (< 6 months of treatment), 13 (8.3%) discontinued IM due to early toxicity, 3 (1.9%) were resistant and 1 (0.7%) died from unrelated cause early after IM initiation: the remaining 131 patients (84.6%) achieved a complete haematological response (CHR). Among these 131 patients in CHR, 11 refused any other karyotipic or molecular evaluation (1 lost CHR and shifted to hydroxyurea, 4 are still alive in CHR, 6 died in CHR from unrelated causes), 17 achieved CHR only and 103 (66.0% of all 156 patients) achieved a cytogenetic response (CyR), which was major in 11 patients and complete (CCyR) in 92 (58.9% of all 156 patients). In addition, among the 92 patients in CCyR, 62 (39.7% of all 156 patients) achieved a molecular response (major molecular response in 40 patients and complete molecular response with an undetectable BCR/ABL hybrid gene at qualitative nested PCR in 22 patients). After a median follow-up of 34.0 months (IR 12.9 – 60.0), 36 patients have died (5 from disease progression and 31 from unrelated causes), 4 patients were lost to follow-up and 116 are still alive: 2-year and 4-year overall survival were 90.2% (CI95% 84.8 – 95.6) and 76.8% (CI95% 68.6 – 85.0), respectively. In conclusion, results from this large unselected cohort of patients show that should be definitely considered unethical to avoid IM therapy to any elderly patient; no upper age limit should be given but also very elderly (and with concomitant severe diseases) patients should have this chance of cure. The role of a reduced starting dose of IM warrants further studies. Disclosures: No relevant conflicts of interest to declare.
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Masarova, Lucia, Naval Daver, Naveen Pemmaraju, Prithviraj Bose, Sherry Pierce, Taghi Manshouri, Jorge E. Cortes, Hagop M. Kantarjian i Srdan Verstovsek. "Do Patients with Post-Essential Thrombocythemia and Post-Polycythemia Vera Differ from Patients with Primary Myelofibrosis?" Blood 126, nr 23 (3.12.2015): 4069. http://dx.doi.org/10.1182/blood.v126.23.4069.4069.
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Abstract Introduction: Clinical characteristics of post-essential thrombocythemia/polycythemia vera myelofibrosis "post ET/PV-MF" are not well defined as for primary myelofibrosis "MF". Objective: We aimed to identify morphological, clinical and prognostic characteristics of patients with post ET/PV-MF seen at our center. Methods: Retrospective chart review of 1120 patients with MF - 766 primary MF, 354 post ET/PV-MF, who were referred to our institution between years 1984-2013 was performed; 92% presented after the year of 2000. Fisher's exact and Mann-Whitney test were used for categorical and continuous variables; Cox proportional hazard model and Kaplan-Meier curves with log rank test for correlation between the variables and survival. Survival analysis were calculated after censoring patients for stem cell transplantation "SCT" (n=92). Results: Overall median follow up was 36 months (0-411), 51% (n=573) patients had died. Progression to AML after median time of 32 months was not different between groups and occurred in 9.5% (n=106) patients over observation period of 5180 persons-years. Incidence rate was 3.4 cases per 100 persons-year. Causes of death were known in 55% of patients, and included progression of MF in 38% (n=122), infection in 27% (n=86), and other reasons with less than 10% occurrence (complications post SCT; secondary malignancy; other medical conditions). Demographics and disease characteristics are depicted in a table. 92% of patients were evaluable for karyotype; abnormalities were detected in 39% (n=404), of which 53% were unfavorable with monosomal (23%), complex (43%) and trisomy 8 (18%) being the most common. Molecularly high risk mutations "MHR" in genes ASXL1, EZH2, and IDH1/2 were positive in 35% of tested patients (n=161) regardless of presence of driver mutation. IPSS and DIPSS plus scores were similar between MF and post ET/PV-MF (with IPSS low in 8.7%, intermediate 1 in 19%, intermediate 2 in 28%, and high in 44%). By multivariate analysis, higher risk categories of IPSS and DIPSSplus predicted shorter overall survival "OS" for both cohorts (by DIPSSplus - high risk: HR 2.7, 95% CI 2.1-3.5; int-2: HR 1.6; 95% CI 1.3-2.0). Median OS stratified by IPSS was 160 (HR 1.8, 95%CI 1.0-3.0), 116 (HR 1.5, 95%CI 1.0 -1.5), 78 (HR 1.4, 95%CI 1.2-1.7) and 54 months, p=0.001. Univariate analysis identified age over 65, anemia, trombocytopenia, leukopenia, increased blasts, splenomegaly, constitutional symptoms, unfavorable karyotype, JAK2 mutation and triple negativity as predictors for inferior survival. Age over 65; hemoglobin below 10, platelets below 100 and peripheral blasts ≥1% showed significance for predicting OS by multivariate analysis. When stratified according to diagnosis, higher age, anemia, thrombocytopenia, high blasts, JAK2 positivity and triple negativity retained prognostic significance for MF whereas anemia, thrombocytopenia, and JAK2 mutation for post ET/PV-MF. Median OS was 73 months (range, 0.1-210) without difference between MF and post ET/PV-MF. Conclusion: Post ET/PV-MF does not appear to have substantial different clinical characteristics than primary MF. Table. Characteristics Total, number or median (% or range) MF, number or median (% or range) PET/PV-MF, number or median (% or range) Age 65 (20-89) 64 (20-88) 64 (27-89) Age > 65 552 (49) 367 (48) 185 (53) Males 675 (60%) 494 (65) 181 (51)* WBC 9.6 (0.4-361) 17.3 (5-19) 16.7 (5-18) WBC > 24 203 (18) 133 (18) 70 (20) WBC < 4 160 (14) 130 (17) 30 (8.5)* Plt 204 (3-2690) 237 (1-1364) 354 (6-2690)* Plt < 100 276 (25) 220 (29) 56 (16)* Hgb 10.5 (5-18) 10 (5-18) 11 (5-19)* Hgb < 10 462 (42) 329 (43) 133 (38)* Transfusion dependency 265 (24) 203 (27) 62 (18)* Blasts ≥ 1% 523 (47) 371 (49) 152 (43) Splenomegaly 668 (60) 459 (63) 209 (65) Symptoms 793 (71) 537 (70) 256 (73) LDH 1246 (189-10343) 1248 (189-10353) 1261 (205-8476) LDH > 620 958 (86) 640 (85) 318 (90)* JAK2 positive 586 (57) 371 (63) 215 (37)* MPL positive 19 (1.9) 16 (84) 3 (16)* CARL positive 53 (5) 27 (51) 26 (49)* Triple negative 26 (2.5) 21 (81) 5 (19)* *statistically significant differences (p<0.05) Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding.
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Moldenhauer, Patrick, Carl Linderholm, Magnus Rydén i Anders Lyngfelt. "Avoiding CO2 capture effort and cost for negative CO2 emissions using industrial waste in chemical-looping combustion/gasification of biomass". Mitigation and Adaptation Strategies for Global Change 25, nr 1 (15.03.2019): 1–24. http://dx.doi.org/10.1007/s11027-019-9843-2.
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Abstract Chemical-looping combustion (CLC) is a combustion process with inherent separation of carbon dioxide (CO2), which is achieved by oxidizing the fuel with a solid oxygen carrier rather than with air. As fuel and combustion air are never mixed, no gas separation is necessary and, consequently, there is no direct cost or energy penalty for the separation of gases. The most common form of design of chemical-looping combustion systems uses circulating fluidized beds, which is an established and widely spread technology. Experiments were conducted in two different laboratory-scale CLC reactors with continuous fuel feeding and nominal fuel inputs of 300 Wth and 10 kWth, respectively. As an oxygen carrier material, ground steel converter slag from the Linz–Donawitz process was used. This material is the second largest flow in an integrated steel mill and it is available in huge quantities, for which there is currently limited demand. Steel converter slag consists mainly of oxides of calcium (Ca), magnesium (Mg), iron (Fe), silicon (Si), and manganese (Mn). In the 300 W unit, chemical-looping combustion experiments were conducted with model fuels syngas (50 vol% hydrogen (H2) in carbon monoxide (CO)) and methane (CH4) at varied reactor temperature, fuel input, and oxygen-carrier circulation. Further, the ability of the oxygen-carrier material to release oxygen to the gas phase was investigated. In the 10 kW unit, the fuels used for combustion tests were steam-exploded pellets and wood char. The purpose of these experiments was to study more realistic biomass fuels and to assess the lifetime of the slag when employed as oxygen carrier. In addition, chemical-looping gasification was investigated in the 10 kW unit using both steam-exploded pellets and regular wood pellets as fuels. In the 300 W unit, up to 99.9% of syngas conversion was achieved at 280 kg/MWth and 900 °C, while the highest conversion achieved with methane was 60% at 280 kg/MWth and 950 °C. The material’s ability to release oxygen to the gas phase, i.e., CLOU property, was developed during the initial hours with fuel operation and the activated material released 1–2 vol% of O2 into a flow of argon between 850 and 950 °C. The material’s initial low density decreased somewhat during CLC operation. In the 10 kW, CO2 yields of 75–82% were achieved with all three fuels tested in CLC conditions, while carbon leakage was very low in most cases, i.e., below 1%. With wood char as fuel, at a fuel input of 1.8 kWth, a CO2 yield of 92% could be achieved. The carbon fraction of C2-species was usually below 2.5% and no C3-species were detected. During chemical-looping gasification investigation a raw gas was produced that contained mostly H2. The oxygen carrier lifetime was estimated to be about 110–170 h. However, due to its high availability and potentially low cost, this type of slag could be suitable for large-scale operation. The study also includes a discussion on the potential advantages of this technology over other technologies available for Bio-Energy Carbon Capture and Storage, BECCS. Furthermore, the paper calls for the use of adequate policy instruments to foster the development of this kind of technologies, with great potential for cost reduction but presently without commercial application because of lack of incentives.
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Maxwell, Lauren, Arijit Nandi, Andrea Benedetti, Karen Devries, Jennifer Wagman i Claudia García-Moreno. "Intimate partner violence and pregnancy spacing: results from a meta-analysis of individual participant time-to-event data from 29 low-and-middle-income countries". BMJ Global Health 3, nr 1 (styczeń 2018): e000304. http://dx.doi.org/10.1136/bmjgh-2017-000304.
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IntroductionInadequately spaced pregnancies, defined as pregnancies fewer than 18 months apart, are linked to maternal, infant, and child morbidity and mortality, and adverse social, educational and economic outcomes in later life for women and children. Quantifying the relation between intimate partner violence (IPV) and women’s ability to space and time their pregnancies is an important part of understanding the burden of disease related to IPV.MethodsWe applied Cox proportional hazards models to monthly data from the Demographic and Health Surveys’ Reproductive Health Calendar to compare interpregnancy intervals for women who experienced physical, sexual and/or emotional IPV in 29 countries. We conducted a one-stage meta-analysis to identify the periods when women who experienced IPV were at the highest risk of unintended and incident pregnancy, and a two-stage meta-analysis to explore cross-country variations in the magnitude of the relation between women’s experience of IPV and pregnancy spacing.ResultsFor the one-stage analysis, considering 52 959 incident pregnancies from 90 446 women, which represented 232 394 person-years at risk, women’s experience of IPV was associated with a 51% increase in the risk of pregnancy (95% CI 1.38 to 1.66), although this association decreased over time. When limiting our inference to unintended pregnancies that resulted in live births, women’s experience of IPV was associated with a 30% increase in the risk of unintended pregnancy (95% CI 1.25 to 1.34; n=13 541 pregnancies, 92 848 women, 310 319 person-years at risk). In the two-stage meta-analyses, women’s experience of IPV was associated with a 13% increase in the probability of incident pregnancy (95% CI 1.07 to 1.20) and a 28% increase in the likelihood of unintended pregnancy (95% CI 1.19 to 1.38).ConclusionsAcross countries, women’s experience of IPV is associated with a reduction in time between pregnancies and an increase in the risk of unintended pregnancy; the magnitude of this effect varied by country and over time.
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Gatama, Samwel Njenga, Mary Akinyi Otieno i Samuel Ndungu Waweru. "Principals` Instructional Leadership and Its Influence on Students’ Academic Achievement in Public Secondary Schools in Nyeri and Nyandarua Counties in Kenya". East African Journal of Education Studies 6, nr 1 (8.02.2023): 148–63. http://dx.doi.org/10.37284/eajes.6.1.1080.
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The study focused on the influence of principals` instructional leadership practices on students` academic performance in public secondary schools in Nyeri and Nyandarua counties. The concern was the low and widely varied academic performance yet the principals` instructional leadership practices were not clear. The study adopted ex-post facto research design and systems theory to study instructional leadership as a determinant of learning outcomes. The sample size comprised 192 principals, 330 Heads of Department, and 352 teachers in 192 schools. The main data collection tools were the principals` questionnaire (r =.89), HoDs` questionnaire (r =.92) and teachers` questionnaire (r =.87). Both qualitative and quantitative data were collected. Qualitative data were analysed using thematic analysis, while quantitative data was analysed using both descriptive and inferential statistics. Due to the non-normality and ordinal nature of data, inferential statistics were done by use of the Kruskal-Wallis H-test as the non-parametric alternative to the one-way analysis of variance F-test. The study findings were that all five dimensions of instructional leadership were positively and significantly related to students’ academic achievement. Strategic provision of instructional materials and promoting teacher capacity building and motivation were the two dimensions with the largest effect sizes since they explained 9.6% and 9.1% of the observed variation in academic performance, respectively. When all five dimensions of instructional leadership were considered together, the overall instructional leadership explained 16.7% of the observed variation in academic performance, implying that for principals to impact significantly on academic achievement in their schools, they must focus and prioritise all the dimensions of instructional leadership. As a major recommendation for the study, though principals have an arduous task of general school management, they need to prioritise instructional leadership to enhance academic performance in their schools. Proper capacity building and stakeholders support to the principals in this endeavour would be a move in the right direction.
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Walters, E. M., J. D. Benson, A. Rieke, J. K. Graham i J. K. Critser. "80 CHOLESTEROL-LOADED METHYL-BETA-CYCLODEXTRIN IMPROVES BOAR SPERMATOZOA CRYOPROTECTANT ADDITION AND REMOVAL TOLERANCE". Reproduction, Fertility and Development 21, nr 1 (2009): 140. http://dx.doi.org/10.1071/rdv21n1ab80.
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Difficulties associated with the cryopreservation of boar sperm include their sensitivities to osmotic stresses and chilling sensitivity. We investigated the effects of cholesterol-loaded cyclodextrin (CLC) on boar sperm motility and membrane integrity following exposure to various osmolalities. Samples were collected using the gloved hand method from crossbred boars, and ejaculates having greater than 75% motility were extended 1:3 with Androhep (Minitube Inc., Verona, WI) for this study. Samples were centrifuged at 700g for 5 min, and the resulting pellets were resuspended to 1.2 × 108 cells mL–1 in Androhep. Samples were then treated with 0, 1.5, or 3.0 mg of CLC/1.2 × 108 cells mL–1 for 10 min at room temperature. In experiment 1, samples were aliquoted into 1.5-mL centrifuge tubes, centrifuged at 700g for 5 min and the sperm exposed to Dulbecco’s PBS at different osmolalities for 5 min before being returned to 300 mOsm by adding Dulbecco’s PBS solutions at differing osmolalities. After returning the sperm to isosmotic conditions, sperm motility was analyzed. In experiment 2, samples were treated as in experiment 1 and following exposure to the various osmolalities, sperm were stained with Alexa 488-PNA and propidium iodide to determine sperm membrane integrity. Ten thousand sperm per treatment were analyzed by flow cytometry. Data were analyzed by standard ANOVA. The CLC-treated sperm (normalized means ± SEM; 33 ± 16, 80 ± 8, 86 ± 5, 100, 64 ± 4, 7 ± 3, 0 ± 0, respectively) exhibited greater percentages of motile cells following hypo-isosmotic exposure than control sperm (4 ± 1.6, 33 ± 9.6, 84 ± 7.1, 100, 37 ± 5.5, 3 ± 1.6, 0 ± 0, respectively), and there was a tendency for CLC-treated sperm (P = 0.0225) to maintain motility following hyper-isosmotic exposure. In addition, CLC-treated sperm (87 ± 4, 93 ± 1, 95 ± 1, 93 ± 2, 88 ± 4, 83 ± 3, 41 ± 9, respectively; P < 0.05) maintained greater percentages of membrane integrity following treatment with anisosmotic solutions compared with controls (29 ± 8, 63 ± 10, 81 ± 7, 92 ± 3, 73 ± 8, 44 ± 5, 21 ± 9, respectively). Using a combination of these osmotic tolerance data with previously published boar sperm membrane permeability characteristics, we mathematically modeled the number of steps needed for the addition or removal of cryoprotectants. Computer simulations indicate that an abrupt addition of 1 m glycerol will cause boar sperm to exceed their osmotic tolerance limits unless they are treated with 3 mg of CLC. Moreover, the addition of 1 m EG causes boar sperm to exceed all osmotic tolerance limits and therefore, the addition and removal of EG requires multiple-step protocols. However, the addition and removal of 1 m DMSO maintains volume excursions well within the osmotic tolerance limits with the addition of cholesterol (1.5 and 3 mg). Empirical data for addition of CPA have shown similar results as seen with the computer simulation. These data support the hypothesis that adding cholesterol to porcine sperm broadens their osmotic tolerance limits and potentially provide a mechanism to increase post-thaw survival of porcine sperm.
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Gonzalez-Barcena, David, Manuel Vadillo Buenfil, Emilo Garcia Procel, Laura Guerra-Arguero, Imelda Cardenas Cornejo, Ana Maria Comaru-Schally i Andrew V. Schally. "Inhibition of luteinizing hormone, follicle-stimulating hormone and sex-steroid levels in men and women with a potent antagonist analog of luteinizing hormone-releasing hormone, Cetrorelix (SB-75)". European Journal of Endocrinology 131, nr 3 (wrzesień 1994): 286–92. http://dx.doi.org/10.1530/eje.0.1310286.
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Gonzalez-Barcena D, Vadillo Buenfil M, Garcia Procel E, Guerra-Arguero L, Cardenas Cornejo I, Comaru-Schally AM, Schally AV. Inhibition of luteinizing hormone, follicle-stimulating hormone and sex-steroid levels in men and women with a potent antagonist analog of LH-RH, Cetrorelix (SB-75). Eur J Endocrinol 1994;131:286–92. ISSN 0804–4643 Cetrorelix (SB-75; [Ac-d-Nal(2)1, d-Phe(4Cl)2, d-Pal(3)3, d-Cit6, d-Ala10] luteinizing hormone-releasing hormone (LHRH)) is a new highly potent antagonist analog of LHRH containing the d-ureidoalkyl amino acid d-citrulline at position 6 and is free of allergenic effects. This study shows the inhibition of LH and follicle-stimulating hormone (FSH) release in normal men, postmenopausal women and patients with gonadal dysgenesis, using different doses and im, sc and iv routes of administration of SB-75. The mean serum levels of LH and FSH in normal men who received one single dose of 300 μg of SB-75 sc started to decline rapidly 1 h after its administration; the LH suppression was sustained for 14 h and that of FSH up to 24 h or longer as the samples were obtained only up to this time. The nadir for LH was reached at 14 h and that for FSH at 24 h or later after administration of the antagonist (p < 0.05). Serum levels of total and free testosterone decreased after the first hour and this inhibition was maintained for up to 14 h. The nadir for total testosterone was at 6 h and that for free testosterone was at 8 h (p < 0.001), corresponding to 56% and 60% of inhibition, respectively. In postmenopausal women, inhibition of the elevated basal serum LH and FSH levels occurred after a single injection of the antagonist analog SB-75 in doses of 75, 150, 300, 600 and 1200 μg using im, sc and iv routes of administration. The mean resting levels of serum LH and FSH showed a significant decrease for all doses and routes of administration of SB-75 (p < 0.01). Maximal inhibition was observed 6–12 h after administration. After administration of 300 μg of SB-75 sc every 12 h for 3 days, serum LH and FSH continued to be secreted but a marked decrease in the basal levels of both gonadotropins was observed. A fall in LH and FSH also was produced in patients with gonadal dysgenesis who were given 300 μg of SB-75. The nadir of serum LH was 61 ± 9.6% for the iv route and 58.5 ± 7.5% for the sc route (p < 0.01); for serum FSH it was 51 ± 7.5% and 48.5 ± 7.5% (p < 0.01), respectively, of the baseline levels. These results show that the antagonistic analog SB-75 is devoid of allergenic effects, extremely active in small doses and can be administered safely to humans. The development of sustained delivery systems for SB-75 should facilitate the clinical use of this powerful LHRH antagonist. David Gonzalez-Barcena, Hospital de Especialidades Centro Medico La Raza, Seris Y Zaachila, Col. La Raza, Mexico D.F.
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Gusev, A. I., A. A. Usol’tsev, N. A. Kozyrev, N. V. Kibko i L. P. Bashchenko. "Development of flux-cored wire for surfacing of parts operating under conditions of wear". Izvestiya Visshikh Uchebnykh Zavedenii. Chernaya Metallurgiya = Izvestiya. Ferrous Metallurgy 61, nr 11 (24.12.2018): 898–906. http://dx.doi.org/10.17073/0368-0797-2018-11-898-906.
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Powder wire for surfacing of abrasive-wearing products of Fe - C - Si - Мп - Cr -Ni - Mo system (type A according to IIW classification) was developed and investigated. Studies in laboratory conditions were performed according to the following scheme: multilayer surfacing of the samples was carried out with preheating of plates up to 350 °C and subsequent slow cooling (after surfacing). Surfacing was made by ASAW-1250 welding tractor with manufactured cored wire in six layers on plates of 09G2S steel. Instead of amorphous carbon, carbon-fluorine-containing dust containing 21 - 46 % Al2O3; 18 - 27 % F; 8 - 15 % Na2O; 0.4 - 6.0 % K2O; 0.7 - 2.3 % CaO; 0.5 - 2.5 % SiO2; 2.1 - 3.3 % Fe2O3; 12.5 - 30.2 % Cgen ; 0.07 - 0.90 % MnO; 0.06 -- 0.90 % MgO; 0.09 - 0.19 % S; 0.10 - 0.18 % P was introduced into the wire. The following powder materials were used as filler: iron powder PZhV1 as per GOST 9849 - 86, ferrosilicon powder FS 75 as per GOST 1415 - 93, high carbon ferrochrome powder F99A as per GOST 4757 - 91, carbon ferromanganese powder FMN 78(A) as per GOST 4755 - 91, PNK-1L5 nickel powder PNK-1L5 as per GOST 9722 - 97, ferromolybdenum powder FMo60 as per GOST 4759 - 91, ferrovanadium powder FV50U 0.6 as per GOST 27130 - 94, cobalt powder PC-1U as per GOST 9721 - 79, tungsten powder PVN as per PS 48-19-72 - 92. Studies of the deposited layer have shown that within the obtained limits, carbon, chromium, molybdenum, nickel, manganese and to a lesser extent vanadium simultaneously increase hardness of the deposited layer and reduce rate of wear of the samples. Increase in concentration of tungsten increases hardness of the deposited metal but reduces wear resistance. Low viscosity of matrix does not allow tungsten carbides to be kept on surface, as a result, wear occurs not according to the uniform surface abrasion scheme, but is reasoned by pitting high-strength carbide particles from the matrix, resulting in additional cracks formed in matrix, contributing to additional wear of matrix. Introduction of cobalt to the mixture composition does not have significant effect on hardness and abrasive wear of the deposited layer, which is associated with obtaining more viscous, but less solid matrix. In case of absence of solid particles of carbides embedded in matrix, the effect of introduction of cobalt is negative. According to the results of multivariate correlation analysis, dependences of hardness of the deposited layer and its wear resistance on mass fraction of elements included in flux-cored wires of the Fe - C - Si - Mn - Cr - Mo - Ni - V - Co system were determined.
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Peterson, Erica A., Paul R. Yenson, Jacobus C. Kritzinger, Lauren J. Lee, Jay Chi, David M. Liu i Agnes Y. Y. Lee. "Prospective Study of an Inferior Vena Cava Filter Management Pathway in a Tertiary Care and Trauma Centre". Blood 124, nr 21 (6.12.2014): 685. http://dx.doi.org/10.1182/blood.v124.21.685.685.
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Abstract Background: In our institution, a retrospective analysis of inferior vena cava (IVC) filter usage demonstrated attempted removal in only 60% of patients. We performed a prospective cohort study to determine if an IVC filter management program (IVCFP) will improve retrieval rates. Methods: Consecutive patients receiving a retrievable IVC filter were approached for study enrollment within 48 hours of placement. Consenting patients received a visible IVC Filter Identification Wristband and pre-printed orders were placed in each patient's chart indicating that the wristband can only be removed by physician order if: 1) the filter has been retrieved; 2) a decision to make the filter permanent has been discussed and agreed upon with the patient; or 3) the patient has been referred to the Thrombosis Clinic for filter follow-up after hospital discharge. Educational pamphlets and Thrombosis Clinic referral information were provided to the patient and care team. All patients were followed up to time of hospital discharge and to the end of the study if the filter was still in situ. Baseline demographics, dates of filter insertion and retrieval, and data on filter indication, documentation of a follow-up plan, reasons for non-retrieval, and all-cause mortality were extracted from electronic and paper medical records using standard forms. The primary outcome was the proportion of patients who underwent attempted filter retrieval. Secondary outcomes included the proportion of patients who had a successful retrieval and documentation of a filter management plan. Results were compared with a historical cohort of 275 patients who had filters placed between Jan 2007 and Dec 2010. Group characteristics were compared using 2-sided t-tests for continuous variables and Chi-squared analysis for categorical variables. Results: Between Nov 2011 and Dec 2013, 92 of 111 eligible patients consented to participate. Mean age was 57.3 years and 67.4% were male. Compared to historical patients, IVCFP patients were more likely to be male (64.7% vs. 54.5%; p=0.03), less likely to have a prior history of venous thromboembolism (7.6% vs. 18.5%; p=0.01) and more likely to have received a filter for an acute VTE with contraindication to anticoagulation (76.1% vs. 72.4%; p=0.03) (see Table). At the end of study in June 2014, total length of follow-up for filter retrieval was 14,823 patient-days (median 48.5; range 4-956). No patient was lost to follow-up. Compared to historical data, the IVCFP significantly improved the proportion of patients with attempted retrieval (73/92 [79.3%] vs. 165/275 [60.0%]; p=0.001), documentation of an IVC filter management plan (91.3% vs. 73.8%; p<0.001) and successful retrieval (72.8% vs. 53.1%; p=0.001). Two patients in the IVCFP cohort and 28 historical controls did not have an attempted retrieval despite no clear reason for the filter to remain in situ permanently (2% vs. 10%; p=0.01). Of the 25 patients discharged with a filter in-situ, 20 were referred to our Thrombosis Clinic and 17 had a retrieval attempt post-discharge. Conclusions: Implementation of an IVCFP – consisting of a patient identification wristband, educational materials and referral for outpatient follow-up – was associated with significant increases in attempted filter retrieval and successful filter retrieval. The IVCFP represents an effective and low cost strategy to improve the follow-up and outcomes of patients receiving retrievable IVC filters. Table Historical Cohort N=275 Prospective Cohort N=92 P value Thrombotic risk factors, n (%) Acute VTE 213 (77.5) 78 (84.8) NS Prior VTE 51 (18.5) 7 (7.6) 0.01 Cancer 97 (35.3) 34 (37.0) NS Trauma 63 (22.9) 22 (23.9) NS Indications for filter insertion, n (%) Contraindication to AC 199 (72.4) 70 (76.1) 0.03 High risk for PE 31 (11.3) 10 (10.9) NS Primary prophylaxis 41 (14.9) 11 (12.0) NS Other 4 (1.5) 1 (1.1) NS Filter removal attempted, n (%) 165 (60.0) 73 (73.9) 0.001 Filter removal successful, n (%) 146 (53.1) 67 (72.8) 0.001 Documentation of a filter management plan, n (%) 203 (73.8) 84 (91.3) <0.001 Reasons for non-retrieval, n (%) Death in hospital/limited life expectancy 41 (14.9) 9 (9.8) NS Filter made permanent 22 (8.0) 4 (4.3) NS Persistent contraindication to AC 10 (3.9) 3 (3.3) NS High risk of PE despite AC 5 (1.8) 1 (1.1) NS Lost to follow-up 4 (1.5) 0 (0.0) NS Unknown 28 (10.2) 2 (2.2) 0.01 VTE, venous thromboembolism; PE, pulmonary embolism, NS, non-significant, AC, anticoagulation. Disclosures No relevant conflicts of interest to declare.
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Sych, Z., i S. Kubrak. "Evaluation of varieties and local forms of winter garlic for their economic characteristics in the conditions of right bank Forest Steppe of Ukraine". Agrobìologìâ, nr 1(157) (25.05.2020): 169–74. http://dx.doi.org/10.33245/2310-9270-2020-157-1-169-174.
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Garlic production for the local market and for export lacks a suffi cient amount of high-yielding varieties with large bulbs and small amount of cloves, resistant to pests, diseases and stressful cultivation conditions. In addition to industrial varieties, adapted local forms of self-breeding are currently cultivated. Winter garlic is a plant with vegetative reproduction and it is reproduces with cloves, single clove and air bulbs, Therefore, the varieties brought from other regions degenerate quickly. Two and three times reproduction leads to a gradual reduction in yield and quality. The transfer of local forms from one region to another requires further study. Researches were carried out in conditions of right bank Forest Steppe of Ukraine. We studied 60 samples of winter garlic. The working collection of winter garlic was composed of varieties and local forms brought from Kyiv, Chernihiv, Dnipropetrovsk, Kirovograd and Cherkassy regions. Some samples (45 pcs.) were received from the National Center of Plant Genetic Resources of Ukraine. The variety of Prometey created at Uman University of gardening was used as the control. The research was conducted according to the "Methods of experimental work in vegetable growing and melon-plot fi eld" (G. L. Bondarenko, K. I. Yakovenko, Kharkiv 2001). The plants density was 340 thousand plants ha. On the average for 2017-2020 the heads formed the largest diameter in the variants of IOB00003-Biryuchekutskiy local (55 mm) and IOB00117 (53 mm). Their average weight was the highest in the sample of IOB00117 – 41 g. The smallest heads were formed in the variant of IOB00083 Spas – 17 g. Essentially higher yield of heads of winter garlic was collected from cultivation of plants of the variant IOB00117 – 12,6 t/ha. The greatest share of commodity heads was observed for samples IOB00003-Biryuchekutskiy local and IOB00117 (92 %). Thus, samples of IOB00003-Biryuchekutskiy local and IOB00117 were the best in the diameter, weight of a head and productivity among the samples studied in the research carried. They yielded 9.6 and 12.6 t/ha, respectively, with head weights of 31 and 41 g and the diameter of 55 and 53 cm. Key words: varieties, local forms, collection, winter garlic, weight of the bulb, marketability.
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Massuti, B., A. Gómez, J. Sastre, J. M. Tabernero, M. Chaves, A. Carrato, A. Abad, J. Aparicio, E. Díaz-Rubio i E. Aranda. "Randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) as first line treatment in advanced or metastatic colorectal cancer (CRC)". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 3580. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3580.
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3580 Background: OX plus CI 5-FU is one of the standard chemotherapy regimens for first-line treatment in patients (p) with advanced CRC. Phase II trials have shown XELOX as a convenient combination, with a high activity and a favourable safety profile. This study is a phase III trial comparing both schedules. Methods: Multicenter, randomized and open labeled study was designed to include p withadvanced/metastatic CRC adenocarcinoma, measurable disease, PS ≥70% and adequate bone marrow, renal and hepatic functions. Previous adjuvant chemotherapy was allowed. Primary endpoint is time to progression (TTP). The study was designed to determined non-inferiority when the median time to progression in the XELOX arm was not lower than 5.5 months (hazard ratio no larger than 1.27). A sample size of 348 p (174 per arm) was necessary (0.05 level test; 80% power). Treatment: P were randomly assigned to receive either Arm A: oral XEL 1000 mg/m2 twice daily from day 1 to day 15, plus OX 130 mg/m2, iv, 2h, day 1 (in 3-week treatment cycles) or Arm B: biweekly 85 mg/m2, OX, iv, 2h, plus weekly CI 5-FU 2250 mg/m2, in 48h (TTD schedule). Treatment was continued, until progressive disease, unacceptable toxicity or consent withdrawal. Results: 340 (170/170) p have been included in the interim analysis over 348 enrolled, (M/F, 61%/39%), median age: 65.6 years (32.3–81.6), PS 90–100%: 62%. Primary tumour sites were colon (66.4%), rectum (28.3%) and both (5.3%). Median relative dose intensity was 90% for XEL and 92% for OX in arm A and 78% for OX and 78% for 5-FU in arm B. Efficacy: overall response rate in each arm (A/B) was 37.1/43.0% (p=0.824). With a median follow up of 12.6 months, median TTP was 8.8/9.6 months (p=0.130). Main grade 3–4 toxicity per p in each arm (A/B) was: paresthesia (17.7/15.9%), asthenia (12.4/17.1%), diarrhea (14.1/23.6%), neutropenia (8.3/10.0%) and vomiting (4.1/7.6%). Mature data on TTP and OS will be presented at the meeting. Conclusions: Efficacy and safety results suggest a similar toxicity profile, response rate and TTP for both regimens. No significant financial relationships to disclose.
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Tsai, Stephanie B., Hongtao Liu, Tsiporah B. Shore, Michael R. Bishop, Melissa M. Cushing, Yun Fan, Usama Gergis i in. "Frequency and Risk Factors of Cord Graft Failure (CGF) Following Reduced Intensity Conditioning Haplo-Cord Hematopoietic Stem Cell Transplantation". Blood 124, nr 21 (6.12.2014): 2463. http://dx.doi.org/10.1182/blood.v124.21.2463.2463.
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Abstract PURPOSE: Delayed engraftment and cord graft failure (CGF) are serious and often fatal complications after unrelated cord blood (UCB) hematopoietic cell transplantation (HCT), precluding use of low cell dose UCB. The haplo-cord HCT approach allows the use of a lower dose single UCB unit by co-infusion of a CD34+ selected haploidentical graft. Although haplo-cord HCT aims to achieve durable UCB hematopoiesis, the haplo graft provides early temporary engraftment. We describe the frequency, complications and risk factors of CGF after haplo-cord HCT after reduced-intensity conditioning (RIC). PATIENTS AND METHODS: Adult hematologic malignancy patients from the University of Chicago or the Weil Cornell medical centers who underwent haplo-cord HCT between 2007 and 2013 were included. Conditioning consisted of fludarabine, melphalan, and rATG (and TBI 400 cGY if high CNS relapse risk), followed by infusion of a CD34+ selected G-CSF mobilized haploidentical graft and the best HLA matched single UCB unit of at least 0.5 or 1.0 x 10^7 total nucleated cells (TNC)/kg, depending on the protocol. CGF was defined as <5% cord blood chimerism by Day 60 in the unfractionated or CD3 compartments irrespective of neutrophil or platelet counts. Death before Day 60 excluded patients from the primary outcome of CGF at Day 60. Univariate analyses were performed to identify potential risk factors for CGF: Fisher's Exact test for dichotomous and logistic regression for continuous predictor variables. RESULTS: 107 patients were evaluated. Chimerism data were not available on two, and 11 (10.3%) died before Day 60, leaving 94 evaluable patients for CGF. Diseases indications were: AML (51%), ALL, (12%), MDS (11%), and other (25%). Median age of patients was 50 years (range 18-73) and many had active disease at HCT (47%). The mean UCB collected dose was 2.1x10^7 TNC/kg (range 0.77-8.3x10^7 TNC/kg) and HLA cord match was 4/6 in 24% and 5/6 or 6/6 in 73%. Few patients had UCB doses below 1x10^7 TNC/kg (N=5). CGF occurred in 14 of 94 (15%) evaluable patients. Of these, 7 died within 1 year of transplant date. The causes of deaths were: poor graft function (N=2), infection (N=2), relapse or progressive disease (N=2) and unknown (N=1). The other 7 remain alive (range: 7 months to 5.5 years) with haplo-derived or mixed haplo-recipient hematopoiesis. Four are in remission and three have relapsed disease. Median survival for the CGF group was 12.7 months. In univariate analyses, no UCB factor, including cell doses, major ABO mismatch, donor specific antibodies, CMV status, and HLA-match, was associated with CGF. (Table) However, higher haploidentical TNC and CD34+ doses were associated with greater risk of CGF. CONCLUSION: Approximately 15% of patients experienced CGF after haplo-cord HCT. Most have died or relapsed, but some have had relatively long-term survival due to sustained haploidentical hematopoiesis. Avoidance of high haploidentical cell doses may reduce risk of CGF. We were unable to identify other determinants of CGF. In ongoing studies, we have limited the haplo graft to <5 x10^6 CD34+/kg and are testing the use of lower UCB cell doses when large units can not be identified. Additional follow-up is needed to determine if sustained or greater cord chimerism improves long-term outcomes compared to haplo chimerism after RIC haplo-cord SCT. Table: Graft Composition and Association with Cord Graft Failure (CGF) at Day 60 No CGF CGF p-value Evaluable Patients, N=94 N=80 N=14 Cord Blood Unit: Mean/Value (+/-SD or %) Mean/Value (+/-SD or %) Cord Bank Reported (post-processing): TNC/kg x 10^7 2.1 (+/-1.1) 1.9 (+/-0.63) 0.61 TNC/kg<1.5x10^7, N=92 27 (35%) 3 (21%) 0.54 CD34+/kg x 10^5 0.88 (+/- 0.71) 0.98 (+/- 0.80) 0.65 Viability (%) 95.6 (+/-4.7) 96.9 (+/-4.6) 0.38 Viability <85%, N=82 1 (1.5%) 1 (7%) 0.31 Post Wash: TNC/kg x 10^7 1.5 (+/-0.72) 1.4 (+/-0.43) 0.72 TNC/Kg<1.5x10^7, N=92 47 (60%) 8 (57%) 1.0 Viability (%) 91.8 (+/-5.3) 91.9 (+/-5.3) 0.96 Viability <85%, N=92 6 (8%) 2 (14%) 0.3 Haploidentical Graft: TNC/kg x 10^6 3.8 (+/-1.6) 5.0 (+/-2.2) 0.03 CD34+/kg x 10^6 3.8 (+/-1.6) 4.8 (+/-2.2) 0.055 CD34+/kg <3.0 x 10^6, N=92 30 (38%) 2 (14%) 0.13 CD3/kg x 10^4 1.2 (+/-3) 0.53 (+/-0.6) 0.29 Disclosures Larson: Novartis: Consultancy, Research Funding. Stock:Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Artz:Miltenyi: Research Funding.
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Fresneau, Brice, Felicia Santos, Rodrigue Allodji, Chiraz Fayech, Stephanie Bolle, Giao Vu-Bezin, Vincent Souchard i in. "New insights in cisplatin and radiation-induced ototoxicity: A French Childhood Cancer Survivors Study (FCCSS)." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): 10061. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.10061.
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10061 Background: Platinum chemotherapy (CT) and cranial radiotherapy (RT) are risk factors of ototoxicity. Effects of RT dose at inner ear and of other CT were investigated. Methods: Of 7670 5-year childhood cancer survivors from the FCCSS treated before 20 years of age in 1942-2000 for solid cancer or lymphoma, 5243 with ototoxicity long-term follow-up data were included. Severe ototoxicity, defined as the need of hearing aids or Brock grade 3-4 hearing loss, was identified from self-administrated questionnaires, clinical visits and cohort linkage with the French Hospital Database and health insurance information system (SNIIRAM). The mean RT dose at inner ear was estimated using home-made software. Multivariable Cox models adjusted for gender, age at diagnosis, time period and social deprivation index was used to identify risk factors for severe ototoxicity. Results: After a mean follow-up of 30 years, 199 cases of severe ototoxicity were identified. Cumulative incidences at 30 and 50 years of age (30,50y-CumInc) were, 2.8% (95%CI = 2.4-3.3) and 5.5% (4.6-6.5), respectively. Mean RT dose at inner ear (Hazard Ratio HR = 1.6 (95%CI = 1.0-2.5), 4.5 (2.7-7.2), 5.7 (3.0-10.8) and 14.0 (9.2-21.2) for 0- < 5, 5- < 30, 30- < 40 and ≥40 Gy), as well as cisplatin (HR = 2.8, 95%CI = 1.9-4.0), melphalan (HR = 3.3, 95%CI = 1.9-5.7) and busulfan exposure (HR = 2.6, 95%CI = 1.6-4.4) were significantly associated with severe ototoxicity. Concerning melphalan (n = 199/5243 exposed), almost all cases were identified in neuroblostma patients (NBL), who also received cisplatin 200mg/m²/cycle (26/92 NBL, 30y-CumInc = 36.4% (95%CI = 25.9-48.4), vs. 3/107 non-NBL, 30y-CumInc = 1.6% (0.4-5.6)). Concerning busulfan (n = 131/5243 exposed), all cases were identified in NBL (n = 16/63, all treated with melphalan and cisplatin) and brain tumors (n = 13/28, all with RT at inner ear ≥5Gy). The 30y-CumInc in patients with RT at inner ear ≥5Gy was 7.4% (95%CI = 5.7-9.6) and 39.8% (22.5-60.0) respectively with and without busulfan. Conclusions: RT at inner ear has significant deleterious impact on audition, with cumulative incidence still worsening > 30years after RT, and with likely potentiation by busulfan. The deleterious effect of melphalan was related to previous treatment with cisplatin, either by interaction between these drugs, or by the high cisplatin dose by cycle used in NBL.
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Richardson, Paul G., Asher Chanan-Khan, Sagar Lonial, Amrita Krishman, Michael Carroll, G. F. Cropp, K. Kersey i in. "Tanespimycin (T) + Bortezomib (BZ) in Multiple Myeloma (MM): Confirmation of the Recommended Dose Using a Novel Formulation." Blood 110, nr 11 (16.11.2007): 1165. http://dx.doi.org/10.1182/blood.v110.11.1165.1165.
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Abstract Introduction: Tanespimycin (17-AAG/KOS-953) disrupts Hsp90, a molecular chaperone of client proteins including IL-6 and IGF-1R, key to MM growth, survival and drug resistance. Single agent T is well tolerated with modest anti-MM activity in Phase 1; preclinical studies suggest synergy with BZ. Methods: To date, 63 patients (pts) received BZ followed by 1-hr infusion of T on D1,4,8,11 q 21d. Dose escalating phase: 36 pts were enrolled in 7 cohorts (T 100–340 mg/m2; BZ 0.7–1.3 mg/m2). Confirmation of the phase 2 dose occurred in 27 pts across 2 groups: 1 group received a Cremophor formulation; a 2nd group received a suspension formulation without steroid premedication (n=13 and 14 pts, respectively). Results: The recommended phase 2 dose equals T 340 / BZ 1.3 mg/m2. At this dose (n=26), common all-grade (G) drug-related toxicity in pts included diarrhea (39%), dizziness (27%), nausea (23%), AST (23%), vomiting (23%), fatigue, ALT and peripheral edema (all 19%). No difference in toxicity was seen between the 2 formulations, consistent with the clinical experience to date using the suspension product (n=31). G3 and G4 thrombocytopenia was noted in 15% and 12%; no other G3 toxicity was observed in more than 1 pt. No G3 neurotoxicity was seen at any dose. For the Cremophor (n=18) and suspension formulation (n=12), AUC (parent+metabolite) equaled 30.1 ± 11.1 and 30.6 ± 15.6 ug/mL*h. PK of T was similar with/without BZ (total AUC: 30.7 ± 14.8 vs. 28.9 ± 10.5). Inhibition of 20S proteasome with T+BZ was similar to BZ single-agent. PBLs maintained induction of Hsp70 throughout the 3–4 day dosing interval; D11 (pre-infusion at 340 mg/m2) showed similar Hsp70 induction for the Cremophor and suspension formulations. Myeloma CD138 cells but not CD4 or CD8 cells from serial BM aspirates showed induction of apoptosis by flow cytometry. Responses were seen across dose levels in BZ-naïve, pre-treated and refractory pts (defined as “no response to or disease progression within 60d of last dose of BZ-containing regimen”). Three BZ-refractory pts achieved a durable response: 1 pt with 3 prior regimens with confirmed PR after 2 cycles, continuing 18+ months on study (M-spike ↓92%); a 2nd pt with 2 prior regimens achieved PR after 2 cycles and continues 14+ months on study; a 3rd pt with 7 prior regimens with confirmed PR withdrew after 8 cycles with 12-month duration of PR. The incidence of objective response in pts receiving the Cremophor and suspension formulations was similar. To date, in the 5 BZ-naive pts evaluable for efficacy treated with the suspension, 4 pts achieved a confirmed response (1 CR, 2 PR and 1 MR); for Cremophor product, 8 out of 14 BZ-naive pts had a confirmed response (2CR, 2 PR and 4 MR). Conclusions: Treatment with T/BZ combination produces durable anti-MM activity in BZ-refractory pts. In BZ-naive pts, both formulations demonstrate substantial activity. The combination has very manageable toxicity without G3 neurotoxicity to date. Data support the use of the suspension formulation in myeloma trials. Phase 2/3 registrational program of T/BZ in relapsed MM is underway.
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Khanna, D., C. J. F. Lin, H. Spotswood, J. Siegel, D. Furst i C. Denton. "THU0328 SAFETY AND EFFICACY OF SUBCUTANEOUS TOCILIZUMAB IN SYSTEMIC SCLEROSIS: RESULTS FROM THE OPEN-LABEL PERIOD OF THE PHASE 3 FOCUSSCED TRIAL". Annals of the Rheumatic Diseases 79, Suppl 1 (czerwiec 2020): 394.1–394. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1535.
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Background:The anti–interleukin-6 (IL-6) receptor-α antibody tocilizumab (TCZ) demonstrated skin score improvement and forced vital capacity (FVC) preservation in patients with systemic sclerosis (SSc) in a phase 2 randomized controlled trial.1,2Data from the 48-week, double-blind (DB), placebo (PBO)-controlled period of the focuSSced phase 3 trial were previously presented,3and open-label (OL) data up to week 96 are presented herein.Objectives:To assess the long-term safety and efficacy of TCZ in SSc patients.Methods:Adult patients with active SSc (≤60-month duration, modified Rodnan skin score [mRSS] 10-35, and elevated acute-phase reactants) treated with PBO or TCZ in the DB period received OL TCZ 162 mg SC weekly from weeks 48 to 96 in the OL period (PBO→OL TCZ and TCZ→OL TCZ, respectively). Exploratory analysis of data up to week 96 included no formal statistical analyses. Changes in mRSS and percent predicted FVC (ppFVC) were assessed.Results:Overall, 92/105 TCZ (88%) and 89/107 PBO (83%) patients entered the OL TCZ treatment period at week 48, and 85/105 TCZ→OL TCZ (81%) and 82/107 PBO→OL TCZ (77%) patients completed treatment up to week 96. Continued decline in mRSS was observed in the OL period for PBO→OL TCZ and TCZ→OL TCZ patients (Table). Change in ppFVC for patients who switched from PBO to TCZ (PBO→OL TCZ) was comparable between weeks 48 and 96 (OL period) to the change in patients who received TCZ from BL to week 48 in the DB period (Table). Rates (95% CI) of serious adverse events from weeks 48 to 96 were 15.8 (8.6, 26.5) per 100 PY for TCZ→OL TCZ patients, 14.8 (7.9, 25.3) per 100 PY for PBO→OL TCZ patients, and 15.4 (11.0, 20.9) for all TCZ exposure over 96 weeks (n = 193). Rates (95% CI) of serious infections were 2.3 (0.3, 8.1) per 100 PY for TCZ→OL TCZ patients, 3.4 (0.7, 10.0) per 100 PY for PBO→OL TCZ patients, and 3.0 (1.3, 5.9) for all TCZ exposure over 96 weeks. One death occurred during the OL period in each arm.Conclusion:Although OL data have to be interpreted with caution, results from OL TCZ treatment show numeric improvements in mRSS and FVC preservation similar to those of the DB period, with a beneficial effect on trajectory of FVC decline in patients who switched from PBO to TCZ. Long-term safety results were consistent with the known safety profile of TCZ, and no new or unexpected events were observed.References:[1]Khanna D et al.Lancet2016;387:2630-40.[2]Khanna D et al.Ann Rheum Dis.2018;77:212-20.[3]Khanna D et al.Arthritis Rheumatol2018;70(suppl 10):abst 898.Table.Change in Efficacy From BaselineBaseline to Week 48Baseline to Week 96Week 48 to Week 96PBOTCZPBO→OL TCZTCZ→OL TCZPBO→OL TCZTCZ→OL TCZmRSS, mean (95% CI)a–5.3 (–6.9, –3.7)n = 92–6.7 (–8.0, –5.4)n = 97–8.4 (–10.0, –6.8)n = 83–9.6 (–10.9, –8.4)n = 85–2.5(–3.3, –1.6)n = 82–2.3(–3.2, –1.5)n = 85ppFVC, mean (95% CI) [median]–4.1 (–5.8, –2.4) [–3.9]n = 92–0.2 (–1.6, 1.2) [–0.7]n = 94–3.3 (–5.1, –1.5) [–3.1]n = 79–0.5 (–2.4, 1.3) [–1.4]n = 840.6 (–0.7, 1.9) [0.3]n = 78–0.3 (–1.7, 1.1) [0.0]n = 82Decline in ppFVC ≥10%, n/N (%)a15/91(16.5)5/93(5.4)14/79 (17.7)11/84 (13.1)NANAImprovement in ppFVC, n/N (%)a26/91(28.6)43/93(46.2)22/79(27.8)35/84(41.7)NANAaObserved data. NA, not assessed.Disclosure of Interests:Dinesh Khanna Shareholder of: Eicos, Grant/research support from: NIH NIAID, NIH NIAMS, Consultant of: Acceleron, Actelion, Bayer, BMS, Boehringer-Ingelheim, Corbus, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-Aventis/Genzyme, UCB Pharma, Celia J. F. Lin Employee of: Genentech, Helen Spotswood Shareholder of: Roche Products Ltd, Employee of: Roche Products Ltd, Jeff Siegel Employee of: Genentech, Daniel Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Consultant of: AbbVie, Actelion, Amgen, BMS, Cytori Therapeutics, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Speakers bureau: CMC Connect (McCann Health Company), Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer
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Söylemez, H., S. N. İspir, H. R. Demirel, E. Yıldız i M. Aydın. "Evaluation of Relationship of Neutrophil/Lymphocyte, Platelet/Lymphocyte, Monocyte/Lymphocyte Monocyte/HDL Ratios and Systemic Immune Inflammatory Index Value with Antipsychotic Treatments in Schizophrenic Patients". European Psychiatry 67, S1 (kwiecień 2024): S173. http://dx.doi.org/10.1192/j.eurpsy.2024.382.
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IntroductionThere are studies showing that the systemic inflammation response in patients diagnosed with schizophrenia is different from healty controls. Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (TLR), monocyte-lymphocyte ratio (MLR), monocyte-HDL ratio (MHO) and systemic immune inflammation index (SII) have recently been used as inflammation indicators.ObjectivesNLR, TLR, MLR, MHO and SII have been evaluated in many studies in schizophrenia patients. The aim of our study is to evaluate the relationship between NLR, TLR, MLR, MHO, SII values and antipsychotic treatments of patients diagnosed with schizophrenia.Methods203 individuals diagnosed with schizophrenia who were followed up in the psychotic disorders outpatient clinic of Selçuk University Faculty of Medicine were included in the study. Neutrophil, lymphocyte, platelet and monocyte counts and HDL values were obtained retrospectively from blood tests. NLR, TLR, MLO, MHO and SII were calculated. The study approved by the ethics committee of Selçuk University Faculty of Medicine.Results45.3% of the patients were female (n = 92); the mean age was 45.8±14.0. The average number of hospitalizations was 3.0±2.7 years; the mean disease duration was 17.0±9.6 years. 56.7% (n=115) use long-acting antipsychotic treatment, 21% (n=43) use monthly paliperidone long-acting (PP1M) treatment, and 14.8% (n=30) use 3-month paliperidone long-acting (PP3M) treatment. No significant difference was observed in NLR, TLR, MLR, MHO and SII values between individuals using and not using long-acting antipsychotics. However, a significant difference in NLR value was observed between PP1M and PP3M treatment (p = 0.039). Oral antipsychotic use was 71% (n=137), 19% (n=38) used clozapine monotherapy, and 25% (n=51) used non-clozapine oral monotherapy. No significant difference was detected in inflammatory markers between clozapine monotherapy and other oral monotherapies.ConclusionsAccording to our findings, NLR levels in patients diagnosed with schizophrenia were found to be significantly higher in those using PP1M treatment compared to those using PP3M. This finding can be interpreted in favor of the fact that PP3M contributes to the reduction of inflammation due to its longer duration of action compared to PP1M. It is thought that schizophrenia progresses through inflammatory processes and antipsychotic treatments play a role in anti-inflammation. It is envisaged that future studies may be helpful in evaluating the onset, exacerbation and remission periods of the disease, including treatment doses and durations, and revealing the relationship between inflammatory markers and schizophrenia disease and the effects of antipsychotic treatments on inflammatory markers such as NLR, TLR, MLR, MHO and SII.Disclosure of InterestNone Declared
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Den Broeder, N., L. M. Verhoef, Y. A. De Man, M. R. Kok, R. M. Thurlings, W. Van der Weele, B. Van den Bemt, F. Van den Hoogen, A. Van der Maas i A. Den Broeder. "POS0652 LONG-TERM EFFECTIVENESS OF ULTRA-LOW DOSES OF RITUXIMAB IN RHEUMATOID ARTHRITIS". Annals of the Rheumatic Diseases 81, Suppl 1 (23.05.2022): 597.2–598. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2903.
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BackgroundThe optimal rituximab (RTX) dose for the treatment of rheumatoid arthritis remains unclear. RTX treatment of 1000mg per 6 months and 2000mg per 6 months were shown to be similarly efficacious (1). The REDO trial showed comparable the 6-month efficacy of continued treatment with 500mg and 200mg compared to 1000mg, though formal non-inferiority could not be established (2).ObjectivesTo assess the long-term effects of ultra-low dose RTX (1×500mg and 1×200mg) in RA patients previously responding well to conventional low dose RTX (1×1000mg).MethodsPatients from the REDO trial were invited to participate in this study. Treatment decisions were left at the discretion of the rheumatologist and patient. Disease activity (DAS28-CRP), and medication use (b/tsDMARD, csDMARD, gluccocorticoids [GC]) were collected from start of the trial to censoring in April 2021. The primary outcome was disease activity, secondary outcomes were RTX persistence, RTX doses and intervals, and use of comedication.Disease activity was analyzed using a longitudinal mixed model with random intercepts to account for intra-patient correlations, in two ways: 1. By original randomization and stratification factors (RF/ACPA and csDMARD use). 2. By time-varying total RTX dose received in the year preceding each disease activity measurement, adjusted for current csDMARD or GC use, and RF/ACPA. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used.Results118 out of 142 REDO patients were included in current analyses (Table 1) Reasons for exclusion were: continuing treatment elsewhere (n=3), no informed consent (n=9) and data yet to be collected in 2 study centers (n=12). Mean follow up was 3.2 years (total of 377 patient-years), with 7 patients switching to another b/tsDMARD (Figure 1) upon which they were censored from disease activity analyses.Table 1.Patient characteristics by original randomization1000mg (n=24)500mg (n=48)200mg (n=46)Age (years)65 (9)64 (11)64 (12)Female15 (63%)28 (58%)34 (74%)Meeting ACR1987 or ACRU/EULAR 2010 RA criteria22 (92%)47 (98%)43 (93%)Disease duration (years)14 (9-24)14 (7-21)13 (8-20)RF or ACPA positive22 (92%)44 (92%)40 (87%)Duration of rituximab use (years)3.0 (1.6-5.5)2.0 (1.0-5.5)3.7 (2.0-5.7)Concomitant csDMARD17 (71%)29 (60%)27 (59%)Previous number of b/tsDMARDs used2 (2-2)2 (1-3)2 (1-2)Previous number of csDMARDs used3 (1-3)2 (1-4)3 (1-3)Oral GC use at baseline3 (13%)8 (17%)5 (11%)Baseline DAS28-CRP2.3 (0.9)2.3 (0.9)2.5 (1.1)Data are n (%), mean (SD), or median (IQR).Figure 1.Rituximab treatment persistence during follow up.Disease activity in both ultra-low dose groups was non-inferior to the 1000mg group, with a mean DAS28-CRP (95% CI) during follow-up of 2.2 (2.0-2.4) in the 1000mg group, 2.2 (2.1-2.4) in the 500mg group and 2.3 (2.2-2.5) in the 200mg group.Analyzed by received RTX dose, lower RTX dose was significantly associated with a higher DAS28-CRP: 0.15 (95% CI: 0.04-0.26) points higher per 1000mg more RTX. The upper limit for relevant RTX doses was below the prespecified NI margin, excluding a relevant effect of RTX dose on disease activity.Median (IQR) yearly RTX dose was 978mg (704mg-1425mg). Final RTX dose per infusion was 200mg in 37 patients (31%), 500mg in 47 (40%) and 1000mg in 34 (29%), with a median (IQR) final interval between infusions of 6.0 (5.7-6.5), 6.2 (6.0-7.4) and 6.4 (6.0-9.6) months respectively. The rate of GC injections was 0.38 (95% CI: 0.32-0.44) per patient-year and initiation rate of oral GC was 0.05 (0.03-0.08) per patient-year.ConclusionA majority of patients treated with ultra-low dose RTX remained on ultra-low doses for up to 4 years, while disease activity remained low and did not relevantly differ between RTX doses, either according to original randomization or by received dose. Switching to other b/tsDMARDS or use of GC was rarely required.References[1]Bredemeier M et al. Clin Rheumatol 2015 Oct;34(10):1801-5.[2]Verhoef LM et al. Lancet Rheumatol. 2019; 1: e145-e153.Disclosure of InterestsNathan den Broeder: None declared, L.M. Verhoef: None declared, Yaël A. de Man: None declared, Marc R Kok: None declared, R.M. Thurlings: None declared, W. van der Weele: None declared, Bart van den Bemt Speakers bureau: UCB, Pfizer, Sanofi-Aventis, Galapagos, Amgen and Eli Lilly, Frank van den Hoogen: None declared, Aatke van der Maas: None declared, Alfons den Broeder Grant/research support from: Abbvie, Galapagos, Pfizer, Novartis, Lilly, Sanofi, Gilead
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Ravichandran, N., N. Sandhu, A. Nune, J. Day, P. Sen, E. Nikiphorou, A. L. Tan i in. "POS0558 FLARES OF AUTOIMMUNE RHEUMATIC DISEASE FOLLOWING COVID-19 INFECTION: OBSERVATIONS FROM THE COVAD STUDY". Annals of the Rheumatic Diseases 82, Suppl 1 (30.05.2023): 546–47. http://dx.doi.org/10.1136/annrheumdis-2023-eular.3976.
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BackgroundViral infections can trigger flare of autoimmune rheumatic diseases through upregulation of interferon axis. However, global data on flares of AIRDs following COVID-19 infection is scarce.ObjectivesWe aimed to study the prevalence and characteristics of patient-self reported flare of AIRDs following COVID-19 infection as part of the ongoing COVID-19 Vaccination in Autoimmune Diseases (COVAD) study.MethodsThe COVAD study, a cross-sectional patient-self reported electronic survey (157 collaborators, 106 countries) collected data on COVID-19 infection, vaccination and flares among AIRDs. The flares were patient self-reported. AIRDs with flare and without flare were compared. Descriptive stats and binary logistic regression (BLR) (adjusting for age, gender, ethnicity, vaccine type, type of immunosuppression, comorbidities, COVID-19 antibody status, and clinical features during previous COVID-19 infection) were performed.ResultsOf the 15165 respondents, 824 patients with AIRDs who contracted COVID-19 infection were identified. Most of the respondents were Caucasians (53.8%), females (86.5%), and had received the Pfizer-BioNTech vaccine (42.8%). Less than half were on glucocorticoids (41.0%), and methotrexate was the most commonly used immunosuppressant (29.9%).One-third (n=324, 36.9%) of patients with AIRDs reported flare following COVID-19 infection. Women and patients with comorbidities such as asthma, chronic obstructive pulmonary disease, diabetes mellitus, mental health disorders, and those with AID comorbidities had higher odds of flare compared to others (Table 1). Notably, certain features of COVID-19 disease such as joint pain (3.1; 2.0-4.9; <0.001), cough (1.5; 1.04-1.2; 0.030), and abdominal pain (2.5; 1.2-5.0; 0.011) were associated with increased risk of flares in BLR while the vaccine type, number of vaccine doses and autoantibodies against COVID-19 were not predictive.Patients who reported flares had worse PROMIS PF10 physical health scores (p=0.038), pain VAS (p<0.001), and lower mental health scores (p<0.001) compared to those who did not report flares.ConclusionOne in three patients with AIRDs reported post-COVID-19 disease flares. A past history of asthma, comorbidities and those with certain acute COVID-19 symptoms were at higher risk.References: NILTable 1.Patient-reported flares following COVID-19 infection among AIRD patients who contracted COVID-19Total AIRDs(n=824)N (%)AIRDs with flare following infection(n=304)N (%)AIRDs without flare following infection(n=520)N (%)OR (95%CI)pAge (median, IQR) years46.0 (36.0-55.0)45.0 (37.0-55.0)46.0 (36.0-57.0)-0.121Gender1.6 (1.04- 2.5)0.032Male105 (12.7)29 (9.5)76 (14.6)Female713 (86.5)274 (90.1)439 (84.4)ComorbiditiesAny comorbidity361 (43.8)151 (49.7)210 (40.4)1.2 (1.06-1.5)0.010Asthma96 (11.7)46 (15.1)50 (9.6)1.6 (1.09-2.5)0.017Chronic obstructive lung disease18 (2.2)12 (3.9)6 (1.2)3.5 (1.3-9.4)0.008Diabetes Mellitus42 (5.1)22 (7.2)20 (3.8)1.9 (1.04-3.6)0.033Mental health disorders258 (31.3)126 (41.4)132 (25.4)1.5 (1.3-1.8)<0.001Non-rheumatic AID comorbiditiesYes218 (26.5)98 (32.2)120 (23.1)1.5 (1.1-2.1)0.004COVID-19 antibody statusAntibodies present124/150 (82.6)48/58 (82.7)76/92 (82.6)1.0 (0.4-2.4)0.981PROMIS PF Global 10a (median, IQR)Global physical health score13.0 (12.0-15.0)14.0 (12.0-15.0)13.0 (12.0-15.0)-0.038Global mental health score13.0 (10.0-15.0)12.0 (9.0-14.0)13.5 (11.0-16.0)-<0.001Fatigue VAS3.0 (3.0-4.0)3.0 (2.0-3.0)4.0 (3.0-4.0)-0.003Pain VAS4.0 (2.0-6.0)5.0 (3.2-7.0)2.0 (1.0-5.0)-<0.001Chi-Square for Categorical variables, Mann Whitney U for scale variable comparisons.AIRDs: Autoimmune rheumatic diseases, IQR: Interquartile range, OR: Odd’s ratio,Acknowledgements:NIL.Disclosure of InterestsNaveen Ravichandran: None declared, Nimrat Sandhu: None declared, Arvind Nune: None declared, Jessica Day Grant/research support from: CSL Limited, Parikshit Sen: None declared, Elena Nikiphorou Speakers bureau: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly, and holds research grants from Pfizer and Lilly., Consultant of: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly, and holds research grants from Pfizer and Lilly., Grant/research support from: EN has received speaker honoraria/participated in advisory boards for Celltrion, Pfizer, Sanofi, Gilead, Galapagos, AbbVie, and Lilly, and holds research grants from Pfizer and Lilly., Ai Lyn Tan Speakers bureau: ALT has received honoraria for advisory boards and speaking for Abbvie, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB., Mrudula Joshi: None declared, Sreoshy Saha: None declared, Samuel Katsuyuki Shinjo: None declared, Kshitij Jagtap: None declared, Vishwesh Agarwal: None declared, Nelly Ziade Speakers bureau: Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre, Grant/research support from: Pfizer, Roche, Abbvie, Eli Lilly, NewBridge, Sanofi-Aventis, Boehringer Ingelheim, Janssen, and Pierre Fabre, Tsvetelina Velikova: None declared, Marcin Milchert: None declared, Masataka Kuwana Speakers bureau: Abbvie, Asahi-Kasei,Astellas, AstraZeneca, Boehringer-Ingelheim, Chugai, Corbus, Eisai, GSK, Horizon, Kissei,BML, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi.Ashima Makol: None declared, Hector Chinoy Speakers bureau: UCB, and Biogen, Consultant of: Novartis, Eli Lilly, Orphazyme, Astra Zeneca, Grant/research support from: Eli Lilly and UCB, Vikas Agarwal: None declared, Rohit Aggarwal Consultant of: Mallinckrodt; Octapharma; CSL Behring; Bristol Myers-Squibb; EMD Serono; Kezar; Pfizer; AstraZeneca; Alexion; Argenx; Boehringer Ingelheim (BI); Corbus; Janssen; Kyverna; Roivant; Merck; Galapagos; Actigraph; Abbvie; Scipher; Horizontal Therapeutics; Teva; Biogen; Beigene; ANI Pharmaceutical; Nuvig; Capella; CabalettaBio, Grant/research support from: Mallinckrodt; Pfizer; Bristol Myers-Squibb; Q32; EMD Serono; Janssen, Boehringer Ingelheim (BI), Latika Gupta: None declared.
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Rathi, Nisha, Andrew Dinh, Sajid A. Haque, Lei Feng, Suyu Liu, Wenli Dong, Joseph L. Nates, Kristen J. Price i Uday Popat. "Outcomes of High Dose Steroid Treatment with or without Aminocaproic Acid in Critically Ill Stem Cell Transplant Recipients with Diffuse Alveolar Hemorrhage". Blood 118, nr 21 (18.11.2011): 3058. http://dx.doi.org/10.1182/blood.v118.21.3058.3058.
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Abstract Abstract 3058 Background: Diffuse alveolar hemorrhage (DAH) complicates Hematopoietic Stem Cell Transplantation (HSCT) at a rate of 2–14%, and carries a mortality of 70 to 100%. For transplant patients that require intensive care unit (ICU) admission, the prevalence of DAH may be as high as 40%. Patients present with diffuse alveolar infiltrates with or without hemoptysis, and are diagnosed based on bronchoscopic and clinical findings. Retrospective studies have shown that high dose steroid therapy may improve outcomes and has thus been the traditional modality of treatment. A recent small retrospective study, however, cited improved mortality using high dose intravenous methylprednisolone (MP) combined with the anti-fibrinolytic agent aminocaproic acid (ACA) (Wanko et al. Biol Blood Marrow Transplant 2006.12: 949–953). We performed a larger study on the use of ACA and MP versus MP alone to evaluate outcomes on survival. Methods: We retrospectively analyzed all HSCT patients greater than 18 years of age admitted to the ICU that were diagnosed with DAH and treated with either high dose MP and ACA, or high dose MP alone in a consecutive 13 month period. Diagnosis of DAH was based on available bronchoscopic findings showing progressively bloody fluid and hemosiderin-laden macrophages, or a clinical presentation consistent with DAH. Mortality was measured from the time of DAH diagnosis to the time of death. Results: A total of 28 HSCT patients were included in the analysis. Of the transplants, 24 were allogeneic and 4 were autologous. The median patient age was 51 years, and the cancer categories included acute myelogenous leukemia (n=13), acute lymphoblastic leukemia (n=4), chronic myeloid leukemia (n=2), chronic lymphocytic leukemia (n=1), multiple myeloma (n=5), and lymphoma (2 Non-Hodgkins, 1 Hodgkins). Eleven of the transplants were from related donors, 14 were unrelated, and two were cord blood. Thirty-six percent of the patients were diagnosed with DAH within 30 days of transplantation, with a mean of 245 days post-transplant amongst the entire group. Overall, 82% of the patients required intubation and mechanical ventilation with an average of 14 ventilator days. A total of 57% (n=16) received high dose MP along with continuous ACA (4 gms IV load, followed by 1 gm/hr) vs. 43% (n=12) who received high dose MP alone. ICU severity of illness scores, coagulation parameters, and duration of steroid treatment were equivalent between the two groups. The incidence of GVHD was equivalent (25%) in each group, and there were no differences in mean absolute neutrophil count (5.6 +/− 4.8 vs. 4.2 +/−4.6, p=0.44) or mean platelet count (53.3 +/− 45.3 vs. 48.3 +/− 68.9, p=0.41) on ICU admission in the MP with ACA vs. MP groups respectively. The group receiving MP alone received a lower average daily dose of steroids (mean 300 mg/day, range 80–1000) as compared to the group receiving MP and ACA (mean 560 mg/day, range 100–1000) (p=0.03). There were no differences in 30, 60, 100 day mortality or overall survival between the two groups, with a 100-day mortality of 94% in the ACA with MP group vs. 92% in the MP alone group. The overall mortality was 100% in the ACA with MP group, and 92% in the MP alone group (p=0.68). Additionally, the average number of ventilator days, ICU length of stay (LOS), and hospital LOS did not differ between the two groups. There was no increase in thrombotic events including deep vein thrombosis, myocardial infarction, and ischemic stroke associated with ACA treatment. Conclusions: Combination therapy with high dose methylprednisolone and aminocaproic acid versus high dose methylprednisolone alone did not improve survival, decrease ventilator days, ICU length of stay or hospital length of stay in critically ill transplant patients with diffuse alveolar hemorrhage. Disclosures: Popat: Otsuka: Research Funding.
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Mcinnes, I., J. F. Merola, P. J. Mease, L. C. Coates, P. Joshi, J. Coarse, B. Ink i C. T. Ritchlin. "SAT0403 EFFICACY AND SAFETY OF 108 WEEKS’ BIMEKIZUMAB TREATMENT IN PATIENTS WITH PSORIATIC ARTHRITIS: INTERIM RESULTS FROM A PHASE 2 OPEN-LABEL EXTENSION STUDY". Annals of the Rheumatic Diseases 79, Suppl 1 (czerwiec 2020): 1153–54. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1850.
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Background:Bimekizumab (BKZ), a monoclonal antibody that selectively neutralises IL-17A and IL-17F, has shown clinical improvements in skin and joint outcomes over 48 weeks (wks) in patients (pts) with active psoriatic arthritis (PsA).1Objectives:To report 2-year interim results from a phase 2b dose-ranging study (BE ACTIVE;NCT02969525) and open-label extension (OLE;NCT03347110) of BKZ in pts with PsA.Methods:Design of the dose-ranging study is described elsewhere.1Pts who completed 48 wks’ BKZ treatment without meeting withdrawal criteria were eligible for OLE entry. All OLE pts received BKZ 160 mg Q4W, irrespective of prior dosing regimen.Data are presented from dose-ranging study baseline (BL) to OLE Wk 60 (Wk 108 total). Efficacy outcomes are reported for the full analysis set (FAS): pts who received ≥1 dose BKZ (specifically those randomised to 160 mg, 160 mg with 320 mg loading dose [LD], or 320 mg at BL), with BL efficacy measurements to allow subsequent determination of ACR50. Outcomes include ACR20/50/70, body surface area (BSA) 0%, minimal disease activity (MDA), and enthesitis/dactylitis resolution. Rates of treatment-emergent adverse events (TEAEs) are reported for the Safety Set (SS; pts who received ≥1 dose BKZ in the dose-ranging study).Results:BL mean (SD) tender/swollen joint counts were 21.7 (15.7) and 11.2 (8.4). 80 (65.0%) pts had BSA ≥3% and dactylitis/enthesitis were present in 41 (33.3%) and 68 (55.3%) pts. Over 108 wks’ BKZ treatment, improvements were observed in skin/joint outcomes: ACR50 (66.7%), BSA 0% (75.4%), MDA (65.6%), and resolution of dactylitis (65.9%) and enthesitis (77.9%) (Table). Serious TEAEs occurred in 9.3% pts (Table); no deaths or major adverse cardiac events were reported. Oral candidiasis occurred in 16 (7.8%) pts (no serious cases).Conclusion:BKZ leads to long-term efficacy for skin/joint manifestations of PsA, with >50% pts achieving high thresholds of disease control (ACR50, BSA 0%, MDA) after 108 wks’ treatment. The safety profile reflects previous observations.1References:[1]Ritchlin CT. Ann Rheum Dis 2019;78:127–8.Table.Outcomes at OLE Wk 60 (Wk 108 total)BKZ 160 mg[a](N=82)BKZ 320 mg[a](N=41)BKZ total(N=123)OCNRIOCNRIOCNRIEfficacy (FAS)n (%)ACR2053/62 (85.5)53 (64.6)29/37 (78.4)29 (70.7)82/99 (82.8)82 (66.7)ACR5041/62 (66.1)41 (50.0)25/37 (67.6)25 (61.0)66/99 (66.7)66 (53.7)ACR7034/62 (54.8)34 (41.5)19/37 (51.4)19 (46.3)53/99 (53.5)53 (43.1)BSA 0% [b]35/42 (83.3)–14/23 (60.9)–49/65 (75.4)–MDA [c]43/61 (70.5)43 (52.4)20/35 (57.1)20 (48.8)63/96 (65.6)63 (51.2)Dactylitis resolution–16/27 (59.3)–11/14 (78.6)–27/41 (65.9)Enthesitis resolution [c]–34/45 (75.6)–19/23 (82.6)–53/68 (77.9)Safety (SS)n (%) [EAER]BKZ 160 mg[d](N=198)BKZ 320 mg[d](N=80)BKZ total[d, e](N=204)Any TEAE163 (82.3) [160.9]57 (71.3) [299.8]179 (87.7) [181.1]Study discontinuation due to TEAEs17 (8.6)1 (1.3)18 (8.8)Permanent withdrawal of study drug due to TEAEs16 (8.1)2 (2.5)18 (8.8)Drug-related TEAEs72 (36.4)29 (36.3)92 (45.1)Serious TEAEs19 (9.6) [4.8]019 (9.3) [4.1][a] BKZ 160 mg pts received this dose continuously to Wk 108 (includes those originally assigned to 160 mg with LD); BKZ 320 mg pts were dose-reduced to 160 mg at OLE entry; [b] Pts with BSA ≥3% at BL; [c] Data from OLE Wk 72 (Wk 120 total); [d] Dose received at TEAE onset (pts may be counted in multiple columns); [e] Includes pt time on BKZ 16 mg. EAER: exposure-adjusted event rate; NRI: non-responder imputation; OC: observed case.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Joseph F. Merola Consultant of: Merck, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB Pharma, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and LEO Pharma, Philip J Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, Pfizer, Sun Pharma, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer, Sun Pharma, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer, UCB Pharma, Laura C Coates: None declared, Paulatsya Joshi Employee of: UCB Pharma, Jason Coarse Employee of: UCB Pharma, Barbara Ink Shareholder of: GlaxoSmithKline and UCB Pharma, Employee of: UCB Pharma, Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen
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Moyers, Justin Tyler, Danielle Brazel, Priyanka Kumar, Hung Doan, Jason Roszik, Jennifer B. Valerin, Roberto Carmagnani Pestana, Warren A. Chow i Vivek K. Subbiah. "Abstract 2184: Landscape of genomic alterations of ultra-rare sarcomas (URS) from 1,079 patients in the AACR GENIE real world database: Clinical implications". Cancer Research 82, nr 12_Supplement (15.06.2022): 2184. http://dx.doi.org/10.1158/1538-7445.am2022-2184.
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Abstract Introduction: Sarcomas are heterogenous tumors of more than 150 different tumor types. Recently, 56 soft tissue (ST-URS) and 21 bone (B-URS) sarcomas were classified as URS based on incidence of less than 1 in a million by the Connective Tissue Oncology Society. There is only one histology-based treatment approved in URS. Methods: AACR GENIE database cBioPortal were accessed. Individual alterations annotated by OncoKB therapeutic evidence level, TCGA PanCancer pathway alterations, and demographic data were gathered. Detailed cancer type was reclassified into genomically distinct diseases as appropriate. Results: From 112, 222 patients, 3,424 soft tissue sarcomas and 832 bone sarcomas were identified. 1,079 of 4,251 (25.4%) sarcomas were URS including 950 ST-URS and 129 B-URS. Patients included were 54.1% (n=584) female and identified race as 66.1% (n=713) white, 8.5% (n=92) black, and 6.8% (n=73) Asian. 39/56 ST-URS and 11/21 B-URS subtypes had cases in database. The median number of alterations was 3.0 (SD 5.94, Range 0-81), 3.0 for B-URS and 4.0 for ST-URS. Oncogenic alterations were present in 63.6% of B-URS versus 74.0% of ST-URS (p=0.01). Genomic sequencing identified Level 1 (L1) (FDA-approved drug) in 4.9% (n=53) of URS; 5.6% (n=53) of ST-URS and 0 B-URS (p=0.006). Level 2 (L2) (Standard of care) alterations were seen in 1.6% (n=15) ST-URS and no B-URS. 19.5% (n=210) of all URS and 19.9% (n=189) of ST-URS versus 16.3% (n=21) of B-URS (p=0.3) had an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Level 1-3). Level 3A gene mutations included BRAF (n=12), NRAS (n=2), TSC2 (n=8). 100 level 3B gene alterations were observed; NRAS (n=21), PIK3CA (n=16), IDH1 (n=8), IDH2 (n=4), TSC2 (n=9), HRAS (n=8), TSC1 (n=5), ATM (n=7), BRCA1/2 (n=4). All L1 (n=36) fusions involved NTRK alterations and all L2 fusions (n=14) involved ALK fusion products in inflammatory myofibroblastic tumors. 17 L1 SMARCB1 copy number alterations (CNA) were seen in epithelioid sarcomas. 1 L3A TSC2 CNA was observed in PECOMA; 29 L3B CNAs were observed including SMARCB1 del (n=7), FGFR1 amp (N=6), BRCA2 del (n=4), and Met amp (n=2). 62.9% of cases had PanCancer pathways altered; TP53 (32.7%), RTK-RAS (33.5%), and cell cycle (33.2%) pathway alterations were most common. TP53 (40.3% versus 31.7%, p=0.05) and cell cycle (41.1% versus 32.1%, p=0.04) alterations were more common in B-URS, while RTK-RAS (34.5% versus 25.6%, p=0.04) alterations were more common in ST-URS. Conclusions: Genomic sequencing of URS reveals actionable alterations, their co-alterations, and key clinical characteristics using a large multi-institution publicly accessible registry of real-world patient data opening additional treatment options. Sequencing should be routine care in URS. Increased racial diversity in genetic samples and public databases is warranted. Citation Format: Justin Tyler Moyers, Danielle Brazel, Priyanka Kumar, Hung Doan, Jason Roszik, Jennifer B. Valerin, Roberto Carmagnani Pestana, Warren A. Chow, Vivek K. Subbiah. Landscape of genomic alterations of ultra-rare sarcomas (URS) from 1,079 patients in the AACR GENIE real world database: Clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2184.
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O., Ademila, Akingboye A. S. i Ojamomi A. I. "Radiometric survey in geological mapping of basement complex area of parts of Southwestern Nigeria". VIETNAM JOURNAL OF EARTH SCIENCES 40, nr 3 (4.06.2018): 288–98. http://dx.doi.org/10.15625/0866-7187/40/3/12619.
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Radiometric methods were used to investigate the radioactive properties of rocks in parts of southwestern Nigeria with a view to interpreting the geological structure and abundance of natural radioactive elements in the main type rocks. The airborne radiometric dataset of Ikole Sheet and ground radiometric data recorded from eight traverses in Akoko axis of the study area were processed. Results presented as maps and profiles displayed variations of high and low radioactive concentrations across the area. These maps showed moderate to very high concentrations and very low to low concentrations of the radioelements; uranium (4.5-13.0 ppm); (LLD-low limit of detection -3.0 ppm), Th (25.0-70.0 ppm); (8.5-16.0 ppm) and K (2.0-4.0 %); but the most often observed values are in the range 2.5-7.0 ppm, 22.0-30.0 ppm and 3.0-4.0% for U, Th, and K respectively. High concentrations imply that the rocks are crystalline, undeformed and are rich in feldspar and U-Th bearing minerals. While low radioactivity is attributed to varying geologic framework compositions; weathered materials or fluids formed as a result of intense metamorphism. The radiometric datasets proved valuable in delineating different rock types and serve as a complementary tool in identifying geochemical zoning of rocks in the area.ReferencesAjibade A.C. and Fitches W.R., 1988. The Nigerian Precambrian and the Pan-African Orogeny, Precambrian Geology of Nigeria, 45-53.Ajibade A.C., Woakes M. and Rahaman M.A., 1987.Proterozoic crustal development in Pan-African regime of Nigeria: In A. Croner (ed.) Proterozoic Lithospheric Evolution Geodynamics, 17, 259-231.Appleton J.D., Miles J.C.H., Green B.M.R, Larmour R., 2008. Pilot study of the application of Tellus airborne radiometric and soil geochemical data for radon mapping. Journal of Environmental Radioactivity, 99, 1687-1697.Arisekola T.M. and Ajenipa R.A., 2013. Geophysical data results preliminary application to uranium and thorium exploration. IAEA-CYTED-UNECE Workshop on UNFC-2009 at Santiago, Chile 9-12, July, 12.Bayowa O.G., Olorunfemi O.M., Akinluyi O.F. and Ademilua O.L., 2014.A Preliminary Approach to Groundwater Potential Appraisal of Ekiti State, Southwestern Nigeria. International Journal of Science and Technology (IJST), 4(3), 48-58.Bierwirth P.N., 1997. The use of airborne gamma-emission data for detecting soil properties.Proceedings of the Third International Airborne Remote Sensing Conference and Exhibition.Copenhagen, Denmark.Grasty R.L. and Multala J., 1991. A correlation technique for separating natural and man-made airborne gamma-ray spectra. In: Current Research, Part D, Geological Survey of Canada, 111-116.Grasty R.L., Minty B.R.S., 1995a. A guide to the technical specifications for airborne gamma ray surveys. Australian Geological Survey Organization, Record.Grasty R.L., Minty B.R.S., 1995b. The standardization of airborne gamma-ray surveys in Australia. Exploration Geophysics, 26, 276-283.IAEA, 1991. Airborne gamma ray spectrometer surveying, International Atomic Energy Agency, Technical Report Series, 323.IAEA, 2007.International Atomic Energy Agency. Safety Glossary, Terminology used in Nuclear Safety and Radiation Protection-2007 Edition.Jones H.A. and Hockey, 1964.The Geology of part of’ Southwestern Nigeria.Geological Survey, Nigeria bulletin, 31.Kearey P., Brooks M. and Hill I., 2002. An Introduction to Geophysical Exploration.3rd ed. Oxford: Blackwell Science, 262.Milsom J., 2003. Field Geophysics: The geological field guide series, John Milsom University College, London. Published by John Wiley and Sons Ltd. Third edition, 51-70.MontajTM Tutorial, 2004. Two - Dimensional frequency domain processing of potential field data.Nigeria Geological Survey Agency (NGSA), 2009. Geological map of Nigeria prepared by Nigeria Geological Survey Agency, 31, ShetimaMangono Crescent Utako District, Garki, Abuja, Nigeria.Omosanya K.O., Ariyo S.O., Kaigama U., Mosuro G.O., and Laniyan T.A., 2015. An outcrop evidence for polycyclic orogenies in the basement complex of Southwestern Nigeria. Journal of Geography and Geology, 7(3), 24-34.Oyawoye, M.O., 1972. The Basement Complex of Nigeria.In African Geology. T.F.J. Dessauvagie and A.J. Whiteman (Eds) Ibadan University Press, 67-99.Oyinloye A.O., 2011. Geology and Geotectonic Setting of the Basement Complex Rocks in Southwestern Nigeria: Implications on Provenance and Evolution. Earth and Environmental Sciences, 98-117. ISBN: 978-953-307-468-9.Rahaman M.A., 1981. Recent Advances in the Study of the Basement Complex of Nigeria.First Symposium on the Precambrian Geology of Nigeria, Summary.Rahaman M.A., Emofureta W.O. and Vachette M., 1983. The potassic-grades of the Igbeti area: Further evaluation of the polycyclic evolution of the Pan-African Belt in South-western Nigeria. Precambrian Resources, 22, 75-92.Woakes M., Rahaman M.A., Ajibade A.C., 1987. Some Metallogenetic Features of the Nigerian Basement. Journal of African Earth Sciences, 6(5), 655-664.
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Koch, Cody A., Terra L. Lasho i Ayalew Tefferi. "Comparison of Platelet-Rich Plasma Serotonin Level and Quantitative Neutrophil PRV-1 Assay in Chronic Myeloproliferative Disorders." Blood 104, nr 11 (16.11.2004): 4740. http://dx.doi.org/10.1182/blood.v104.11.4740.4740.
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Abstract In a prospective study of 100 subjects, an ELISA assay was used to measure platelet-rich plasma (PRP) serotonin levels in patients with polycythemia vera (PV; n=26), essential thrombocythemia (ET; n=14), myelofibrosis with myeloid metaplasia (MMM; n=26), secondary or spurious polycythemia (SP; n=20) and controls (n=14). Neutrophil PRV-1 expression was concurrently assayed by real-time PCR in 69 patients (23 PV, 17 SP, 12 ET, 7 MMM, 10 controls). Table 1 outlines the median and range of measured values across the different study groups. Table 1 Controls SP PV ET MMM Age in years N/A 49 (18–77) 64 (32–83) 52 (18–81) 60 (22–80) Plt count x 109/L N/A 249 (157–371) 509 (191–940) 613 (284–1100) 259 (64–955) PRP serotonin; ng/109 plts 567 (360–1071) 609 (369–1780) 205 (0–496) 385 (137–1026) 90 (0–278) PRV-1/GAPDH ratio 1.28 (1.20–1.43) 1.23 (1.13–1.38) 1.03 (0.84–1.28) 1.24 (0.99–1.44) 1.25 (1.11–1.40) A highly significant difference (p < 0.0001), in PRP serotonin levels, was seen among the different disease categories and control group (table 1). The lowest levels were registered for MMM and PV with a statistically significant difference between the two groups (p = 0.015) but a large degree of overlap. The results in both were significantly as well as markedly lower than those of controls as well as SP with only slight overlap in the PV group and no overlap in the MMM group (p < 0.0001; table 1). The PRP serotonin levels in patients with ET were significantly reduced compared to both controls (p = 0.019) and SP (p = 0.002) and significantly increased compared to both PV (p = 0.0008) and MMM (p < 0.0001). However, there was a substantial degree of overlap in values between ET and other disease categories and controls. Neither aspirin nor cytoreductive therapy correlated with PRP serotonin levels (p = 0.116 and p = 0.148, respectively). Similarly, within a specific disease category, PRP serotonin level did not significantly correlate with platelet count, hemoglobin level, leukocyte count, spleen size, disease duration, or gender. However, an inverse correlation with age was noted only in MMM. In general, there was not a significant correlation between PRP serotonin level and neutrophil PRV-1 expression in each of the three myeloproliferative disease variants. Tests of sensitivity, specificity, and accuracy in distinguishing PV from SP were 92, 95, and 93% for the PRP serotonin assay and 78, 95, 86% for neutrophil PRV-1 assay, respectively. The current study suggests that PRP serotonin concentration might be considered as one of several biological markers that complement each other for the diagnosis of PV.
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Hildebrandt, Gerhard C., Sung Choi, Krystyna M. Olkiewicz, Stephen W. Chensue, Chen Liu i Kenneth R. Cooke. "CCR1 Expression on Donor Leukocytes Is Critical to the Development of Graft Versus Host Disease after Allogeneic SCT." Blood 104, nr 11 (16.11.2004): 3067. http://dx.doi.org/10.1182/blood.v104.11.3067.3067.
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Abstract Acute graft versus host disease (aGVHD) is the major complication of allogeneic stem cell transplantation (allo-SCT) and limits the utility of this treatment strategy. The pathophysiology of aGVHD involves injury to host tissues by inflammatory cytokines and donor-derived cellular effectors, the recruitment of which is likely mediated by chemokine receptor: ligand interactions. CCR1 is expressed on various cell types such as T cells, monocytes and macrophages and binds to a group of CC chemokines that includes RANTES (CCL5) and Mip-1a (CCL3). In light of the previously described role for both donor T cells and monocytes in the development of aGVHD, we tested the hypothesis that CCR1 expression on donor leukocytes contributes to systemic and target organ inflammation that occurs in this setting by using a well established murine SCT model (B6→B6D2F1) and mutant mice deficient in CCR1. Lethally (1100cGy) irradiated B6D2F1 mice received SCT either from syngeneic (B6D2F1) or allogeneic (B6) CCR1+/+ or CCR1−/− donors. The severity of GVHD was assessed after SCT by survival and a clinical scoring system that incorporates changes in weight loss, fur texture, skin integrity, mobility and posture. As expected, syngeneic SCT recipients all survived and where indistinguishable from naïve, untransplanted controls, whereas animals receiving allo-SCT from CCR1+/+ donors developed significant GVHD and only 50% of animals survived by day 35. By contrast, allo-SCT with CCR1−/− donor cells resulted in significantly improved survival (92% vs. 50%) and less severe clinical GVHD (1.0±0.3 vs. 3.0±0.5) compared to allo-CCR1+/+ controls. In addition, serum TNFa levels were significantly decreased by day +7 following CCR1−/− SCT (4.7±2.7 vs. 55.3±14.4 pg/ml) and correlated with a significant reduction in intestinal histopathology both on day 7 (16.3±1.0 vs. 21.5±0.9) and on day 14 (15.8±1.8 vs. 23.8±1.0). GVHD injury to liver and skin was mild at these time points and did not differ between allo groups. Next we investigated the impact of CCR1 expression on allo-specific T cell responses in vivo and found that by day +7 after SCT both splenic T cell expansion (3.7±0.4 vs. 9.6±0.9 x 106 cells) and serum IFNγ levels (4561±559 vs. 10028±681 pg/ml) were significantly lower when CCR1 was absent on donor cells. In summary, we describe a heretofore unknown role for CCR1 on donor leukocytes in the development of aGVHD. The improvement in systemic and target organ disease observed after CCR1−/− SCT may be attributed to 1) alterations in leukocyte recruitment to the intestinal tract resulting in improved intestinal integrity, reduced translocation of endotoxin and decreased TNFa production and 2) modulation of donor T cell responses to host allo-antigens. Experiments are ongoing to determine whether strategies targeting CCR1 signalling can be exploited to prevent GVHD but maintain GVL effects and thereby improve overall survival after allo-SCT.
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Schimmel, Marein, Erfan Nur, Sacha Zeerleder, Gerard J. van Mierlo, Shabnam Solati, Dees P. Brandjes, Hans-Martin Otten, John-John Schnog i Bart J. Biemond. "Increased Circulating Nucleosomes and Neutrophil Activation As a Measure of the Formation of Neutrophil Extracellular Traps (NETs) During Sickle Cell Painful Crisis". Blood 120, nr 21 (16.11.2012): 821. http://dx.doi.org/10.1182/blood.v120.21.821.821.
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Abstract Abstract 821 Introduction: Sickle cell disease (SCD) is characterized by recurrent acute vaso-occlusive painful crisis frequently leading to SCD related complications such as acute chest syndrome, stroke, multi-organ failure and even sudden death. The complex pathophysiology of the vaso-occlusive painful crisis is mediated by activation of endothelial cells, adhesion of sickled erythrocytes and neutrophils, oxidative stress, coagulation activation and increased release of inflammatory mediators, resulting in ischemic organ damage. Recently, neutrophils have been demonstrated to form neutrophil extracellular traps (NETs) upon activation. Nucleosomes and histones exposed together with neutrophil proteases, such as elastase on these NETs have been shown to kill efficiently bacteria. NET formation has been shown to propagate coagulation in sepsis and in deep venous thrombosis. In addition, nucleosomes and histones exposed on NETs have been shown to be strongly cytotoxic to endothelial cells. Beside the exposure on NETs, nucleosomes can be actively released into the circulation from dead cells. Circulating nucleosomes detected in sepsis have been reported to correlate with severity of inflammation, organ dysfunction and mortality. However, no studies are available yet on the dynamics of nucleosomes and NETs in sickle cell patients suffering from painful crisis. The aim of this case-control study was to assess plasma levels of circulating nucleosomes and human neutrophil elastase–α1-antitrypsin (EA) complexes as measure of systemic neutrophil activation, in sickle cell patients during steady state and painful crisis. Methods: Plasma levels of nucleosomes and EA as a measure of neutrophil activation were measured in 74 patients in asymptomatic state (49 HbSS/HbSβ0-thalassemia, and 25 HbSC/HbSβ+-thalassemia), 70 painful crises (53 HbSS/HbSβ°-thalassemia and 17 HbSC/HbSβ+-thalassemia) in 49 patients and in 24 HbAA healthy controls using Enzyme-Linked Immunosorbent Assay (ELISA). Results: Plasma levels of nucleosomes in both HbSS/HbSβ°-thalassemia and HbSC/HbSβ+-thalassemia patients were significantly higher during painful crisis (median; interquartile range, 20.2; 8.9 – 129.0 U/ml, P < 0.0001 and 11.7; 5.1 – 67.7 U/ml, P = 0.045 respectively) as compared to patients in steady state (6.0; 3.0 – 9.8 U/ml and 7.1; 4.6 – 9.6 U/ml respectively). Nucleosomes levels in healthy controls were just above the detection limit of the assay (5.0; 5.0 – 6.5) U/ml). Plasma levels of EA in HbSS/HbSβ°-thalassemia patients were significantly increased during painful crisis as compared to steady state (75.1; 56.5 – 102.4 vs. 45.7; 34.7 – 59.7 ng/ml, P < 0.0001). Also in HbSC/HbSβ+-thalassemia patients, EA levels were higher during painful crisis than in steady state, though the difference did not reach statistical significance (62.0; 48.0 – 96.7 vs. 50.2; 33.3 – 67.7, P = 0.051). Plasma levels of EA in healthy controls (39.9; 31.5 – 62.2 ng/ml) were comparable with those in steady state patients. In a paired analysis of 36 patients, included both during steady state and painful crisis, significant increments were observed during painful crisis in levels of both nucleosomes (from 5.0; 3.0 – 10.8 to 20.2; 6.8 – 94.3 U/ml, P < 0.0001) and EA (from 47.9; 36.0 – 67.6 to 70.6; 55.9 – 101.4 ng/ml, P < 0.0001), as compared to steady state. During painful crisis, EA levels were strongly correlated with levels of nucleosomes in both HbSS/HbSβ°-thalassemia (Spearman's rank (Sr)=0.55, P<0.0001) and HbSC/HbSβ+-thalassemia patients (Sr=0.90, P=<0.0001). In steady state the correlation was significant only in HbSC/HbSβ+-thalassemia patients (Sr=0.63, P=0.001) Four patients who developed an acute chest syndrome during painful crisis were among the patients with the highest nucleosome (359, 130, 128 and 100 U/ml) and EA levels (121, 87, 92 and 64 ng/ml respectively). Conclusion: Sickle cell painful crisis is associated with increased levels of nucleosome and stronger neutrophil activation. This might point to a crucial role of NET formation in the pathogenesis of painful crisis. Disclosures: No relevant conflicts of interest to declare.
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Lilleoja, R., E. Reimann, Ü. Jaakma i S. Köks. "133 SEQUENCING AND ANNOTATION OF THE GENOME OF THE HOLSTEIN COW". Reproduction, Fertility and Development 24, nr 1 (2012): 179. http://dx.doi.org/10.1071/rdv24n1ab133.
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This paper presents the preliminary results of whole genome resequencing of the Holstein cow using the SOLiD 4 System. The aim of this study was to obtain a high-quality Holstein cow genome reference sequence, which could be used as a reference for genomic studies on the Estonian Holstein cattle. Furthermore, the new reference sequence would be made available for other research groups. We generated one mate-paired library and one fragment library from 30 μg of genomic DNA. Libraries were sequenced in 4 flow cells. Colour space fasta files (.csfasta) and appropriate quality files (.qual) were mapped and paired to the reference cow (Bos taurus) genome assembly from Oct. 2007 (Baylor 4.0/bosTau4). Mapping and pairing was performed using the Max Mapper algorithm implemented in the Bioscope Software (version 1.3). Initial sequencing resulted in the 2 842 744 008 fifty-basepair reads. Average mapping efficiency with mismatch penalty –2.00 and clearzone 5 was 73.3%. Altogether 2 065 066 215 reads and 92 778 710 937 bp were successfully mapped, resulting in 35.2 coverage. Pairing indicated that the insert range was 665 to 2195 bp and mean insert size was 1363 bp. Tertiary analysis found 5 472 870 SNP in the cow genome; 3 517 351 were heterozygous and 1 955 519 were homozygous variants. Also, 3 747 199 were transition SNP and 1 093 307 were transversion SNP, with a transition-transversion ratio of 2.17:1.00. Annotation revealed that only 889 901 of all discovered SNP were annotated in the SNP database dbSNP. This means that around 4 582 969 SNP were novel. The number of large indels was 144 035, out of which 68 817 were heterozygous and 75 218 were homozygous variants. The longest deletion was 15 089 bp and there were 18 deletions between 10 000 and 20 000 bp. The largest insertion range was 1000 to 5000 bp and there were 358 insertions falling into this span. Interestingly, the most numerous group of deletions was between 200 and 500 bp and between 100 and 200 bp. Altogether, in these size groups there were 114 578 deletions. Large indels variations accounted for 48 582 675 bp of the entire genome. Analysis of the small indel polymorphisms identified 452 113 small indels, out of which 287 491 were heterozygous and 164 622 were homozygous. Only 1197 small indels were listed in the dbSNP. Most of the small indels were single nucleotide insertions/deletions (261 897). Small indels accounted for the total variation of 1 722 303 nucleotides in the genome. Finally, we identified 287 inversions (largest 151 000 bp) in the genome of the cow. In conclusion, the genome of the cow contains huge amounts of still unknown variations. Better knowledge of these variations could explain significant phenotypic differences (e.g. reproduction) between different breeds. The European Regional Development Fund together with the Archimedes Foundation, target finance grant from the Ministry of Education and Science SF1080045s07, grant from the Estonian University of Life Sciences P8001 and Estonian Science Foundation grant GARFS7479 supported this study.
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Varela-Constantino, Ana L., Michelle Morcos, Andres Noyola-Perez, Nereida Méndez-Ramírez, Eli Fuentes-Chavez, Rosario Salazar-Riojas, César Homero Gutierrez-Aguirre i in. "Optimizing Conditioning Intensity to Disease Burden in Adults with Acute Myeloid Leukemia Undergoing Transplantation: Results of a Prospective Multicenter Study". Blood 144, Supplement 1 (5.11.2024): 4873. https://doi.org/10.1182/blood-2024-211711.
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Background: Myeloablative conditioning (MAC) is standard in fit adults with acute myeloid leukemia (AML) undergoing allogeneic transplantation (alloHCT), albeit reduced intensity conditioning (RIC) has led to similar outcomes to MAC in patients without genetic evidence of residual disease in retrospective studies. Methods: This was a prospective multicenter study including consecutive adults and adolescents with AML from 2015-2024 who received alloHCT using peripheral blood hematopoietic cells from matched siblings (MSD) or haploidentical donors, performed in a limited-resource setting. Before 2019 patients received MAC based on cyclophosphamide 350 mg/m2, fludarabine 25 mg/m2 for 3 days (CyFlu) plus melphalan 200 mg/m2 or busulfan 9-12 mg/kg if considered fit. After 2019, those with undetectable MRD centralized and measured with Euroflow protocols could proceed to RIC regardless of age, comorbidities or fitness, using CyFlu plus melphalan 140 mg/m2 with or without total body irradiation 2Gy to reduce short-term complications. Patients with detectable (MRDpos) or active disease (>5% blasts) could proceed to sequential conditioning, MAC or RIC according to fitness. Graft-versus-host disease (GVHD) prophylaxis was based on post-transplant cyclophosphamide (PTCy) or calcineurin inhibitor (CNI) plus methotrexate. RIC-MRDneg, MAC-MRDneg, MRDpos and active disease groups were compared. The primary outcome was overall survival (OS). Secondary outcomes included, event-free survival (EFS), non-relapse mortality (NRM) and GVHD-relapse-free survival (GRFS). Results: 92 patients were analyzed. Median age was 41 years (range 15-75), n=51 were men (55.4%), 41 women (44.6%), with a median of 2 treatment lines (range 1-4), and 8.7x106 CD34 cells/kg (range 1.8-23) infused. N=54 received haploidentical grafts (58.7%) and n=38 MSD (41.3%), n=82 received PTCy (89.1%). N=39 were MRDneg and received RIC (42.4%), n=29 MRDneg and received MAC (25%), n=9 were MRDpos (9.8%) and n=15 had active disease (16.3%). Similar sex, donor type, HCT-CI and GVHD prophylaxis were observed between groups. Patients with MRDpos or active disease had ≥2 treatment lines (86.7% and 100%, respectively) than RIC or MAC-MRDneg (51.3% and 41.4%, respectively) (p=.001). Patients that received RIC-MRDneg were older than MAC-MRDneg (median of 46 vs 29 years). Statistically similar OS, EFS, NRM and GRFS rates were observed between RIC-MRDneg vs MAC-MRDneg. 2-year OS was 60.3% in RIC MRDneg and 60.5% in MAC-MRDneg, 51.9% in MRDpos and 30% in active disease. 2-year NRM was 9.6% in RIC-MRDneg vs. 11% in MAC-MRDneg, 36% in MRDpos and 31% in active disease. 2-year EFS was 38.6% in RIC-MRDneg vs. 49.3% in MAC-MRDneg, 41.7% in MRDpos and 13.3% in active disease. 2-year GRFS was 27.8% for RIC-MRDneg, 34.8% in MAC-MRDneg, 20.8% for MRDpos and 7% in active disease. GVHD rates and severities were similar. MAC vs RIC was not associated with OS or EFS in the univariable analysis. Treatment lines and disease status were the only variables associated with EFS, but not OS. In the multivariable model only MRD negativity was associated with EFS HR 0.44 (95%CI 0.21-0.95).