Journal articles on the topic '616.993 83'

Background and Objectives Traditionally, transoral laser microsurgery (TLM) is commonly used to treat early glottic cancer. However, the long-term oncologic results have not been thoroughly investigated. Therefore, this study aimed to analyze long-term oncologic outcomes of TLM for early glottic cancer.Subjects and Method We retrospectively studied 132 patients who underwent TLM for early glottis cancer from January 2001 to August 2020. We assessed overall and disease-free survival according to the T classification and types of cordectomy proposed by the European Laryngological Society in 2007.Results Of the 132 patients, 125 were male and 7 female. The mean age was 61.6±9.3 years. We found 5 (3.8%), 112 (84.8%), and 15 (11.3%) patients staged as CIS, T1, and T2, respectively. For the cordectomy types, there were 6 in type I, 22 in type II, 83 in type III, 6 in type IV, 13 in type V, and 2 in type VI. Ten-year overall and disease-free survival rates were 99.2% and 87.1%, respectively. Overall and disease-free survival curves were not different according to different T classification and cordectomy types.Conclusion TLM is an excellent treatment modality for the long-term oncologic control of early glottic cancer.

613 Background: Several IO-COMBO regimens are under investigation in front-line mRCC. The clinical outcome of pts who progress on an IO-COMBO regimen and receive subsequent systemic therapy is unknown. Methods: A retrospective analysis of all pts with clear-cell mRCC enrolled in one of seven clinical trials investigating an IO-COMBO at Cleveland Clinic Taussig Cancer Institute and Barts Cancer Institute was conducted. Clinical outcome of subsequent therapy including best objective response according to RECIST v1.1, progression-free survival (PFS) and adverse events (AEs) using CTCAE v4.0, were collected. Results: From a total of 89 pts enrolled on an IO-COMBO trial, final analysis included 32 pts with PD who received ≥1 line of subsequent therapy, median age 57 (41-77), 83% male, 72% ECOG 0, 78% IMDC fav-/intm- risk. Prior IO-COMBO included atezolizumab/bevacizumab (n = 20), ipilimumab/nivolumab (n = 10) and axitinib/avelumab (n = 2). All except 1 pt received IO-COMBO in the front-line setting. All pts received 1 subsequent therapy (axitinib n = 15; pazopanib n = 9; sunitinib n = 4; cabozantinib n = 3; nivolumab n = 1) after progression on IO-COMBO, 12 pts were treated with a second subsequent therapy and 5 pts were treated with ≥3 subsequent lines of treatment. For pts with available response (n = 26), the overall best response to first subsequent therapy was 27% PR, 50% SD and 15% PD. Median PFS for the first subsequent therapy was 7.9 months (95% CI, 4.5-11.3) with 8 pts remaining on treatment. The median PFS for pts previously treated with a combination of IO plus anti-VEGF was 7.9 months (95% CI, 3.1-12.7) and was 9.3 months (95% CI, 3.5-15.0) for pts treated with a prior IO plus IO combination (p = 0.732). The most frequent G3/G4 treatment-related AEs observed with first subsequent therapy were LFT elevation (9%) and diarrhea (7%); 2 pts discontinued subsequent treatment due to toxicity. Conclusions: VEGF-TKIs have clinical activity in mRCC refractory to IO-COMBO therapy, possibly impacted by the inclusion of an anti-VEGF agent in prior IO-COMBO therapy. Subsequent therapy was in general well tolerated.

The purpose of the current study was to examine the effect of flavor on voluntary drinking and thermoregulatory responses in Chinese boys and girls exercising intermittently in a hot environment. Fourteen boys and girls (9 to 11 years old) performed four 3-hour intermittent exercise sessions (20-min walking sessions at 50% VO2peak followed by a 25-minute rest period) in a hot and humid environment (~30 °C ambient temperature and ~70% relative humidity). The participants consumed 1 of 4 beverages ad libitum in a randomized sequence by using a Latin-square principle: unflavored water (W), orange-flavored water (OF), lemon-flavored water (LF), and grape-flavored water (GF). No differences were observed in the total fluid intake (W vs. OF vs. LF vs. GF: Boys, 441 ± 114 vs. 493 ± 106 vs. 387 ± 83 vs. 568 ± 146 ml; Girls, 613 ± 131 vs. 923 ± 204 vs. 825 ± 157 vs. 790 ± 166 ml), urine and sweat output, and physiological perceptual variables among trials and between sexes. The results suggested that Chinese children can maintain body fluid balance while exercising moderately in a hot and humid environment by ad libitum drinking. The flavor of the beverages had no impact on the voluntary drinking and the state of hydration in the current study.

IntroductionScreening programs for perinatal depression are systematicly implemented in developed countries. To circumvent the most commonly pointed limitation by the primary healthcare professionals (the questionnaires length), we have developed shorter forms of the Beck and Gable Postpartum Depression Screening Scale-35. The shortest version consists of seven items, each one representing a dimension evaluated by the PDSS. This PDSS-7 demonstrated equal levels of reliability and validity as the 35-item PDSS with the advantage of being completed in as little as 1-2 minutes(Pereira et al. 2013).ObjectivesTo analyze the construct validity of the PDSS-7 using Confirmatory Factor Analysis, to use both in Portugal and in Brazil.MethodsThe Portuguese sample was composed of 616 women (Mean age: 32.29±4.466; Mean gestation weeks=17.13±4.929). These participants were not the same who participated in the psychometric study that led to the selection of the seven items. The Brazilian sample was composed of 350 women (Mean age: 30.01±5.452; Mean gestation weeks=25.17±6.55). They all had uncomplicated pregnancies and completed the European/Brazilian Portuguese versions of PDSS-24 (Pereira et al. 2013/ Barros et al. 2021), which was composed of the same items and included the seven items that compose the PDSS-7.ResultsThe unidimensional model of PDSS-7 presented a good fit in both samples (Portuguese/Brazilian: χ2/d.f.=3.439/2.653; RMSEA=.066/.069, CFI=.974/.981, TLI=.947/.957, GFI=.939/.957; p<.001). The PDSS-7 Cronbach’s alphas were .82/.83 and all the items contribute to the internal consistency.ConclusionsThe PDSS-7 is a valid and precise, economic, fast and easy screening instrument for perinatal depression, a major public health problem, both in Portugal and in Brazil.

Background: Bronchoscopy can play a major role in both diagnosis and treatment. Diagnostic bronchoscopy is a useful tool for the diagnosis of pulmonary lesions particularly bronchogenic carcinoma and pulmonary tuberculosisAim: To find out the role of fibre-optic bronchoscopy in the diagnosis of pulmonary diseases.Methods: This observational study was conducted in the Indoor patient, Department of Medicine in Rangpur Medical College Hospital. Of all patients aged 18 years and above Undiagnosed pulmonary lesion in the medical wards between October 2012 to October 2014.Results: Out of 256 cases, mean age ±SD was 61.01(±11.51), minimum age was 23 and maximum age was 86 years. Majority 84% were male and 16% were female. Most of the respondent were smoker whereas (82%). Most common presenting complains were cough, dyspnoea, haemoptysis and fever 83%, 59.3%,53% and 36% respectively. General Physical examination findings, 97% were anamia and clubbing were 41% and cyanosis 02%. Respiratory system examination findings, 54% were features suggestive of complete collapse, 15% features suggestive of consolidation and 31% normal chest findings. Chest x-ray findings of the study population, 25.8% were dense homogenous opacity involving right or left lung field, 17.9% were complete collapse of affected lungs , 5.5% were right middle lobe collapse, 4.3% Unilateral hilar lymphadenopathy, 7.03% were elevation of hemidiaphragm of affected site and 7.03% were pleural effusion. 6.6% patient had normal CxR. In present study shows bronchoscopic findings in patients studied, Vocal cord paralysis were 9.3%, Right main bronchus were 15.6% , Right upper lobe bronchus were 7.03% , Right middle lobe bronchus were 7.8%, Right lower lobe bronchus were 9.8%, Left main bronchus were 14% , Left upper lobe 4.3%, Left lingular were 1.9% and Left lower lobe bronchus were 9.3%.In this study shows histologhical findings majority 18% were squamaus cell carcinoma,8.2% were small cell carcinoma,2.3% were adeno carcinoma,6.6% infiltration of Inflammatory cell and granuloma 1.2%.Conclusion: In this study male are predominant. Most of the respondent was smoker. Most common presenting complains were cough, haemoptysis, fever and chest pain. Most of general physical examination findings were anamia and clubbing. Respiratory system examination findings were features suggestive of complete collapse, features suggestive of consolidation and normal chest findings. chest x-ray findings of the study population were complete collapse of affected lungs, rtight middle lobe collapse, Dense homogenous opacity involving right or left lung field, Unilateral hilar lymphadenopathy. Bronchoscopic findings were vocal cord paralysis, right main bronchus, right upper lobe bronchus, right middle lobe bronchus, right lower lobe bronchus, left main bronchus, left lingual and left lower lobe bronchus. Histologhical findings majority were squamaus cell carcinoma. Most of the patient poorly differentiated carcinoma among the study subjectsBangladesh J Medicine Jan 2016; 27(1) : 16-21

e22020 Background: The pediatric cancers is in the global agenda to improve the survival rates which is still low in LMICs although it is more than 80% in HICs. More than 300.000 pediatric cancer cases annually are expected in children and adolescents aged 0-14 globally. Registry is the first step of an efficient cancer control. Here, we present the most updated results of the pediatric cancer registry fromTurkey. Methods: Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association has established the pediatric cancer registry in 2002. The childhood cancer cases registered between 2009-2021 was included in this analysis. International Childhood Cancer Classification System was used for the classification. Essential demographic findings, ICD-O-3 morphology and topography codes were recorded for each case. Results: During the 13 years from 2009 to 2021, 24080 cases were registered. For all cases, median age was 6.7 year (0-19; M/F 13461/10609, 4 hermaphrodite, 6 unknown). Age distribution was 0-4 yrs, 40.8%; 5-9 yrs, 23.8%; 10-14 yrs, 23.3%; 15-19 yrs, 12.1%) The distribution of the tumor types were [number of cases, percentage of total, median age yrs, M/F]: Leukemia (5819, 24.2%, 5.5, 3366/2453); Lymphoma & other RES tumors (4446, 18.5%, 9.8, 2956/1487, 1 hermaphrodite & 2 unknown); CNS [brain & spinal] (3730, 15.5%, 6.8, 2061/1668, 1 unkown); Symphatetic system (1965, 8.2%, 2.3, 1010/955); Retinoblastoma (675, 2.8%, 1.4, 375/300); Renal (1160, 4.8%, 3.1, 557/601, 1 hermaphrodite & 1 unknown); Liver (409, 1.7%, 2.2, 234/175); Malignant bone (1584, 6.6%, 12.6, 864/720); Soft tissue sarcomas (1726, 7.2%, 7.7, 983/743); Germ cell (1593, 6.6%, 9.6, 588/1001, 2 hermaphrodite, 2 unknown); Carcinoma & other malignant epithelial (804, 3.3%, 13.5, 381/423); Other/non-specific malignant (169, 0.7%, 7.9, 86/83). Five year survival rate was found as 72.3%. Conclusions: The registry shows that the survival rates for children and adolescents have been improved to 72% which reflects the status of the pediatric cancer care in Turkey. The data from this work became a valuable source for all stakeholders in national and international level working on improvement the pediatric cancer control.

Introducción: el parasitismo es uno de los principales problemas de salud y producción animal en Colombia, como lo es en otros países de la región; por lo tanto, es importante identificar aquellos más frecuentes con el propósito de considerar estrategias de prevención y control. Este trabajo se realizó con el objetivo de aportar al conocimiento sobre los endoparásitos y ectoparásitos presentes en los équidos sacrificados entre octubre y diciembre de 2015 en la Planta de Beneficio Villa Rosa, Piedecuesta, Santander, Colombia. Metodología: para la identificación de los ectoparásitos y hemoparásitos se utilizaron 83 équidos, y 75, para los parásitos gastrointestinales. Los ectoparásitos se colectaron directamente de la piel y para los hemoparásitos se utilizaron las técnicas de hemocultivo, Woo, preparaciones en fresco, extendidos coloreados y Knott. Los parásitos gastrointestinales se estudiaron mediante las técnicas de McMaster, sedimentación-flotación, cultivo de heces y necropsia helmintológica. Resultados: el 31,32 % de los équidos examinados estaban parasitados con Anocentor nitens y el 8,43 % presentó infestación mixta con Amblyomma cajennense s.l. El piojo Haematopinus asini fue colectado en un animal. Salvo la presencia de microfilarias de Setaria equina en 7,2 % de las muestras, no se detectaron hemoparásitos con los procedimientos parasitológicos empleados. Se observaron huevos tipo Strongylida en 88 % de las muestras; Dictyocaulus sp. en 6,6 %; Parascaris sp. en 5,33 %; Oxyuris sp. en 5,33 %; Strongyloides sp. en 1,33 % y Anoplocephala sp. en 9,3 %. En el cultivo de heces se observaron 12 larvas L3 de la subfamilia Cyathostominae o “pequeños Strongylus” y una del nematodo Trichostrongylus axei. En las necropsias se hallaron adultos de: Habronema megastoma, Setaria equina, Oxyuris equi, Strongylus sp., Triodontophorus, Cyathostominae y Anoplocephala perfoliata. Conclusiones: los parasitismos por garrapatas, grandes y pequeños estróngilos y tenias, son frecuentes en los equinos sacrificados. Se recomiendan técnicas serológicas y moleculares para detectar hemoparásitos en estudios posteriores.

Background: Four million newborn babies die in the neonatal period, India 1.2 million neonatal deaths every year. India contributes for a quarter of global neonatal deaths and thus faces the biggest newborn health challenge of any country in the world. The aims of the study were done with the objective to conclude the morbidity and mortality pattern of neonates admitted to a neonatal intensive care unit (NICU).Methods: Hospital based prospective study was conducted at NICU Government Medical Collage, Srikakulam, Andhra Pradesh, India. Neonates from admission to discharge flowed, LAMA or death collecting the data by using a predesigned standardized preform.Results: Neonates were admitted in the NICU during period April 2014 to March 2019. The data analysis for the morbidity showed that the neonatal jaundice (NNJ) were 765(10.57%) , septicemia were 1110 (15.34%), prematurity were 593 (8.19%), birth asphyxia were 963 (13.30%), respiratory distress syndrome (RDS) were 184 (2.54%),hypoxic ischemic encephalopathy (HIE) were 984 (8.46%), meconium aspiration syndrome (MAS)were 612 (8.46%),transient tachypnea of neonate (TTN) were 634 (8.76%), low birth weight (LBW) were 418 (5.77%), intra uterine growth retardation (IUGR) were 179 (2.47%), congenital anomalies were 131 (1.81%), meningitis were 83 (1.15%), seizure disorder were 49 (0.68%) and others. The disease wise mortality among the neonates admitted to NICU was studied and were found that prematurity 212 (35.75%), septicemia were 74 (6.67%), birth asphyxia were 91 (21.70%), meconium aspiration syndrome were 70 (11.44%) and respiratory distress syndrome were 66 (35.87%), low birth weight were 102 (24.40%) congenital anomalies were 31 (23.66%) the top major contributors to the neonatal mortality.Conclusions: The commonest causes of admission were neonatal jaundice (NNJ), sepsis, prematurity, meconium aspiration syndrome, birth asphyxia, low birth weight, congenital anomalies. The most common cause of case fatality was prematurity, meconium aspiration syndrome, birth asphyxia, low birth weight, congenital anomalies in NICU in a tertiary care teaching hospital, government medical college, Srikakulam, Andhra Pradesh, India.

Self-medication is an important issue, especially in developing countries. Self-medication is the concept in which individuals use medicine to ease and manage their minor illnesses. The current survey was designed to conduct interviews at different universities based on the availability of the students from August 2021 to October 2021 in Hazara region of Khyber Pakhtunkhwa (KPK), Pakistan. Overall, 1250 questionnaires were distributed to students from various departments. Students of microbiology (n = 305, 24.4%) and agriculture 236 (n = 18.8%) were the most elevated members in this study, while other participants were from medical lab technology (n = 118, 9.4%), chemistry (n = 103, 8.2%), food science (n = 92, 7.3%), business administration (n = 83, 6.6%), sociology (n = 78, 6.2%), math/physics (n = 6, 14.8%), Pak study (n = 58, 4.6%), English (n = 47, 3.7%), and psychology (n = 19, 1.5%). Students working towards their Bachelor numbered (n = 913, 73.0%), Master (minor) numbered (n = 80, 6.4%), Master (major) numbered (n = 221, 17.6%), and Doctorate numbered (n = 36, 2.8%). The age group of participants was majorly 20–25 years (61.0%), while others belonged to the age groups 25–30 years (20.6%), 30–35 years (9.8%), and 35–40 years (8.4%). The mean and standard deviation of daily practices of self-medication were observed (M = 416.667, SD = 1,026,108.667) and p = 0.002. The mean and standard deviation of daily practices of antibiotic knowledge was (M = 431.5, SD = 1,615,917) and p = 0.002. Antimicrobial agents were leading over others with 631 (50.4%), followed by anti-inflammatory with 331 (26.4%), multivitamins with 142 (11.3%), gynecological purpose with 59 (4.7%), and analgesic with 72 (5.7%), while the lowest frequency rate was observed against herbal remedies with 15 (1.2%). The results of the current study concluded that students practiced self-medication for reasons such as convenience to obtain these medications from cheap sources and to avoid the fee of a physician. They searched for the medicine on social media platforms and purchased it blindly from the pharmacy without any prescription from a physician.

Background—Increased concentrations of 5-hydroxytryptamine (5-HT) can be detected in the systemic circulation after a meal and may be involved in the physiological control of gastrointestinal motility. Abnormalities of 5-HT release after a meal might explain some of the postprandial symptoms associated with the irritable bowel syndrome (IBS).Aim—To investigate the effect of a standard meal on plasma 5-HT and urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations in patients with diarrhoea predominant IBS and in healthy volunteers.Methods—After an overnight fast, six volunteers and five patients with IBS were given a carbohydrate-rich meal. Blood and urine samples were taken before and for four hours after the meal. Platelet-poor plasma 5-HT and urinary 5-HIAA were analysed by reversed phase high performance liquid chromatography with fluorometric detection. 5-HIAA was expressed as a ratio with urinary creatinine concentration, which was measured by spectrophotometry.Results—During the four hour postprandial period, 5-HT concentrations were significantly higher in patients with IBS than in healthy volunteers at 0.5 hours (p<0.05), 2 hours (p<0.05) and 2.5 hours (p<0.05). 5-HT was not detected in the plasma in the fasting state in patients or volunteers. Median peak 5-HT in patients with IBS (359 (198–796) nmol/l) was significantly greater than volunteers (83 (7–190)) (p<0.05). “Area under the curve” for 5-HT detection was greater for patients with IBS (317 (138–771)) than for healthy volunteers (51 (4–129); p<0.05).The duration of the 5-HT peak was significantly longer in patients with IBS (3 (1–3) hours) than in the healthy volunteers (1 (1–1) hours; p<0.01). Postprandial urinary median 5-HIAA values in controls (5.6 (5.5–5.8) μmol/mmol creatinine) and patients with IBS (3.0 (2.5–6.8) μmol/mmol creatinine) were not significantly different from preprandial values (controls: 5.9 (5.5–6.6) μmol/mmol creatinine; patients with IBS: (6.2 (2.4–9.3) μmol/mmol creatinine).Conclusion—These findings indicate that there may be a difference in the way that 5-HT is released in patients with diarrhoea predominant IBS, and could suggest a possible role for 5-HT in the postprandial symptoms of these patients.

11071 Background: There are currently several second-line options for the treatment of ASTS as gemcitabine combinations, trabectedin, pazopanib, eribulin or olaratumab plus doxorubicin in cases where anthracyclins are still possible. There is an unmet need for predictive biomarkers which hinders the rational selection of the best sequence in second line. We already published the prognostic value of FAS in first line of ASTS while this study analyzes its predictive role in different second line schemes. Methods: Most relevant selection criteria for this study were having received trabectedin in 2nd line or beyond for ASTS, progressive disease after at least one previous line for ASTS and signed CI. A TMA was set up for FAS staining (Cell Signaling) with blocks from diagnostic time. Two expert blinded pathologists reviewed and classified the cases as negative, weak or strong. Kaplan–Meier estimations were used for time-to-event variables and the log-rank test was used to compare groups. Results: A series of 198 patients accomplished selection criteria. Metastases at diagnosis occurred in 46 (24%) and median time to metastases was 18.8 months (CI 16,3; 21.3). Previous line to trabectedin consisted of gemcitabine combination 83 (42%), Doxorubicin-based 65 (33%) and others 50 (25%). Median PFS for previous and trabectedin lines were 3.5 (2.8-4.2) and 3.4 (2.8-4) months respectively. FAS positive entailed significantly better PFS for the previous trabectedin line: 4.1 (1.5-6.7) vs 3.0 (2.5-3.5) months, p = 0.01 whereas FAS positive was related with worse PFS for the trabectedin line 2.5 (2.2-2.8) vs 3.7 (2.7-4.8) months, p = 0.028. These results were more notorious for L-sarcoma cases: 7.0 (3.6-10.5) vs 4.3 (1.9-6.6) months, p = 0.017 in previous line and 2.4 (2.2-2.6) vs 6.5 (3.8-9.3) months, p < 0.001 in trabectedin. From trabectedin administration, FAS+ had significantly worse OS especially in L-sarcomas: 11.9 (5.2-18.7) vs 21.7 (12.7-30.8) months, p = 0.002. Conclusions: FAS showed predictive value in PFS and OS for trabectedin administration in ASTS. The different prognostic role of FAS across distinct lines and its relevance in L-sarcomas deserve further attention.

654 Background: Nivolumab (nivo) has been approved for the treatment of refractory metastatic renal cell carcinoma (mRCC). Data regarding the characteristics and outcomes of patients (pts) who progress on nivo are lacking. Methods: A retrospective analysis of pts with clear cell mRCC who received nivo at Cleveland Clinic (2015-2017) was performed. Pts were divided into two groups; 1) PD group; pts with progressive disease (PD) per RECIST v1.1 or clinical PD, and 2) NPD group; pts with non-progressive disease on nivo. Results: Ninety pts (PD group n = 55, NPD group n = 35) with median age of 67 (33-83), 74% men, and 79% ECOG 0-1 were included. Pts had received 1 (44%), 2 (29%), or ≥ 3 (27%) prior systemic treatments, most commonly with sunitinib (71%), axitinib (39%) and pazopanib (33%). Pts in the PD group had a greater incidence of baseline liver metastases (PD, 40% vs. NPD, 14%; p = 0.01), with other baseline characteristics not significantly different. Median follow up was similar in both groups (PD group, 8.0 months (95% CI, 5.5-10.5) and NPD group, 7.1 months (95% CI, 4.9-9.3); p = 0.87). Median duration of treatment for PD group was 8.7 months (95% CI, 7.3-10.1) compared to 16.1 months (95% CI, 8.6-23.6) for NPD group (p = 0.02). In the PD group, 50 (91%) pts developed PD per RECIST v1.1 whereas 5 (9%) pts had clinical PD. New organ sites of metastases were found in 20/55 (36%) pts; brain (8/20; 40%), liver (4/20; 20%), soft tissue (4/20; 20%), and locoregional (4/20; 20%) were the most common new organ sites, whereas lungs, lymph nodes and pancreas were never involved at PD as new organ sites. Twelve pts received treatment beyond progression (TBP) with a median duration of TBP of 2.8 months (95% CI, 0.6-5.0) and 50% of pts had stable disease as their best response. Median overall survival (OS) and progression free survival (PFS) on nivo were 10.1 months (95% CI, 6.6-13.6) and 5.5 months (95% CI, 2.9-8.1), respectively. Conclusions: Pts with PD on nivo have a higher incidence of hepatic metastases at baseline, and one third of these pts develop new sites of metastases at PD, most commonly brain.

Abstract Background: The EUMDS registry is a prospective observational registry to collect data on lower risk MDS. 17 Countries and 133 centers are participating. We analyzed serum from 101 patients for ferritin, hepcidin, growth differentiation factor 15 (GDF15) and C-reactive protein (CRP) at six-month intervals in order to evaluate temporal changes in iron metabolism. Objective: To explore hepcidin and GDF15 levels over time in lower risk MDS patients and their relation with WHO2001 subtype, transfusion history and conventional iron parameters. Results: The median age of the study population was 73 years (range 44-95 years). The majority was male: 64%. Distribution according to WHO2001 MDS subtype was RCMD (41%), RARS (25%), RA (14%), RAEB (11%), 5q-syndrome (6%) and RCMD-RS (3%). Table 1 shows iron parameters at registration, 1 year and 2 years follow-up both in transfusion-dependent (TD) and transfusion-independent (TI) patients and stratified according to MDS subtypes: RS (RARS/RCMD-RS) or MDS Other (RA/RCMD/RAEB/5q-syndrome). Serum ferritin was increased in TD patients with a median concentration at registration of 550µg/L and at 2 years 818µg/L, compared to TI patients (median <250µg/L, all time points). During follow-up ferritin was most elevated in patients who received >10 red blood cell (RBC) units: median at registration 1482µg/L - 2 years 1970µg/L. Ferritin correlated significantly with hepcidin (r=0.57; p<0.001) as well as CRP: r=0.27, p<0.001. Median CRP was within reference range (<10mg/L) for both TD and TI patients at registration and during follow-up, but mainly TD patients had elevated CRP levels >50mg/L. Median serum hepcidin levels were elevated in TD patients at registration and remained elevated during follow-up, especially in patients with >10 RBC units transfused (median 27.4nmol/l at registration, 12.8nmol/l at 2 years). Remarkable fluctuation in hepcidin levels occurred in patients with elevated hepcidin during follow-up. Even in the longitudinal cohorts hepcidin fluctuated considerably, maybe due to the interval between the previous transfusion and the measurement of hepcidin or due to diurnal fluctuation. Hepcidin was lowest in MDS RS TI patients and showed a tendency to decrease over time from a median level of 4.4nmol/l at registration to 2.4nmol/l after 2 years, associated with ineffective erythropoiesis. This is supported by the high median GDF15 in these patients. Lowest GDF15 was found in TD patients with ‘MDS Other’ associated with transfusional load. The number of transfused RBC units did not affect the median GDF15 levels. Conclusions: Hepcidin levels were influenced by RBC transfusion history, but hepcidin levels appear to decrease over time in the RS subtype only. Interestingly, increase in hepcidin after transfusions was already visible early in follow-up, depending on the transfusional load and erythropoietic activity of the bone marrow. GDF15 concentration appeared to be most related to MDS subtype, functioning as a marker of ineffective erythropoiesis. Table1: ferritin, hepcidin and GDF15 during-follow-up Registration 1 yr follow-up 2 yrs follow-up N Median (p25-p75) N Median (p25-p75) N Median (p25-p75) Ferritin (µg/L) 101 286 (138 - 558) 83 287 (149 - 845) 66 347 (191 - 818) MDS Other: TI 53 205 (87 - 389) 31 148 (78 - 288) 25 202 (71 - 319) MDS Other: TD 20 479 (279 - 877) 29 845 (481 - 1538) 22 841 (323 - 2387) RARS/RCMD-RS: TI 25 268 (195 - 558) 19 233 (170 - 323) 10 319 (222 - 379) RARS/RCMD-RS: TD 3 610 (108 - 1382) 4 1909 (1206 - 2935) 9 712 (590 - 1222) Hepcidin (nmol/L) 100 5.2 (3.0 - 9.9) 83 5.8 (2.7 - 14.0) 66 5.2 (2.5 - 9.9) MDS Other: TI 53 4.6 (2.8 - 8.4) 31 4.4 (2.3 - 8.1) 25 4.2 (2.5 - 6.8) MDS Other: TD 20 11.1 (4.9 - 21.0) 29 17.2 (9.2 - 22.3) 22 9.6 (4.5 - 17.1) RARS/RCMD-RS: TI 24 4.2 (2.1 - 6.1) 19 3.5 (1.6 - 5.1) 10 2.4 (1.6 - 3.9) RARS/RCMD-RS: TD 3 9.8 (6.0 - 11.1) 4 9.3 (7.3 - 12.1) 9 5.2 (2.9 - 9.3) TI: 0 RBC units 81 4.5 (2.8 - 8.4) 51 4.0 (2.0 - 7.5) 37 3.1 (2.1 - 6.7) TD: ≤10 RBC units 17 10.6 (4.7 - 14.9) 14 9.2 (5.3 - 17.2) 14 4.3 (2.4 - 8.7) TD: >10 RBC units 2 27.4 (15.7 - 39.1) 18 18.1 (12.7 - 24.5) 15 12.8 (9.3 - 21.3) GDF15 (ng/L) 101 1945 (1207 - 3611) 82 2467 (1659 - 4318) 66 2582 (1519- 5332) MDS Other: TI 53 1831 (1100 - 3176) 31 1902 (1076 - 2698) 25 1702 (1136 - 3564) MDS Other: TD 20 1452 (1169 - 2789) 28 2583 (1937 - 4493) 22 2556 (1661 - 4050) RARS/RCMD-RS: TI 25 3532 (2124 - 4211) 19 3148 (2195 - 4560) 10 3661 (1986 - 5524) RARS/RCMD-RS: TD 3 2196 (1869 - 2893) 4 2996 (1806 - 5141) 9 5555 (3204 - 7488) Disclosures Hellström-Lindberg: Celgene: Research Funding. Symeonidis:Celgene: Research Funding; Novartis Oncology: Research Funding; Amgen: Research Funding; Novartis Oncology: Consultancy; Amgen: Consultancy. de Witte:Novartis: Research Funding; Novartis: Honoraria; Celgene: Consultancy; Novartis: Consultancy.

Abstract Background: Total lymphocyte count (TLC) has been shown to correlate with outcomes in patients (pts) with acute leukemia. The clinical correlation to TLC in pts with chronic myeloid leukemia in chronic phase (CML-CP) who were treated with a tyrosine-kinase inhibitor (TKI) is unclear. Methods: Lymphocyte data in pts with newly diagnosed CML-CP who were enrolled in consecutive or parallel clinical trials with front-line imatinib (IM), nilotinib (Nilo), or dasatinib (Dasa) were collected at the time of diagnosis, and 3 and 6 months (M) after the start of TKI. Relative lymphocytrosis (RLC) was defined as lymphocyte >150% at 3 or 6M compared with baseline at diagnosis. Absolute lymphocytosis (ALC) was defined as lymphocyte > 4,000 /µL at 3 or 6M after the start of TKI. Pts were assessed for response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) based on ALC and RLC. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test and Cox regression were used for univariate (UVA) and multivariate analysis (MVA), respectively. Results: A total of 483 pts were enrolled in this study: 271 in IM, 105 in Nilo, and 107 in Dasa. Patient characteristics and outcomes are summarized in Table 1. Median age at diagnosis was 48 years, and median follow-up was 85M and ongoing (5-154+). Time from diagnosis to start of TKI, Sokal risk score, and ALC at baseline between groups did not differ clinically. Of 481 pts, 93 (19%) developed RLC at 3 or 6M; IM, 38 (14%); Nilo, 23 (22%); Dasa, 32 (30%) (p= .001). ALC at 3 or 6M was observed in 15 (3%); IM, 3 (1%); Nilo, 1 (1%); Dasa, 11 (10%) (p<.001). Overall, cumulative incidence of complete cytogenetic response (CCyR) at 6M, major molecular response (MMR) at 12M, molecular response with 4.5 log reduction by IS (MR4.5) at 24M did not differ significantly between RLC and non-RLC (3 or 6M), or between ALC and non-ALC (3 or 6M). 5-y TFS, EFS and OS in ALC group were significantly worse than those in non-ALC group (p= .002, p=.016, p=.008, respectively). By UVA and MVA related to OS, age [p <.001; Hazard ratio (HR), 1.062; 95% confidence interval (95%CI), 1.036-1.089], presence of ALC at 3 or 6M [p = .028; HR, 10.948; 95%CI, 1.297-92.415], absence of MMR at 24M [p=.016; HR, 2.263; 95%CI, 1.165-4.393] were identified as adverse prognostic factors for OS. Conclusion: The presence of ALC ≥4,000/µL at 3 or 6M of TKI therapies is rare but is adversely associated with overall survival. Table 1. Patient Characteristics and Outcomes (N=483)a Overall [n= 481] IM [n= 271] Nilo [n= 105] Dasa [n= 107] Age, (year) 48 (15-85) 48 (15-85) 49 (17-82) 48 (16-83) Sokal Risk, No. (%) Low 334 (69) 175 (65) 79 (75) 80 (75) Intermediate 114 (24) 74 (27) 18 (17) 22 (21) High 32 (7) 20 (7) 8 (8) 4 (4) Time from diagnosis to start of TKI, (M) 0.9 (0-12.6) 1.0 (0-12.6) 0.5 (0-5.6) 0.7 (0.1-7.8) ALC at baseline, (/109L) 2.5 (0-86.6) 2.4 (0-16.7) 2.6 (0.4-9.2) 2.7 (0.3-86.6) Incidence of Relative Lymphocytosis, No. (%) At 3M 65 (14) 25 (9) 16 (15) 24 (22) At 6M 76 (16) 32 (12) 20 (19) 24 (22) Overall 93 (19) 38 (14) 23 (22) 32 (30) Incidence of Absolute Lymphocytosis, No. (%) At 3M 8 (2) 1 (0) 0 7 (7) At 6M 11 (2) 3 (1) 1 (1) 7 (7) Overall 15 (3) 3 (1) 1 (1) 11 (10) Outcomes of RLC and ALC at any time in each group, +/- (%/%) (p) <10% BCR-ABL/ABL at 3M RLC 36/40 (.596) 22/44 (.213) 50/37 (.280) 31/38 (.537) ALC 38/39 (.952) 0/42 (.394) 100/39 (.214) 36/35 (.952) Cumulative CCyR at 6M RLC 75/75 (.288) 50/66 (.063) 96/90 (.413) 90/87 (.628) ALC 67/75 (.711) 33/64 (.276) 0/92 (.001) 82/89 (.599) Cumulative MMR at 12M RLC 67/74 (.406) 53/70 (.030) 83/82 (.921) 72/74 (.903) ALC 60/73 (.488) 33/68 (.197) 0/83 (.033) 73/74 (.745) Cumulative MR4.5 at 24M RLC 46/52 (.564) 37/50 (.139) 57/55 (.889) 50/57 (.729) ALC 33/52 (.332) 33/48 (.610) 0/56 (.264) 36/57 (.252) 5-y FFS RLC 61/71 (.133) 56/69 (.167) 62/70 (.710) 61/74 (.285) ALC 50/69 (.076) 0/68 (<.001) 0/70 (<.001) 71/70 (.974) 5-y TFS RLC 90/93 (.369) 88/93 (.597) 91/88 (.115) 91/99 (.213) ALC 72/93 (.002) 67/93 (.014) 0/90 (<.001) 80/97 (.121) 5-y EFS RLC 80/86 (.213) 71/83 (.154) 84/87 (.450) 86/93 (.486) ALC 64/85 (.016) 33/82 (<.001) 0/87 (<.001) 80/92 (.574) 5-y OS RLC 89/93 (.068) 81/94 (.007) 100/84 (.126) 96/99 (.207) ALC 82/93 (.008) 67/93 (.001) 100/88 (.847) 83/99 (.040) a Two in IM and 1 in Dasa were not evaluable due to lack of differential data at 3 and 6M. Figure 1. OS in Pts with ALC Figure 1. OS in Pts with ALC Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

BackgroundChildhood Chronic Idiopathic Uveitis (cCIU) is a severe ocular condition that account for the 40% of uveitis in children. Its timely and proper treatment is critical to prevent severe complications.ObjectivesThe purpose of this study was to describe the treatments of a large cohort of cCIU.MethodsThis is a retrospective medical chart review study of cCIU followed at Meyer children’s hospital IRCCS and Bristol Royal hospital for children (1stJan2019 - 31stJan 2020). Children were included if they have a diagnosis of CIU prior to 16 years old according to SUN. We collected demographic, clinical and laboratory data. Achievement of remission on treatment was evaluated as persistent inactivity for at least 3 months without drops and systemic corticosteroids.ResultsData about 126 cCIU (61 female, median age at onset 9.3 years (3-16), ANA positive in 33 (77.6%)) were collected. 68 have anterior uveitis, 29 intermediate, 15 anterior + intermediate, 1 posterior and 13 panuveitis. Excluding the patient with posterior involvement, 97 children (77.6%) underwent to at least one systemic treatment, 65 (52%) to two, 18 (14.4%) to three and 2 (1.6%) to four (Infliximab and tacrolimus), with a median follow-up of 46 months (IQR 22-67). The first drug was administered after a median time of 5 months (IQR 2-10). Treatments performed were summarized in table 1. Among the first line treatment, children treated with adalimumab are more likely to achieve remission and maintain remission for a longer time after drug withdrawal compared to the other drugs (χ² 7.59 p 0.006 and p 0.036 respectively). No significant differences have been evaluated stratifying analysis for anatomical subtype, ANA status, ethnicity, sex, ESR and CRP at onset for achievement remission with the first line treatment. However, patients treated with methotrexate who did not achieve remission have lower visual acuity in LogMar (0.53 vs 0.36, Mann-Whitney U test p 0.02). The superiority of Adalimumab in terms of remission achievement was confirmed when it was used as second line treatment too (χ² 6.29 p 0.04), however they relapsed more frequently out of therapy (χ² 6.6 p 0.03). Moreover, with the II line treatment, panuveitis showed higher proportion of remission achievement with adalimumab and worse response to MMF (χ² 2 p 0.03).ConclusionTreatment of cCIU is extremely challenging, achieving remission with the first line treatment in only the 50% of patients. However, patients treated with adalimumab have better chance to achieve remission and patients who showed worse visual acuity at onset would benefit of a more aggressive treatment with biologics since onset.Table 1.Treatment performed in cohort of Childhood CNIUTreatmentFirst Course of Systemic treatmentSecond course of systemic treatmentThird course of Systemic treatmentOverall(97)Mtx(89)MM(1)ADA(7)*P valueOverall(65)Mtx(6)ADA(45)MM(14)P valueOverall(18)ADA(16)MM(1)IFN (1)P valueConcomitant therapy*2 MTX41 MTX and 2 MM (Group ADA)11 MTX, 5 MMF, 1 AZATime of administration median (IQR)5(2-10)5(2-9)410(3-24)NS15 (8.25-27)44.5 (35.2-53.5)12(7-19.5)16(7.7-32)<0.00143.5(327-55)47 (12-90)4827NsDuration of therapy23(10-36)24 (11-38)522(7-24)NS24 (11.25-34.75)21.5 (9.7-26)23(11.2-32.7)33.5(6.5-52.5)NS19 (7-33)21.6 (2-55)255NsAchievement of remission on therapyN (%)45/90(50%)38/83-7/7χ² 7.59 p 0.00652/56(91.2%)5/638/399/12χ² 6.29 p 0.0414/15 (93.3%)13/14-1/1nsTime for achievement remission6(5-7)6(5-7.5)5(4-6.75)NS6(5-9)5 (4.5-7.5)6 (5-9)9(4-11.5)Ns6(4-9.25)6.6 (4-12)-9NsN of pts who stop drug for persistent remission23(25%)21/38-2/7NS26 (41.5%)3194NS3(18.7%)3/1500nsRelapse out of therapyN (%)13 (56.5%)12/21-1/2NS17 (63%)0152χ² 6.6 p 0.031/3(33.3%)1/3--nsTime free from relapse out of therapy3(2-21)3 (2-20)-40 (2-40)0.0366(3.75-9)4(2-4)6(4-9)6.5 (3.5-33.5)ns8(8-12)8(8-12)--NsList of abbreviations: ADA: adalimumab, MM: mycophenolate mofetil, MTX methotrexate, IFN: infliximab, N number, IQR interquartile range, NS non significant.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsIlaria Maccora: None declared, Catherine Guly Consultant of: Eli Lilly and Company, Cinzia De Libero: None declared, Roberto Caputo: None declared, Athimalaipet Ramanan Speakers bureau: Speaker fees – Abbvie, Roche, UCB, Lilly, Novartis and SOBI, Consultant of: Consulting fees from Abbvie, Eli Lilly, UCB and Alimera, Employee of: Participation on a Data Safety Monitoring Board or Advisory Board: Eli Lilly, Gabriele Simonini: None declared.

Background:Limited data on early Psoriatic Arthritis (PsA) are available1,2.Objectives:To describe baseline data of PsA patients naive to any DMARDs.Methods:SIRENA study is an Italian, prospective Registry of Spondyloarthritis patients diagnosed according to ASAS criteria and naïve to any DMARDs. Data on demographic and clinical characteristics of PsA cohort were collected and analysed, also by gender.Results:203/350 (58%) subjects included in SIRENA Registry had PsA (mean age 51.9 years) and in 190/203 (94%) CASPAR classification criteria were fulfilled. In 70% of patients the diagnosis was performed within 24 months from symptom onset. At baseline, 194/203 (95.6%) had mainly peripheral manifestations, 74.4% of patients had skin psoriasis, 40% nail psoriasis, 39.3% clinical enthesitis and 25.9% dactylitis. Mean SJC66 and TJC68 were, respectively, 3 and 7.2; mean PhGA was 46.3; 14.7% of patients were in MDA.The higher tender joint count in women (mean TJC68 9.3 in women vs 5.3 in men) resulted in a higher disease activity according to DAPSA (high disease activity: 11.5% women vs 4.1% men), a higher joint VAS score (mean score 47.1 women vs 39.8 men) and a lower prevalence of MDA (8.3% women vs 20% men). We observed a higher prevalence of moderate or severe psoriasis in men (BSA≥3%: 37% men vs 27.8% women) while all PROs collected (PtGA, pain VAS score, sleep VAS score, BASFI, BASDAI, HAQ-DI, WPAI) were worse in women.The most common comorbidities were cardiometabolic (35.5%), endocrine (9.4%), and gastrointestinal disorders (7.4%). Cardiometabolic disorders were more frequently reported by men, endocrine and gastrointestinal disorders by women; depression exclusively by women.Conclusion:This analysis provides real-life data in a cohort of early PsA subjects. Relevant gender differences were observed, with women showing a higher disease activity and more joint pain and men having more severe psoriasis. Women also perceived a worse disease burden.References:[1]Theander E, et al. Ann Rheum Dis 2014; 73:407–413.[2]Nas K, et al. Mod Rheumatol 2017; 27(2):345-349.Table 1.Baseline dataPsAAll patients (n=203)Women (n=98)Men (n=105)Age (years), mean (SD)51.9 (13.1)51.1 (13.2)52.7 (13.0)Men, n (%)105 (51.7)0 (0)105 (100)BMI (kg/m2), mean (SD)25.9 (4.4)25.4 (4.9)26.4 (3.9)BMI categories^, n (%) Obese40 (21.2)20 (22.2)20 (20.2) Overweight44 (23.3)15 (16.7)29 (29.3) Under/normal weight105 (55.6)55 (61.1)50 (50.5)Comorbidities > 5%*, n (%) Cardiometabolic72 (35.5)28 (28.6)44 (41.9) Endocrine disease19 (9.4)15 (15.3)4 (3.8) Gastrointestinal15 (7.4)10 (10.2)5 (4.8) Depression/Anxiety8 (3.9)8 (8.2)0 (0) Hepatic diseases7 (3.5)1 (1.0)6 (5.7)Clinical assessmentCRP (mg/dl), median (min-max)0.40 (0 – 7.12)0.31 (0 - 5.40)0.49 (0 - 7.12)SJC66, mean (SD)3.0 (4.0)3.2 (4.0)2.7 (4.0)TJC68, mean (SD)7.2 (8.8)9.3 (10.3)5.3 (6.6)Dactylitis, n/tot assessed (%)35/135 (25.9)12/63 (19.1)23/72 (31.9)Enthesitis, n/tot assessed (%)66/168 (39.3)39/80 (48.8)27/88 (30.7)Psoriasis skin, n (%)151 (74.4)68 (69.4)83 (79.1)Psoriasis nails, n/tot assessed (%)62/155 (40.0)29/75 (38.7)33/80 (41.3)Fibromyalgia, n (%)6 (3.0)5 (5.2)1 (1.0)VAS, mean (SD) [range: 0-100] PhGA score46.3 (25.8)51.2 (25.4)41.7 (25.4) Joint score43.3 (26.8)47.1 (25.2)39.8 (27.8) Skin score20.3 (24.0)17.8 (23.1)22.6 (24.8)DAPSA, mean (SD)22.3 (14.1)26.8 (15.4)18.7 (11.9)DAPSA categories^, n (%)High disease activity13 (7.4)9 (11.5)4 (4.1)Moderate disease activity83 (47.2)43 (55.1)40 (40.8)Low disease activity71 (40.3)24 (30.8)47 (48.0)Remission9 (5.1)2 (2.6)7 (7.1)MDA°, n (%)23 (14.7)6 (8.3)17 (20.0)BSA categories, n (%) 3-10% (moderate psoriasis)35 (24.6)13 (21.2)22 (27.1) >10% (severe psoriasis)12 (8.5)4 (6.6)8 (9.9)* A patient could report one or more comorbidities. ^The sum does not add up to the total because of some missing values. ° According to Coates et al. (Ann Rheum Dis. 2010;69: 48).Disclosure of Interests:Alen Zabotti: None declared, Michele Maria Luchetti Speakers bureau: Honorary fees for conferences and workshops by Janssen, Abbvie, Novartis, Lilly, Celgene, Pfizer, Carlo Selmi Speakers bureau: Honoraria and/or speaker bureau from AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, Pfizer, Sanofi-Regeneron, Grant/research support from: Research support from Amgen, Janssen, Novartis, Pfizer, Roberta Ramonda Speakers bureau: Honoraria and speaker fees from Novartis, Abbvie, Pfizer, MSD, Janssen, Rosa Daniela Grembiale: None declared, Lorenzo Dagna Consultant of: Consultation honoraria from Abbvie, Amgen, Biogen, Celltrion, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI, Salvatore D’Angelo Speakers bureau: Consulting fees and/or speakers bureau from AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi and UCB, Giacomo Cafaro: None declared, Salvatore De Vita: None declared, Mara Felicetti: None declared, Silvia Marelli Employee of: Janssen-Cilag SpA, Daniela Frigerio Employee of: Janssen-Cilag SpA, Ennio Favalli Speakers bureau: Consulting fees and/or speaking engagements from AbbVie, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Pfizer, Galapagos, Sanofi-Genzyme, and UCB.

Работа направлена на установление закономерностей изменения сдвиговой упругости, возникающих при структурной релаксации металлических стекол на основе Pd и Zr. Измерения модуля сдвига выполнялись на частотах около 500 кГц. Несмотря на отличия в физических свойствах исследованных металлических стекол (химический состав, стеклообразующая способность, температуры стеклования и др.), наблюдаются определенные общие закономерности релаксации их сдвиговой упругости при термообработке. ИСТОЧНИК ФИНАНСИРОВАНИЯ Работа поддержана грантом Минобрнауки РФ № 3.1310.2017/4.6. БЛАГОДАРНОСТИ Автор выражает благодарность проф. В.А. Хонику за обсуждение статьи ЛИТЕРАТУРА Dyre С. Reviews of Modern Physics, 2006, vol. 78, pp. 953–972. https://doi.org/10.1103/revmodphys.78.953 Dyre J. C., Olsen N. B., Christensen T. Physical Review B, 1996, vol. 53, pp. 2171–2174. https://doi.org/10.1103/physrevb.53.2171 Khonik V. A., Mitrofanov Yu. P., Lyakhov S. A., Vasiliev A. N., Khonik S. V., Khoviv D. A. Physical Review B, 2009, vol. 79, pp. 132204-1–132204-4. https://doi.org/10.1103/physrevb.79.132204 Chen H. S. Reports on Progress in Physics, 1980, vol. 43, pp. 353–432. https://doi.org/10.1088/0034-4885/43/4/001 Hirao M., Ogi H. EMATS for Science and Industry: Noncontacting Ultrasonic Measurements. New-York, Springer, 2003, p. 372. Vasil'ev A. N., Buchel'nikov V. D., Gurevich M. I., Kaganov M. I., Gajdukov Ju. P. Electromagnetic Excitation of Sound in Metals. Cheljabinsk, Izd-vo JuUrGU Publ., 2001, 339 p. Wang W. H. Progress in Materials Science, 2012, vol. 57, pp. 487–656. https://doi.org/10.1016/j.pmatsci.2011.07.001 Watanabe L. Y., Roberts S. N., Baca N., Wiest A., Garrett S. J., Conner R. D. Materials Science and Engineering: C, 2013, vol. 33, pp. 4021–4025. https://doi.org/10.1016/j.msec.2013.05.044 Wang D. P., Zhao D. Q., Ding D. W., Bai H. Y., Wang W. H. Journal of Applied Physics, 2014, vol. 115, pp. 123507-1–123507-4. https://doi.org/10.1063/1.4869548 Zhang Z., Keppens V., Liaw P. K., Yokoyama Y. Journal of Materials Research, 2006, vol. 22, pp. 364–367. https://doi.org/10.1557/jmr.2007.0040 Khonik V. A. Izvestija Akademii Nauk. Serija fizicheskaja [Bulletin of the Russian Academy of Sciences: Physics], 2001, vol. 65, no. 10, pp. 1465–1471. (in Russ.) Shtremel' M. A. The Strength of the Alloys. Part Defects of the Lattice. Moscow, MISIS Publ., 1999, 384 p. (in Russ.) Gordon C. A., Granato A. V. Materials Science and Engineering A, 2004, vol. 370, pp. 83–87. https://doi.org/10.1016/j.msea.2003.08.077 Shen T. D., Schwarz R. B. Applied Physics Letters, 2006, vol. 88, pp. 091903-1–091903-3. https://doi.org/10.1063/1.2172160 Tsyplakov A. N., Mitrofanov Yu. P., Khonik V. A., Kobelev N. P., Kaloyan A. A. Journal of Alloys and Compounds, 2015, vol. 618, pp. 449–454. https://doi.org/10.1016/j.jallcom.2014.08.198 Mitrofanov Y. P., Wang D. P., Makarov A. S., Wang W. H., Khonik V. A. // Scientific Reports, 2016, vol. 6, p. 23026-1–23026-6. https://doi.org/10.1038/srep23026 Afonin G. V., Mitrofanov Yu. P., Makarov A. S., Kobelev N. P., Khonik V. A. // Journal of Non-Crystalline Solids, 2017, vol. 475, pp. 48–52. https://doi.org/10.1016/j.jnoncrysol.2017.08.029

Abstract Abstract 2901 Poster Board II-877 Thalidomide and lenalidomide are two immunomodulatory agents that engender an intriguing treatment activity in a subset of pts with MF that includes a clinically relevant benefit in terms of both anemia and splenomegaly. Using the International Working Group (IWG) consensus criteria, we assessed the efficacy and longterm outcome of these two agents in three consecutive studies run at MD Anderson Cancer Center between February 2000 and March 2007 in pts with MF. One hundred and six pts were treated in three phase II trials. Twenty-five pts received single-agent thalidomide; 41 pts received single-agent lenalidomide; and 40 pts were treated with a combination of lenalidomide and prednisone. Patients' characteristics are summarized in Table 1. There was no significant difference between the 3 study groups except for a higher percentage of splenomegaly (p=0.012) and a performance status 1 (p=0.017) observed in pts treated with the combination of lenalidomide-prednisone. In addition, pts receiving lenalidomide therapy had received more previous therapies. After a median follow-up of 15 months (range, 2 to 112 months), 7 the 25 pts (28%) treated with thalidomide responded with complete response (CR) observed in 1 pt (4%), partial response (PR) in 1 pt (4%) and clinical improvement (CI) in 5 pts (20%). The median duration of response was 7 months (range, 3 to 40 months). Of the 41 pts treated with single-agent lenalidomide, 14 (34%) responded with 3 (7%) CR, 4 (10%) PR, and 7 (17%) CI. The median follow-up and median duration of response were 20 months (range, 2 to 55 months) and 16 months (range, 6 to 44 months), respectively. After a median follow-up of 8 months (range, 4 to 37 months), 15 of the 40 pts (38%) treated with the combination of prednisone and lenalidomide responded: 2 (5%) CR, 2 (5%) PR, and 11 (28%) CI. The median duration of response was 14+ months (range, 4 to 30+ months). One of the pts treated with a combination of lenalidomide-prednisone converted his response from PR to CR recently. There was a trend for faster responses in pts treated with combination versus single agent-lenalidomide: the median time to response was 60 and 80 days respectively (p=0.06). We then compared the efficacy of these three regimens. There was a trend for a higher efficacy in pts receiving the lenalidomide-prednisone combination (Table 2). In conclusion, immunomodulatory agents such as thalidomide and lenalidomide are effective in the treatment of pts with MF. The combination of lenalidomide and prednisone appears to be more effective and can induce faster responses.Table 1.Patients' CharacteristicsLenalidomideLenalidomide-PrednisoneThalidomidep-value N= 41N=40N=25 Age, median (yrs)64 (42-83)64(42-86)66 (40-85)0.862No. of prior treatments (range)2 (1-7)2(1-5)1 (1-3)0.000Hemoglobin (gm/dL, range)9.8 (6.9-14.8)9.8(6.6-15.4)9.3 (6.6-12.6)0.092Platelet (x 109/L, range)203 (34-901)237(8-1005)130 (20-391)0.111WBC Count (x 109/L, range)9 (2.4-45.4)8.6(1.1-28.3)7.3 (2-59.5)0.507%Neutrophils (range)66 (32-89)66(10-89)64 (30-90)0.825SplenomegalyYes (%)20 (49)31 (78)14 (56)0.012No (%)14 (34)9 (22)10 (40)Splenectomy (%)7 (17)0 (0)1 (4)Spleen Size (cm, range)12 (3-30)11.5 (1-25)12.5 (3-25)0.54Cytogenetics (%) Diploid25 (61)21 (52)15 (60)0.651Non-Diploid15 (37)19 (48)9 (36)Not available1 (2)0 (0)1 (4)Myelofibrosis (%)Primary29 (71)31 (78)18 (72)0.96Post ET7 (17)5 (12)5 (20)0.77Post PV5 (12)4 (10)2 (8)0.24Performance Status (%)016 (39)4 (10)5 (20)0.017122 (54)32 (80)15 (60)23 (7)4 (10)5 (20)Table 2.ParameterLenalidomide N=41Lenalidomide-Prednisone N=40Thalidomide N=25P-value Response (%)Overall14 (34)15 (38)7 (28)0.66CR3 (7)2 (5)1 (4)PR4 (10)2 (5)1 (4)CI7 (17)11 (28)5 (20)Median Follow-up (mo, range)20 (2-55)8 (4-37)67 (2-112)Median Response (mo, range)16 (6-44)14+ (4-30)7 (3-40)0.37 Disclosures: Jabbour: Novartis: Speakers Bureau; Bristol Myers Squibb : Speakers Bureau.

Abstract Abstract 3125 Poster Board III-62 VTE is the most frequent complication of OS and it can be prevented through anticoagulant prophylaxis. Numerous studies have evaluated different agents for this purpose and there are new agents currently under development or recently approved for this indication. We conducted a systematic review of randomized controlled trials (RCT) evaluating administration of anticoagulants for VTE prophylaxis in OS and performed a MA of proportions to estimate the overall incidence of major VTE (proximal VTE, pulmonary embolism (PE), or death from PE), total VTE (proximal and distal VTE, PE or death from PE), symptomatic VTE and major bleeding episodes (as defined by the International Society on Thrombosis and Hemostasis). We included RCT comparing currently approved anticoagulants (head-to-head or placebo-controlled) for VTE prophylaxis in OS (hip and knee arthroplasty and hip fracture surgery) using systematic evaluation of VTE (ultrasound or venography, pulmonary angiography, CT pulmonary angiography, or ventilation perfusion scan). Heterogeneity of proportions was evaluated using a chi2 test and pooled estimates of proportions were obtained using either a fixed or a random effects model in which the weights were estimated as proposed by Laird and Mosteller. We retrieved 74 studies including180 research arms and enrolling 71,012 patients. The total number of events and evaluable patients, percentage of events and 95% CI, and number of study arms included are shown in the table. We found differences in the percentage of VTE and bleeding events associated with the use of different anticoagulants for VTE prophylaxis after OS. Due to the nature of the analysis no effect measure can be estimated. These estimates might help to design future studies. Major VTE Total VTE Symptomatic VTE Major Bleeding Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) All patients LMWH 993/23692 5.96 (5.81, 6.11) 72 4068/22610 20.29 (20.04, 20.55) 80 193/19431 1.32 (1.27, 1.37) 35 476/28725 1.98 (1.93, 2.02) 70 UFH 234/2407 13.39 (12.86, 13.93) 14 596/2537 22.54 (22, 23.08) 17 11/339 3.24 (3.06, 3.43) 4 70/2849 2.75 (2.61, 2.89) 16 Warfarin 269/5677 6.28 (6.09, 6.46) 12 1317/4203 31.05 (30.44, 31.66) 12 71/4146 1.95 (1.83, 2.08) 6 96/6751 1.78 (1.69, 1.87) 12 Fonda 96/3673 3.81 (3.53, 4.09) 7 223/3477 6.82 (6.57, 7.07) 6 69/6398 1.06 (1.01, 1.1) 8 121/6576 1.63 (1.55, 1.71) 9 Riva 50/5025 2.02 (1.86, 2.19) 8 242/4595 13.05 (12.16, 13.94) 8 29/6252 0.46 (0.45, 0.48) 6 31/6643 0.63 (0.59, 0.68) 8 Dabi 149/4091 3.64 (3.59, 3.69) 6 834/4051 22.96 (21.91, 24.01) 6 26/3664 0.71 (0.67, 0.75) 4 67/5419 1.21 (1.17, 1.26) 6 Placebo 193/710 24.26 (23.17, 25.34) 10 379/816 49.35 (48.08, 50.62) 11 19/198 12.02 (10.32, 13.72) 3 12/753 1.59 (1.5, 1.68) 7 Total 1984/45275 129 7659/42289 140 418/40428 66 873/57716 128 Total Hip Arthroplasty LMWH 653/15978 6 (5.85, 6.16) 50 1817/14480 15.58 (15.35, 15.82) 55 81/11552 0.7 (0.69, 0.72) 19 306/18010 1.97 (1.92, 2.02) 45 UFH 187/1739 14.3 (13.64, 14.96) 11 354/1836 20.13 (19.46, 20.8) 13 11/246 4.47 (4.21, 4.73) 3 52/1451 3.2 (3.01, 3.39) 11 Warfarin 77/2758 4.28 (4.08, 4.48) 6 265/1273 20.82 (20.59, 21.04) 6 32/1833 1.75 (1.69, 1.81) 2 47/2856 2.23 (2.09, 2.37) 5 Fonda 28/1799 2.96 (2.58, 3.33) 3 85/1695 5.01 (4.91, 5.12) 2 15/2255 0.67 (0.63, 0.7) 2 69/2349 2.94 (2.87, 3.01) 3 Riva 25/2938 2.21 (1.95, 2.46) 5 73/2749 9.72 (8.92, 10.53) 5 10/3468 0.29 (0.27, 0.31) 3 14/3795 0.49 (0.44, 0.54) 5 Dabi 72/1803 3.99 (3.88, 4.11) 2 124/1766 7.02 (6.77, 7.27) 2 21/2293 0.92 (0.91, 0.93) 2 38/2309 1.65 (1.58, 1.72) 2 Placebo 105/414 26.01 (24.76, 27.27) 7 174/418 45.43 (43.74, 47.13) 7 4/147 2.72 (2.46, 2.98) 2 3/388 0.77 (0.69, 0.86) 5 Total 1147/27429 84 2892/24217 90 174/21794 33 529/31158 76 Total Knee Arthroplasty LMWH 277/6916 4.45 (4.34, 4.55) 25 2062/7326 30.72 (30.37, 31.07) 32 83/4902 1.69 (1.66, 1.73) 11 89/7808 1.14 (1.12, 1.16) 26 UFH 42/638 6.58 (6.39, 6.78) 3 226/638 35.42 (35.05, 35.79) 3 0/93 NE 1 3/318 0.94 (0.84, 1.05) 2 Warfarin 192/2919 8.1 (7.88, 8.32) 9 1052/2930 39.36 (38.69, 40.02) 9 39/2056 1.9 (1.84, 1.96) 3 28/3407 0.82 (0.79, 0.85) 8 Fonda 23/452 9.3 (7.93, 10.67) 2 45/361 12.47 (12.12, 12.81) 1 3/517 0.58 (0.51, 0.65) 1 12/601 2 (1.88, 2.11) 2 Riva 25/2087 1.2 (1.15, 1.24) 3 169/1846 18.55 (16.47, 20.63) 3 19/2784 0.68 (0.65, 0.71) 3 17/2848 0.6 (0.57, 0.63) 3 Dabi 77/2288 3.37 (3.32, 3.41) 4 710/2285 30.98 (30.42, 31.55) 4 5/1371 0.36 (0.32, 0.41) 2 29/3110 0.93 (0.89, 0.98) 4 Placebo 88/296 27.12 (24.54, 29.7) 4 205/398 55.19 (53.53, 56.84) 5 15/51 29.41 (28.16, 30.66) 1 9/365 2.47 (2.31, 2.62) 4 Total 724/15596 50 4469/15784 57 164/11774 22 187/18457 49 LMWH Low molecular weight heparin, UFH unfractionated heparin, Riva Rivaroxaban, Dabi Dabigatran etexilate Disclosures Lazo-Langner: Boehringer Ingelheim: Honoraria. Rodger:Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding.

Abstract Purpose: H3B-6545, a novel Selective ERα Covalent Antagonist (SERCA), inactivates both and wild-type and mutant ERα by targeting cysteine 530 and enforcing antagonist conformation. H3B-6545 demonstrated preclinical high activity in breast cancer models with constitutively active ESR1 mutations (Furman C, SABCS 2020) and clinical activity in pretreated women with ER+ breast cancer (Hamilton EP, ASCO 2021). Patients and Methods: The primary objective of the phase II is to estimate the objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and secondary objectives include safety. Results: 94 pts were treated with 450 mg daily, the recommended phase II dose: 11 in the phase I and 83 in the phase II parts of the trial. Patients and tumor characteristics were presented previously (Hamilton EP, ASCO, 2021). As of March 31, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), nausea (17%), fatigue (16%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (39%), hemoglobin decrease (38%), Lymphocytes decrease (37%), ALT increase (14%), AST increase (13%), bilirubin increase (12%), and creatinine increase (12%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 35% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in Table 1. CI: Confidence interval. N: total number of pts in full analysis set, used in PFS analysis. n: number of response-evaluable pts, used in ORR and CBR analysis. Efficacy estimates were consistent across the various subgroups. Responses were demonstrated in heavily pretreated pts, pts with visceral metastases, pts with constitutionally active ESR1 Y537S mutations, and in pts who received chemotherapy in the metastatic setting. Numerically higher response rate and longer PFS were observed in pts with ESR1 Y537s. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was consistent across the various subgroups. Tumors harboring the constitutionally active ESR1 Y537S mutation may present higher ERα activity, and consequently enrich for luminal A traits and demonstrate greater lineage dependence on ERα. Table 1.Consistency of H3B-6545 activity across the key subgroupsEfficacyClinical CharacteristicORR % (95% CI)CBR % (95% CI)Median PFS mo (95% CI)Overall population (N=94, n=72)16.7 (8.9, 27.3)40.3 (28.9, 52.5)5.1 (3.2, 6.2)Liver and/or lung metastases (N=76, n=62)17.7 (9.2, 29.5)41.9 (29.5, 55.2)5.4 (1.8, 7.2)≥3 prior regimens (N=49, n=39)20.5 (9.3, 36.5)48.7 (32.4, 65.2)5.4 (3.5, 7.3)Prior chemotherapy (N=47, n=35)17.1 (6.6, 33.6)51.4 (34.0, 68.6)5.5 (3.6, 7.3)PgR+ (N=38, n=32)15.6 (5.3, 32.8)50.0 (31.9, 68.1)5.4 (2.0, 8.8)ESR1 clonal Y537S (N=10, n=10)30.0 (6.7, 65.2)60.0 (26.2, 87.8)7.3 (0.8, 11.2)ESR1 clonal D538G (N=19, n=17)0.0 (0.0, 19.5)35.3 (14.2, 61.7)5.4 (1.7, 7.2) Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Aki Morikawa, E Claire Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail S Wright, Fadi Kayali, Lisa Cantagallo, Manav Korpal, Jenny Long, Jianjun Xiao, Benoit Destenaves, Lei Gao, Tarek Sahmoud, Antonio Gualberto, Dejan Juric. H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer - A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-10.

Background:Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors involved in innate and adaptive immune cell development and homeostasis, and linked to the genetic risk for systemic lupus erythematosus (SLE). A phase 2, placebo-controlled study evaluated the efficacy and safety of iberdomide in patients (pts) with moderate to severe SLE.Objectives:To examine the effect of iberdomide on cutaneous manifestations in SLE pts.Methods:Adult autoantibody-positive SLE pts with a SLE Disease Activity Index 2000 (SLEDAI 2K) score ≥6 were randomized (2:2:1:2) to oral iberdomide (0.45, 0.3, 0.15 mg) or placebo once daily (QD) for 24 weeks while continuing standard background lupus medications. The Cutaneous Lupus Area and Severity Index Activity score (CLASI-A) was assessed every 4 weeks through week 24. As prespecified, exploratory analyses, change from baseline and the proportion of pts who achieved ≥50% reduction from baseline (CLASI-50) were evaluated for all pts, pts with baseline CLASI-A ≥8, and by cutaneous lupus subtypes (acute [ACLE], subacute [SCLE], chronic [CCLE]). CLASI-A outcomes were also evaluated post hoc for subgroups with high baseline expression of IKZF3 or the type 1 interferon (IFN) gene signatures in the blood.Results:Of 288 randomized pts, the mean and median (range) baseline CLASI-A scores were 6.9 and 5.0 (0-49), with 28% of pts having a score ≥8. 56% of pts had ACLE, 29% CCLE, and 16% SCLE. CLASI-50 responses were not significantly different comparing iberdomide to placebo in all pts and pts with baseline CLASI-A ≥8 at week 24, where high placebo response rates were observed (Table). Numerically greater mean improvement from baseline in CLASI-A scores in pts with baseline CLASI-A ≥8 was observed for iberdomide 0.45 mg vs placebo beginning at week 4, with continuous improvement through week 24. For pts with SCLE or CCLE, CLASI-50 response rates were significantly higher with iberdomide 0.45 mg vs placebo (P<0.04; Table). SCLE pts had significantly greater mean change and median percent improvement in CLASI-A from baseline with iberdomide 0.45 mg vs placebo at week 24 (P<0.03). Treatment differences in CLASI-A between iberdomide 0.45 mg and placebo were larger for SCLE and CCLE subgroups with high baseline IKZF3 or type 1 IFN gene signatures, with statistical significance achieved for SCLE pts but not CCLE pts (Figure).Table 1.CLASI-50 Response Rates by Subgroups at Week 240.15 mg QD0.3 mg QD0.45 mg QD(n=42)(n=82)(n=81)PlaceboSubgroup(n=83)0.15 mg QD vs Placebo0.3 mg QD vs Placebo0.45 mg QD vs Placebon/m (%)n/m (%)Str Diff in % (95% CI)P valuen/m (%)Str Diff in % (95% CI)P valuen/m (%)Str Diff in % (95% CI)P valueAll pts37/83 (44.6)19/42 (45.2)0.4 (-17.33, 18.55) P=0.96141/82 (50.0)5.3 (-9.93, 20.11) P=0.49945/81 (55.6)10.9 (-4.30, 25.51) P=0.163CLASI-A ≥810/20 (50.0)8/13 (61.5)15.9 (-17.42, 45.45) P=0.39913/24 (54.2)12.1 (-17.57, 39.97) P=0.45816/24 (66.7)15.1 (-15.51, 42.49) P=0.368ACLE23/50 (46.0)15/30 (50.0)4.8 (-17.22, 26.31) P=0.66220/43 (46.5)-3.3 (-22.95, 16.67) P=0.73817/38 (44.7)-3.0 (-23.20, 17.65) P=0.782SCLE9/17 (52.9)5/9 (55.6)2.6a (-33.04, 36.33) P=0.9663/9 (33.3)-6.6 (-38.98, 31.86) P>0.99911/12 (91.7)38.7a(4.54, 61.75) P=0.035CCLE5/18 (27.8)7/14 (50.0)22.2a (-10.51, 50.00) P=0.19810/23 (43.5)23.8 (-6.89, 48.88) P=0.12918/29 (62.1)34.1 (4.43, 56.16) P=0.029CI, confidence interval; Str Diff, stratified difference.aUnstratified difference.Conclusion:Iberdomide showed beneficial effects on skin manifestations in pts with SLE. Efficacy appears to be more pronounced in pts with SCLE and CCLE skin subtypes, and in pts with high IKZF3 or IFN gene expression signatures.Δ, treatment difference of adjusted means; CCLE, chronic cutaneous lupus erythematosus; CLASI-A, Cutaneous Lupus Erythematosus Disease Area and Severity Index-activity score; IFN, interferon; SCLE, subacute cutaneous lupus erythematosus.Acknowledgements:This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.Disclosure of Interests:Victoria Werth Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Joan Merrill Consultant of: UCB, GlaxoSmithKline, AbbVie, EMD Serono, Remegen, Celgene/Bristol Myers Squibb, AstraZeneca, Lilly, Immupharma, Amgen, Janssen, Resolve, Alpine, Aurinia, Astellas, Alexion, and Provention, Grant/research support from: GlaxoSmithKline and AstraZeneca, Richard Furie Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Thomas Dörner Consultant of: support for clinical studies and honoraria for scientific advice: AbbVie, Bristol Myers Squibb Company, Celgene, Eli Lilly, Janssen, Novartis, Roche, Employee of: Charite Universitätsmedizin, Berlin and DRFZ Berlin, Germany, Ronald van Vollenhoven Speakers bureau: UCB, AbbVie, Galapagos, Janssen, Pfizer, Paid instructor for: support for educational programs: Pfizer, Roche, Consultant of: AstraZeneca, Biogen, Biotest, Celgene, Gilead, Servier, UCB, AbbVie, Galapagos, Janssen, Pfizer, Grant/research support from: Bristol Myers Squibb, GlaxoSmithKline, Eli Lilly, UCB, Peter Lipsky Employee of: RILITE Foundation, Michael Weiswasser Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shimon Korish Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Peter Schafer Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mark Stern Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Zhaohui Liu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shaojun Tang Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

Abstract Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) results from incomplete reconstitution of immune tolerance. CD4+CD25+FOXP3+ regulatory T cells (Treg) are required for tolerance and function as dominant suppressors of innate and adaptive immune effector cells. In our prior phase 1 cGVHD study daily subcutaneous (SC) low-dose interleukin-2 (IL-2) for 8 weeks induced Treg expansion in vivo and objective clinical responses in 12 of 23 evaluable participants (NEJM 2011). We now report on a phase 2 trial of daily low-dose SC IL-2 at 1x106 IU/m2/d for 12 weeks in steroid-refractory cGVHD. The study comprised 35 HCT recipients (51% male, 91% HLA-matched PBSC grafts). Median participant age was 51 years (range, 22-72). Median time from HCT and from cGVHD onset to start of IL-2 treatment was 616 days (range, 270-2145) and 252 days (range, 28-1880) respectively. Participants had a median of 4 cGVHD organ sites (range, 1-7), and 2 concurrent cGVHD therapies (range, 1-3) at enrollment. The median baseline prednisone dose was 20 mg (range, 2.5-50). The median follow-up in survivors was 21 months (range, 4-35). 12 week low dose IL-2 was well tolerated: 2 participants withdrew and 5 required IL-2 dose reduction for constitutional AE (n=6) and thrombocytopenia (n=1); 1 had Gr 3 infection (bacteremia); and none experienced relapse. At week 12, objective cGVHD responses (PR) were documented in 21 of 33 evaluable participants (64%). Two (6%) had cGVHD progression. cGVHD response sites included skin (n=9), joint/fascia/muscle (n=4), liver (n=7), lung (n=3), and GI tract (n=4). Overall 2-year OS/PFS was 91% (responders 94%; non-responders 83%). 23 participants with clinical benefit (PR or SD with minor response) proceeded on extended IL-2 therapy. Immunologically, low dose IL-2 induced a >4-fold increase in median Treg count/µL (p<0.001): a rapid rise from a baseline of 17.1 (Q1-Q3, 8.6-40.6) to a week 4 peak of 137.9 (Q1-Q3, 51.8-188) and subsequent stabilization with a week 12 count of 104.1 (Q1-Q3, 53.9-167.1). No significant change in CD4 conventional T cell (Tcon), CD8 T cell, or CD20 B cell count was noted. NK cell count increased >3-fold (p<0.001). The median Treg:Tcon ratio increased >4-fold (p<0.001): a rapid rise from baseline of 0.06 (Q1-Q3, 0.05-0.13) to a week 2 peak of 0.35 (Q1-Q3, 0.26-0.48) that remained elevated through a week 12 ratio of 0.31 (Q1-Q3, 0.27-0.39) (Figure). Treg count and Treg:Tcon ratio declined during 4 weeks off IL-2 and rose thereafter on restarting IL-2. Clinical responders were younger (50 vs. 61.5 years, p=0.01) and initiated IL-2 earlier (499 vs. 903 days post HCT, p=0.015). Responders had a higher median Treg:Tcon ratio at study baseline (0.09 vs. 0.06, p=0.052) and at week 1 of IL-2 (0.3 vs. 0.14, p=0.01). Combining phase 1 and 2 data, Treg:Tcon ratios of ≥0.07 at baseline and ≥0.2 at week 1 of IL-2 were highly predictive of clinical response (p=0.007; p=0.0013 respectively). The combined phase 1 and 2 extended IL-2 cohort comprised 35 participants with a median follow up of 16.2 months (range, 4.1-66.8), with 20 and 12 participants receiving over 1 and 2 years of IL-2 respectively. Extended daily low dose IL-2 was well tolerated, and only 4 participants had Gr 3 AEs deemed IL-2 related: lung infection (n=1), arthralgia (n=1), and injection site induration (n=2). 5 participants required IL-2 dose reduction and 1 had hematologic malignancy relapse. Clinical responses were typically sustained during taper of concomitant immunosuppression. Treg augmentation persisted for the duration of IL-2 therapy. Tcon count slowly recovered to normal levels and Treg:Tcon ratio gradually normalized over a 2 year period. There was no change in CD8 count. The median steroid taper was 50% (range, -20-100). In summary, daily low dose IL-2 therapy induced profound Treg enhancement, and clinical responses in over half of refractory cGVHD patients. Early clinical response predictors suggest IL-2 is more effective earlier in the cGVHD course and when starting numbers of Treg are higher. Sustained clinical and immunologic response during extended IL-2 was documented. Long term tolerance induction with daily low dose IL-2 is a promising and feasible strategy. Optimizing IL-2 clinical response by further augmenting Treg and the Treg;Tcon ratio early in the course of cGVHD is worth exploring. Figure 1 Figure 1. Disclosures Koreth: Prometheus Laboratories Inc: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Takeda Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Low-dose Interleukin-2 for immune tolerance. Chen:Bayer Pharmaceuticals, Inc.: Other, Research Funding. Avigan:Astex Pharmaceuticals : Research Funding.

In many countries, relationship between decentralization of government activities and the extent of rent extraction by private parties is an important element in the recent debate on institutional design. The topic of corruption was actively, openly and debated in Indonesia by government, its development partners, and a broadly based group of political and civil society leaders are engaged in meetings and exchange on a daily basis. In the ongoing debate on corruption a lot of attention is paid to the role of public sector salaries, particularly in the decentralization era. Based on this phenomenon, the authors want to analyze the relationship between corruption and decentralization. Using OSL model, we can find a very strong and consistent positive association between the two variables across a sample of region, thereby providing some support for theories of decentralization that emphasize its benefits. This association is robust to controlling for a wide range of potential sources of omitted variable bias as well as endogeneity bias. Keywords: Corruption, Decentralization, OSL Model Abstrak.Di banyak negara, hubungan antara desentralisasi pemerintah dan tingkat ekstraksi sewa oleh pihak swasta merupakan elemen penting dalam perdebatan baru pada desain institusional. Topik korupsi secara aktif, terbuka dan diperdebatkan di Indonesia oleh Pemerintah, mitra pembangunan, dan kelompok berbasis luas dari para pemimpin politik dan masyarakat sipil yang terlibat dalam pertemuan dan pertukaran setiap hari. Dalam perdebatan tentang korupsi banyak perhatian diarahkan untuk peran gaji sektor publik, terutama di era desentralisasi. Berdasarkan fenomena ini, penulis ingin menganalisis hubungan antara korupsi dan desentralisasi. Menggunakan OSL model, kita dapat menemukan hubungan positif yang sangat kuat dan konsisten antara dua variabel di seluruh sampel dari daerah, sehingga memberikan beberapa dukungan untuk teori desentralisasi yang menekankan manfaat. Asosiasi ini adalah kuat untuk mengendalikan berbagai kemungkinan potensial dari upaya menghilangkan sebagian variabel serta bias endogenitas. Kata Kunci: Korupsi, Desentralisasi, OSL Model REFERENCES,Ades, Alberto and Di Tella, Rafael, 1994, “Competition and corruption” Institute of Economics and Statistics Discussion Papers 169. University of Oxford.____, 1995, “National champions and corruption: some unpleasant competitiveness arithmetic”.University of Oxford. Photocopy.Barro, Robert, 1992, “Human capital and economic growth”. in policies for long run economic growth. 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Washington, DC: International Monetary Fund.Hines, James, 1995, “Forbidden payment: foreign bribery and american business.” NBER Working Papers 5266. Cambridge, MA: National Bureau of Economic Research.Keefer, Philip, and Stephen Knack, 1995, “Institutions and economic performance: cross-country tests using alternative institutional measures.” Economics and Politics.Kraay, Aart, and Van Rijckeghem, Caroline, 1995, “Employment and wages in public sector-a cross-country study.” IMF Working Papers 95/70. Washingtin, DC: International Monetary Fund.Krueger, Anne, 1974, “The Political economy of the rent-seeking society.” American Economic Review 64, No.3 (June): 291-303.Levine, Ross and David Renelt, 1992, “A sentivity analysis of cross-country growth regressions.” American Economic Review 82, No.4 (September): 942-963.Loayza, Norman, 1996, “The economics of informal sector: a simple model and some empirical; evidence from Latin America.” The World Bank. Photocopy.Martinez. Jorge-Vazquez, F. Javier Arze, Jameson Boex, 2004, “Corruption, fiscal policy and fiscal management, USAID Report (October).Mauro, Paolo, 1995, “Corruption and growth.” Quarterly Journal of Economics CX, no.3 (August): 681-712._____, 1997, “The Effect of Corruption on growth, investment and government ex-penditure: a cross country analysis, in Corruption and the global economy, K.A. Elliot, ed., Eashington D.C., Institute for International Economics, pp.83-107._____, 1998, corruption and the composition of government expenditure, Journal of Public Economics, vol.69:263-279.Megantara, Andie and Noor Fuad, 2003, “The impact of institutional environment on public official performance: does institutional environment affect the rate of corruption?”, Jurnal Keuangan Publik vol.1, no.1 (September):1-23.Murphy, Kevin, Andrei Shleifer and Robert Vishny, 1991, “Allocation of talent: implications for growth.” Quarterly Journal of Economics, 106.Raunch, James, 1995, “Bureaucracy, infrastructure and economic growth: evidence from U.S. Cities During the Progressive Era.” American Economic Review 85, no.4 (September): 968-979.Rose-Ackerman, Susan, 1978, Corruption: a study in political economy, New York, NY: Academic Press._____, 1996, Democracy and grand corruption, International Social Science Journal, vol.48. no.3._____, 1997, Corruption and development, Paper presented at the annual Bank Conference on Development Economics, Washington D.C._____, 1999, Corruption and government: causes, consequences and reform, Cambridge University Press.Sachs, Jeffrey, and Warner, Andrew, 1995, “Natural resource abundance and economic growth.” NBER Working Papers 5398. 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Introduction: Iron deficiency anemia (IDA) not responding to oral iron replacement usually requires a hematologic evaluation. 48 patients taking a proton pump inhibitor (PPI) and not responding to oral iron replacement were found to have an elevated serum gastrin (SG). No patient had gastrointestinal bleeding, gastric resection, bariatric surgery, or menorrhagia. Other causes for iron malabsorption such as celiac disease or helicobacter infection were not present. 94 percent responded to intravenous iron (IV iron). Methods: All patients previously had undergone diagnostic gastrointestinal evaluations. Testing for celiac disease and helicobacter infection was negative. Gastric biopsies did not demonstrate atrophy. Most referrals were from gastroenterologists. Results: 94% responded to IV iron with a rise in their hemoglobin of &gt;/= 2 grams per cent. 83 percent (40/48) were women. Iron dextran (ID) at a fixed dose of 825 mgm was given to 85% of the patients. Twelve of these 41 patients were given a second infusion of ID as the first dose did not produce a satisfactory response. Ferric carboxymaltose and ferumoxytol were each given once at the fixed recommended dose, and second infusions was not necessary. Four patients received iron sucrose at a weight based dose, and a second series of infusions were not necessary. One patient responded to ferumoxytol after a suboptimal response to iron dextran. An elevated SG was defined as &gt;100 pg/mL. The average SG was 370.25 pg/mL (114 to 2101 pg/mL). Hemoglobin rose an average of 3.35 gram% (9.56 to 12.91 gm%). The change in hemoglobin was minus 0.4 to plus 7.0 gm% with a baseline hemoglobin ranging between 6.6 to 14.3 gm% and rising between 9.3 to 16.2 gram%. Ferritin rose an average of 14.8 to 158 ng/mL with baseline ferritin ranging between 3 to 73 ng/mL and rising between 22 to 659 ng/mL The average MCV rose from 75.89 to 84.93 fL with baseline MCV ranging between 61 to 93 fL rising between 69 to 96 fL The average iron saturation rose from 7.49 to 22.89% with baseline saturation ranging between 2 to 34% and rising between 10 to 39%. Discussion: Dietary iron consists of both heme and non heme iron. Heme iron is derived from the hemoglobin and myoglobin in animal food sources such as meat, seafood, and poultry. Heme iron is in the ferrous (II) oxidation state, is easily absorbable, and contributes 10% or somewhat more of total absorbed iron. Non heme iron is in the ferric (III) form and is derived from plants and iron fortified food. Normally 1-2 mgm of iron is absorbed daily. Heme iron is well absorbed after its release by pancreatic enzymes. Non heme iron is less well absorbed and requires acid secretion from gastric parietal cells for the denaturing of ingested proteins and subsequent proteolysis. PPI causes decreased hydrogen ion (H+) production by inhibiting the hydrogen/potassium pump within gastric parietal cells. The elevated SG derives from G cell hyperplasia as a response to the lowered H+ activity caused by PPI. The decreased H+ activity inhibits the release of ferric iron from non animal sources. Iron absorption occurs in the proximal duodenum through the action of a brush border ferrireductase such as duodenal cytochrome B which reduces ferric iron to ferrous iron. With less ferric iron available for reduction less ferrous iron is absorbed, and iron deficiency results. Intravenous iron fully corrected the IDA in 94% of treated patients. Two of the 3 non responders were obese and only received one infusion of ID. Perhaps a second infusion might have been beneficial. However no relation between weight, response, and ID dosing could be detected. Both patients had normal hemoglobins before the iron infusion but were very symptomatic from their iron deficiency. Both patients experienced a rise in their hemoglobin (1.9 gram% and 1.4 gm%). The third non responder actually had a fall in the hemoglobin from 10.5 to 10.1 gm%. No clear explanation was apparent. No clear explanation for the female predominance was apparent. Conclusion: In 2009 119 million prescriptions for PPI were written in the USA. The gastrointestinal literature suggests that anemia from PPI is uncommon. Very likely IDA due to IM from PPI is much more common than recognized and should be considered for any iron deficient patients without evidence for other causes for IDA. Intravenous iron is highly effective. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction There has been dramatic evolution in multiple myeloma (MM) therapy in the last decade. The novel agents (Thal, Bor, and Len) have been reported to improve natural history of the cases with MM. In order to use optimal drugs for each patient, we should investigate the actual conditions of the clinical practice. However, we could not have the information regarding epidemiology, clinical features, treatment results, prognosis, and so on because there is no large-scale database demonstrating the clinical features of MM-related diseases in Japan. Therefore, we have founded the study group, named as Kansai Myeloma Forum (KMF), for the purpose of registering the cases with MM-related diseases in Kansai area of Japan on November, 2012. In this study, we analyzed the clinical characteristics and outcomes of MM-related diseases registered in KMF and evaluated the treatment strategies in the novel agent era. Patients & Results Among a total of 923 cases initially diagnosed since 2006 and registered to KMF database until March 31, 2013, we analyzed 434 symptomatic MM cases (213 females/221 males), who were treated since 2006. The median age was 69 (range: 32-96), and the OS rates at 3 and 5 years were 68.7% and 45.3%, respectively. The prognosis of the cases treated after 2010 became significantly better than that of the cases treated between 2006 and 2009 (log-rank test: P=0.019). The prognosis of the cases treated with the novel agents was significantly better than without them (p=0.005). Among the non-transplanted 339 cases, the effects of the novel drugs were shown more clearly (p=0.002). The best response during the course differentiated the prognosis; the hazard ratios of CR, VGPR, PR, SD and PD compared to sCR were 2.23, 3.19, 9.54, 16.84 and 432.01, respectively (P<0.001). Ninety-five cases received the high-dose melphalan therapy (HD-MEL) with stem cell support. The OS rate of these 95 cases was significantly better than that of non-transplanted 339 cases (90.1% at 3-year/61.4% at 5-year vs. 61.6%/40.2%, p<0.001). CR/sCR rate after HD-MEL was 50%. Also, 83 out of 95 cases received at least one of the novel agents during their clinical courses, and 51 cases achieved CR/sCR as best response, showing significant better survival than the cases with best response of VGPR or <PR (p=0.008). The superiority of OS in HD-MEL group was also observed even when less than 65 years old patients (74 out of 95 patients) were compared to 55 patients (≤ 65 years) without HD-MEL but receiving novel agents (90.6% at 3-year/71.4% at 5-year vs. 73.6%/47.3%, p=0.036). Next, we analyzed 123 cases with MGUS and 54 with smoldering MM (SMM), who had diagnosed in 2006 or later. The median age at diagnosis was 66.0 (range: 34-88) in 123 MGUS cases (53 females/70 males). The type of paraprotein detected was IgA in 15.4% of the cases and IgG in 69.1 %. With a median follow-up period of 27.2 months, 8 cases (6.5%) received chemotherapies due to the disease evolution. The evolution rates at 1, 3 and 5 years after the diagnosis were 2.1%, 9.0% and 12.0%, respectively (2.4% per year). The 3-year OS after the start of treatments was 75.0%. In 54 SMM cases (29 females/25 males), the median age was 68.2 (range: 40-87), and IgG and IgA types comprised 72.2% and 14.8%, respectively. With a median follow-up period of 22.4 months, 15 cases (27.8%) received chemotherapy due to progression to symptomatic MM. The evolution rates at 1, 3 and 5 years after diagnosis were 15.4%, 36.7% and 62.5%, respectively (12.5% per year). The 3-year OS after the start of treatments was 76.9%. Discussion & Conclusion The current study revealed the significant effects of novel agents on symptomatic MM cases in the practical use. It has been still unknown and controversial whether HD-MEL with auto-PBSCT is necessary or not in the novel agent era. In this analysis, it was shown that HD-MEL could provide significant survival benefit to symptomatic MM cases even in the novel-agent era. However, it is necessary to determine when and how we should perform HD-MEL for MM during therapeutic sequences including novel agents. This study also suggested that it might be unnecessary to generally consider an early chemotherapy to MGUS or SMM cases before the evolution, since the prognosis after the evolution seemed not to be inferior to that of the de-novo symptomatic MM. Thus, KMF database would provide abundant and beneficial information to consider the treatment strategies of the cases with MM-related diseases. Disclosures: Tanaka: celgene: Research Funding. Kosugi:Janssen: Honoraria; celgene: Research Funding. Kida:celgene: Research Funding. Ohta:celgene: Research Funding. Yamamura:celgene: Research Funding. Shibayama:Janssen: Honoraria; celgene: Honoraria, Research Funding. Kohara:celgene: Research Funding. Kaneko:celgene: Research Funding. Fuchida:celgene: Research Funding. Kobayashi:celgene: Research Funding. Miyamoto:celgene: Research Funding. Shindo:celgene: Research Funding. Kuroda:celgene: Research Funding. Uoshima:celgene: Research Funding. Matsumura:celgene: Research Funding. Yoshii:celgene: Research Funding. Kamitsuji:celgene: Research Funding. Boku:celgene: Research Funding. Ishii:celgene: Research Funding. Matsuda:celgene: Research Funding. Takahashi:celgene: Research Funding. Hamada:celgene: Research Funding. Adachi:celgene: Research Funding. Nakatani:celgene: Research Funding. Nomura:celgene: Research Funding. Taniwaki:celgene: Research Funding. Takaori:celgene: Research Funding. Shimazaki:celgene: Research Funding. Tsudo:celgene: Research Funding. Hino:celgene: Research Funding. Matsumura:Janssen: Honoraria, Research Funding; celgene: Research Funding. Kanakura:celgene: Research Funding.

Abstract Objectives Despite azacitidine prolonging the survival of patients (pts) with myelodysplastic syndromes (MDS), the overall survival (OS) of those with complex karyotype (CK) or monosomal karyotype (MK) remains dismal, and optimal treatments for these pts have not been established. Furthermore, the prognostic impact of acquisition of additional cytogenetic abnormalities (ACA) during the follow-up periods is poorly understood. In this retrospective study, we aimed to evaluate the prognostic impact of CK, MK, and ACA in MDS pts, and determine optimal treatments. Methods We collected clinical data on consecutive adult MDS pts who first visited Kobe City Medical Center General Hospital or Kyoto University Hospital between January 2004 and April 2014. Patients were divided into groups based on the number of chromosomal abnormalities (abns) and presence or absence of MK. ACA was defined as any gain in the number of chromosomal abns before treatments. Survival analysis was adjusted using the following variables; sex, age, IPSS-R parameters and MK. A Cox regression model was applied to the results. ACA was fit into the model as a time-dependent covariate. Results A total of 299 pts with MDS were identified, five of which were excluded from the study due to a lack of chromosomal information. Median follow-up time was 24.5 months (M). Pts' characteristics, treatments and incidence of ACA are summarized in Table 1. Among 47 CK pts, 34 (72%) carried MK. Survival analysis revealed that presence of 4 or more chromosomal abns was significantly associated with increased mortality. Among pts with 2–3 chromosomal abns, the presence of MK was a poor prognostic factor, although it had no significant impact on survival in pts with 4 or more abns (Figure 1). Median survival times of pts with 2–3-abns without MK, with 2–3-abns together with MK, and 4 or more abns were 39 M, 12 M (HR 6.6, 95% confident interval, [2.6-17], p < 0.001), and 9 M(HR 5.4, [3.1–9.3], p < 0.001) respectively. Regarding ACA, changes from normal karyotype (NK) to 1 abn (N=15) had no effect on mortality, but changes from NK to 2 or more abns (N=10) led to a significant increase in mortality (HR 9.2 [3.7–24], p < 0.001). Further, changes from 0–3 chromosomal abns without MK to either MK or 4 or more abns were associated with higher mortality (HR 2.7 [1.0–7.1], p = 0.045). Among pts with 2–3-chromosomal abns with MK or those with 4 or more abns at diagnosis (N=45) or during follow-up (N=10), 20 (36%) underwent allogeneic stem cell transplantation (allo-SCT) and only six survived beyond 24 M. Five of these received allo-SCT and were alive at the last follow-up. The other was treated with azacitidine and lived for 33 M. Conclusion This study revealed that MK or 4 or more chromosomal abns is significantly associated with high mortality. Among NK pts, acquisition of 2 or more abns was associated with a poor outcome. Allo-SCT is the only strategy to increase the chance of long-term survival for pts with MK or 4 or more chromosomal abns, although only a few survivors were identified even after allo-SCT. More data are needed to identify the optimal therapeutic options for this subgroup. Table 1 Clinical parameters and treatments received by patients Number of abnormalities <3 (N=247) (%) 3 (N=10) (%) 4<= (N=37) (%) p-value Sex (male/female) (N=195/99) 170(69)/77(31) 4(40)/6(60) 21(57)/16(43) 0.04 Age =<65 (N=158) >65 (N=136) 130(53) 117(47) 7(70) 3(30) 21(57) 16(43) 0.89 Bone marrow blast% <=2 (N=123) >2-<5 (N=45) >=5-<=10 (N=50) >10 (N=74) Missing (N=2) 112(45) 35(14) 39(16) 59(24) 2(0.81) 4(40) 3(30) 2(20) 1(10) 0 7(19) 7(19) 9(24) 14(38) 0 0.06 Hemoglobin (g/dL) >=10 (N=91) >=8-<10 (N=93) <8 (N=106) Missing (N=4) 83(34) 72(29) 88(36) 4(1.6) 3(30) 5(50) 2(20) 0 5(14) 16(43) 16(43) 0 0.076 Platelets (103/ƒÊL) >=100 (N=118) >50-<100 (N=82) <50 (N=90) Missing (N=4) 100(40) 68(28) 75(30) 4(1.6) 6(60) 1(10) 3(30) 0(0) 12(32) 13(35) 12(32) 0 0.50 Neutrophils (/ƒÊL) >=800 (N=183) <800 (N=106) Missing (N=5) 160(65) 82(33) 5(2.0) 5(50) 5(50) 0 18(49) 19(51) 0 0.078 Monosomal karyotype (N=39) 5(2) 3(30) 31(79) <0.001 ACA (N=37) 30(12) 1(10) 6(16) 0.7 Initial treatments CC (N=92) azacitidine (±CC) (N=63) Chemo-naïve allo-SCT (N=37) Palliative CT/BSC (N=102) 78(32) 43(17) 31(13) 95(38) 1(10) 3(30) 3(30) 3(30) 13(35) 17(46) 3(8) 4(11) <0.001 Allo-SCT (total) 79(32) 7(70) 13(35) 0.77 Figure 1 Kaplan-Meier curves in groups divided by chromosomal abnormalities Figure 1. Kaplan-Meier curves in groups divided by chromosomal abnormalities Disclosures No relevant conflicts of interest to declare.

BackgroundBimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A. In a phase 2b study, BKZ showed rapid and sustained efficacy and was well tolerated up to 156 weeks (wks) in patients (pts) with active ankylosing spondylitis (AS).1,2ObjectivesTo assess efficacy and safety of BKZ vs placebo (PBO) in pts with active AS up to Wk 24 in the ongoing pivotal phase 3 study, BE MOBILE 2.MethodsBE MOBILE 2 (NCT03928743) comprises a 16-wk double-blind, PBO-controlled period and 36-wk maintenance period. Pts were aged ≥18 yrs, met modified New York criteria and had active AS (BASDAI ≥4, spinal pain ≥4) at BL. Pts were randomised 2:1, BKZ 160 mg Q4W:PBO. From Wk 16, all pts received BKZ 160 mg Q4W. Primary and secondary efficacy endpoints were assessed at Wk 16.ResultsOf 332 randomised pts (BKZ: 221; PBO: 111), 322 (97.0%) completed Wk 16 and 313 (94.3%) Wk 24. BL characteristics were comparable between groups: mean age 40.4 yrs, symptom duration 13.5 yrs; 72.3% pts male, 85.5% HLA-B27+, 16.3% TNFi-experienced. At Wk 16, the primary (ASAS40: 44.8% BKZ vs 22.5% PBO; p<0.001) and all ranked secondary endpoints were met (Table 1). Responses with BKZ were rapid, including in PBO pts who switched to BKZ at Wk 16, and increased to Wk 24 (Figure 1; Table 1). Substantial reductions of hs-CRP by Wk 2 and MRI SIJ and spine inflammation by Wk 16 were achieved with BKZ vs PBO (Table 1). At Wk 24, ≥50% pts had achieved ASDAS <2.1 (Figure 1).Table 1.Efficacy at Wks 16 and 24BLWk 16Wk 24PBO N=111BKZ 160 mg Q4W N=221PBO N=111BKZ 160 mg Q4W N=221p valuePBO→BKZ 160 mg Q4W N=111BKZ 160 mg Q4W N=221Ranked endpoints in hierarchical orderASAS40* [NRI] n (%)--25 (22.5)99 (44.8)<0.00163 (56.8)119 (53.8)ASAS40 in TNFi-naïve† [NRI] n (%)--22 (23.4)a84 (45.7)b<0.00156 (59.6)a100 (54.3)bASAS20† [NRI]n (%)--48 (43.2)146 (66.1)<0.00185 (76.6)159 (71.9)BASDAI CfB† [MI] mean (SE)6.5 (0.1)6.5 (0.1)–1.9 (0.2)–2.9 (0.1)<0.001–3.3 (0.2)–3.3 (0.1)ASAS PR† [NRI]n (%)--8 (7.2)53 (24.0)<0.00128 (25.2)56 (25.3)ASDAS-MI† [NRI] n (%)--6 (5.4)57 (25.8)<0.00143 (38.7)67 (30.3)ASAS 5/6† [NRI]n (%)--16 (14.4)94 (42.5)<0.00157 (51.4)107 (48.4)BASFI CfB† [MI] mean (SE)5.2 (0.2)5.3 (0.2)–1.1 (0.2)–2.2 (0.1)<0.001–2.2 (0.2)–2.4 (0.2)Nocturnal spinal pain CfB† [MI]mean (SE)6.8 (0.2)6.6 (0.1)–1.9 (0.2)–3.3 (0.2)<0.001–3.7 (0.3)–3.8 (0.2)ASQoL CfB† [MI] mean (SE)8.5 (0.4)9.0 (0.3)–3.2 (0.3)–4.9 (0.3)<0.001–4.9 (0.4)–5.4 (0.3)SF-36 PCS CfB† [MI] mean (SE)34.6 (0.8)34.4 (0.6)5.9 (0.8)9.3 (0.6)<0.00110.6 (0.8)10.8 (0.6)BASMI CfB† [MI] mean (SE)3.8 (0.2)3.9 (0.1)–0.2 (0.1)–0.5 (0.1)0.005–0.5 (0.1)–0.6 (0.1)Other endpointsnEnthesitis-free state†c [NRI]n (%)--22 (32.8)d68 (51.5)e-33 (49.3)d70 (53.0)eASAS40 in TNFi-experienced [NRI]n (%)--3 (17.6)f15 (40.5)g---ASDAS-CRP CfB [MI]mean (SE)3.7 (0.1)3.7 (0.1)–0.7 (0.1)–1.4 (0.1)-–1.7 (0.1)–1.6 (0.1)hs-CRP (mg/L) [MI] geometric mean (median)6.7 (6.3)6.5 (8.2)6.0 (6.3)2.4 (2.4)-1.9 (2.2)2.1 (2.3)MRI spine Berlin CfBh [OC] mean (SD)3.3 (4.9)i3.8 (5.3)j0.0 (1.4)k–2.3 (3.9)l---SPARCC MRI SIJ score CfBh [OC] mean (SD)5.8 (7.7)i7.4 (10.7)m1.1 (6.9)k–5.6 (9.9)l---Randomised set. *Primary endpoint; †Secondary endpoint; an=94; bn=184; cMASES=0 in pts with BL MASES >0; dn=67; en=132; fn=17; gn=37; hIn pts in MRI sub-study; in=45; jn=82; kn=43; ln=79; mn=83; nNominal p values not shown.Over 16 wks, 120/221 (54.3%) BKZ pts had ≥1 TEAE vs 48/111 (43.2%) PBO; three most frequent on BKZ were nasopharyngitis (BKZ: 7.7%; PBO: 3.6%), headache (4.1%; 4.5%) and oral candidiasis (4.1%; 0%). No systemic candidiasis was observed. Up to 16 wks, incidence of SAEs was low (1.8%; 0.9%); no MACE or deaths were reported; 2 (0.9%) IBD cases occurred in pts on BKZ.ConclusionDual inhibition of IL-17A and IL-17F with BKZ in pts with active AS resulted in rapid, clinically relevant improvements in efficacy outcomes vs PBO. No new safety signals were observed.1,2References[1]van der Heijde D. Ann Rheum Dis 2020;79:595–604; 2. Gensler L. Arthritis Rheumatol 2021;73(suppl 10):0491.AcknowledgementsThis study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of InterestsDésirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer, UCB Pharma, Employee of: Imaging Rheumatology BV (Director), Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB Pharma, Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB Pharma, Maxime Dougados Consultant of: AbbVie, Eli Lilly, Novartis, Merck, Pfizer, and UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, Novartis, Pfizer, and UCB Pharma, Matt Brown Speakers bureau: Novartis, Consultant of: Pfizer, Clementia, Ipsen, Regeneron, Grey Wolf Therapeutics, Grant/research support from: UCB Pharma, Denis Poddubnyy Speakers bureau: AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, and UCB Pharma, Consultant of: AbbVie, Biocad, Eli Lilly, Gilead, GSK, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB Pharma, Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Filip van den Bosch Speakers bureau: AbbVie, Bristol Myers-Squibb, Celgene, Janssen, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer and UCB Pharma, Nigil Haroon Consultant of: AbbVie, Amgen, Janssen, Merck, Novartis and UCB Pharma, Huji Xu: None declared, Tetsuya Tomita Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly, Janssen, Kyowa Kirin, Mitsubishi-Tanabe, Novartis, and Pfizer, Consultant of: AbbVie, Eli Lilly, Gilead, Novartis, and Pfizer, Lianne S. Gensler Consultant of: AbbVie, Eli Lilly, Gilead, GSK, Novartis, Pfizer, and UCB Pharma, Grant/research support from: Novartis, Pfizer, and UCB Pharma; paid to institution, Marga Oortgiesen Employee of: UCB Pharma, Carmen Fleurinck Employee of: UCB Pharma, Thomas Vaux Employee of: UCB Pharma, Alexander Marten Employee of: UCB Pharma, Atul Deodhar Speakers bureau: Janssen, Novartis, and Pfizer; consultant of AbbVie, Amgen, Aurinia, BMS, Celgene, Eli Lilly, GSK, Janssen, MoonLake, Novartis, Pfizer, and UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, and UCB Pharma.

Abstract Background . Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells are a major therapeutic advance in the management of patients (pts) with relapsed/refractory aggressive B-cell lymphoma (R/R aggressive BCL) with reported overall response rates between 40% and 83% in the pivotal trials (ZUMA1, JULIET, TRANSCEND) as well as in the real-life cohorts with either axicabtagene ciloleucel (axi-cel, Yescarta) or tisagenlecleucel (tisa-cel, Kymriah). However, a significant number of pts will experience progression or relapse after infusion with an estimated 24-month progression-free survival (PFS) of between 33% and 42%. DESCAR-T is a nationwide registry that aims to collect real-life data for all pts treated with commercialized CAR T-cells in France. It represents a unique opportunity to investigate the outcome of pts who relapse after CAR T-cell therapy. Patients and Methods . In all, 680 pts with R/R aggressive BCL were registered in DESCAR-T from August 2018 and 550 were infused at the time of the present analysis (April 12, 2021) with either axi-cel (n=350) or tisa-cel, n=200). All pts gave informed informed consent before DESCAR-T registration. Progression and relapse after CAR T-cells were defined based on the Cheson 2014 response assessment criteria. Results . With a median follow-up (F-up) of 7.9 months, 238 pts (43.3%) out of 550 treated pts relapsed, after axi-cel in 136 pts (F-up = 9.0 months [5.1 - 9.7]) and after tisa-cel in 102 pts (F-up = 7.8 months [5.9 - 10.4]). Histological subtypes were DLBCL (n 178, 74.8%), PMBL (n=11, 4.6%), HGBCL (n= 3, 1.3%), transformed follicular lymphoma (tr FL) (n=31, 13%), or other histologies (FL n=2, PCNSL n=1, tr MZL n=3, unclassifiable hodgkin/DLBCL n=9). At time of registration, median age was 62 years (range 18;77), 43.6% were aged &gt;65 yrs, and 67.2% were male; 184 (79.7%) presented with advanced disease (stage III or IV), and 13 (5.9%) with low age-adjusted International Prognostic Index (aaIPI), 82 (37.1%) with low-intermediate aaIPI, 110 (49.8%) with high-intermediate aaIPI, and 16 (7.2%) with high aaIPI. At time of CAR T-cell infusion, 36 (18.9%) pts presented with ECOG PS &gt;=2 and 72 (38.9%) with an elevated LDH level. The median number of lines prior to CAR T-cell infusion was 3 (range 2-9), including 48 (20.1%) transplant (46 auto-HSCT and 2 allo-HSCT). Median time between order and infusion was 50 days (IQR 43; 59). Bridging therapy was administered to 87.8% of the pts, with a high-dose regimen including combined immunochemotherapy for 84.5% of the pts. Failure after CAR T-cells occurred after a median time of 2.71 months (range 0.2; 21.5), 54 (22.7%) being during the first month after infusion (&lt; M1) and 156 (65.5%) during the first-three months after infusion (&lt;M3). At failure, 154 (64%) patients received treatments that maybe combined and described as followed : 70 (45.5%) lenalidomide, 70 (45.5%) various immunotherapies (rituximab, daratumomab, polatuzumab), 31 (20.1%) a combined immunochemotherapy with various regimens (R-DHAX, RICE, Pola-R-Benda,...), 21 (13.6%) an anti-PD1 immune checkpoint inhibitor (Nivolumab, pembrolizumab), 11 (7.1%) bi-specific T-cell engagers (TCE), 18 (11.7%) radiotherapy, and 3 a transplant (1 an auto-HSCT and 2 an allo-HSCT). The overall response rate to the salvage therapy after CAR T-cells was 11% (complete response rate 5.2%). The median PFS was 2.8 months (95% CL, 2.4 -3.1). The median overall survival (OS) was 5.2 months (95% CL, 4.1- 6.6) (Figure 1A). The median OS was even shorter in pts who failed during the first month (1.9 months [95% CL, 1.1- 3.2] vs 6.7 months [95 CL 5.5 : 9.3] p&lt;0.0001) (Figure 1B). 26.9% of the pts in the overall cohort were alive at 6 months, but only 18.9% were alive in the group of pts relapsing during the first month. In multivariate analysis, predictors of OS were high LDH level at time of infusion, time to failure &lt; 1 month after CAR T-cells, no access to immuno-oncology treatment such as TCE or lenalidomide. Conclusion . This study is the first analysis reporting the outcome of patients with R/R aggressive BCL relapsing after anti-CD19 CAR T-cells. These results demonstrate the poor outcome of these pts and identifies the need for further innovative treatment strategies. Figure1. Overall survival from the CAR T-cell infusion in patients with R/R LBCL relapsing after CAR T-cells. (A) overall population. (B) according to the interval between CAR T-infusion and relapse (&lt; 1 month and &gt; 1 month) Figure 1 Figure 1. Disclosures Di Blasi: Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Le Bras: Takeda: Honoraria, Research Funding; Kite Gilead: Honoraria; Novartis: Honoraria; Celgene BMS: Research Funding. Feugier: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Mohty: Amgen: Honoraria; Jazz: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Adaptive Biotechnologies: Honoraria. Sesques: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Chugai: Honoraria. Morschhauser: Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees.

E-learning is aptly a practical response to continuous learning given the surge in the use of information technology, and economic disruptions impinging on the schools. The need to shift to e-learning has been exacerbated by the COVID-19 pandemic. In this regard, we sought to develop an organizational assessment instrument to internally ascertain the level of readiness of the school for sustainable e- learning in the new normal. This assessment instrument was primarily developed for the use of the Mendiola Consortium member schools in their pursuit to conduct elearning. We intended that as an internal self-assessment it can diminish the threat of failure and provide some assurance of the successful implementation of e-learning. We noted that many survey instruments had been made to assess organizational readiness as a construct for e-learning. However, it revealed that these instruments have varying limitations in validity and reliability to establish the domains of organizational readiness for e-learning. We anchored our study on the organizational readiness model developed by Schreurs and Al-Huneidi (2012) and Mercado (2002). From our review of related literature, we were able to generate seven basic dimensions of our model, namely: teacher, student, curriculum, technology, administrative support, financial support, and learning environment. We used a mixed method of qualitative and quantitative approach to come up with a validated instrument. We conducted a three-phase approach in developing the instrument. The final instrument yielded 45 items to be rated on a five-point Likert scale. For its content validity, the Item-Content Validity Index ranged from 0.91 to 0.96, while the Scale-Content Validity Index was 0.94. It has a Cronbach alpha of .975 for its reliability. ReferencesAlok , Kumar (2011). 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Background: Localized hypersensitivity (HS) has been reported as a pathologic risk factor for late DES thrombosis (DES-LST). The objectives of the study were to examine the pathologic features of HS in DES-LST and correlate with stent characteristics, underlying plaque morphologies and patient risk factors. Materials and methods: From a registry of 153 DES patients, 33 patients with DES-LST were identified. LST was defined as platelet-rich thrombus in a coronary stent implanted > 30 days. Stented arteries were serially sectioned at 2–3 mm intervals and stained with H&E, Movat stain, Luna stain (eosinophils), and UCHL (T-lymphocytes). Localized HS was defined as an inflammatory cell infiltrate composed predominantly of eosinophils and T-lymphocytes limited to the arterial wall surrounding the stent. Patient data, risk factors, stent characteristics, and underlying plaque morphology were compared between two groups: hypersensitivity (HS), and non-hypersensitivity LST (NHS). Results: Of the 33 DES-LST cases with occlusive thrombus, 6 (4 men, 2 women) demonstrated HS histologically (18%). The mean age was 54 years (range 40 – 62 years). All 6 had Cypher stents (mean stent length=24 mm), 4 had >1 stent, 2 with overlapping stents. The mean stent duration was 624 days (range 112 to 990 days). Three patients were on ASA and clopidogrel, 2 ASA only, 1 discontinued ASA/clopidogrel prior to non-cardiac surgery. Patient risk factors included hyperlipidemia (n=6), hypertension (n=5) and smoking (n=4). All demonstrated underlying fibroatheroma with stent struts penetrating necrotic core in 3 and 2 with previous rupture sites. Stent malapposition was present in 5 (83%). Twenty-seven patients demonstrated NHS-LST (Cypher=7, Taxus=20). Mean stent duration was 326 days (range 31–1200 days). Malapposition was identified in 10 (37%). Compared to NHS, the HS LST group was more likely to demonstrate stent malapposition (p=0.04) and longer implant times (p=0.049). Conclusions: DES-LST is related to HS in 18% of cases, is associated with Cypher stents, malapposition and longer implantation time. Localized HS with stent thrombosis is a clinically important problem that may occur late after stenting and warrants further pathologic study.

Long-term prognosis following exclusion of coronary artery stenosis by noninvasive coronary angiography using multislice computed tomography (MSCT) up to now has not been determined. We therefore performed noninvasive coronary angiography using MSCT (Philips Brilliance, 4 – 64 slices, retrospective ECG gating, 0.625mm collimation, 0.4sec gantry rotation time) in 1017 consecutive patients (657 male, 360 female, age 64±11years, 240 patients with known coronary artery disease (CAD)) referred to MSCT-study with chest pain. Patients with acute coronary syndromes, stents, atrial fibrillation and calcium scores > 1500 were not included. Based on MSCT results invasive study was recommended or not. All patients or the referring clinician were contacted by telephone or mail at least 6 months after their scan. Diagnostic image quality could be obtained in 992/1017 (98%) patients. In 620 of 992 patients (=63%) coronary artery stenosis could be excluded and invasive study was not recommended. Despite these recommendations invasive study was performed due to other clinical indications in 83/620 patients within < 30 days and in 43/537 patients within > 30days after the scan. Only in 13/126 patients stenoses >50% were found but no treatment was necessary. During the mean follow-up period of 612±192days 7/620 patients died but no patient suffered from cardiac death or acute myocardial infarction. In 372 of 992 patients invasive coronary angiography was recommended and performed in 230 patients (n=167 within < 30days, n=63 within >30days). In 165/230 patients stenoses >50% were found, treated by angioplasty or stents in 139/165 patients. During the mean follow-up period of 602±161days 11/372 patients died, two patients suffered from sudden, two patients from non-sudden cardiac death and one patient survived acute myocardial infarction. Thus, exclusion of coronary artery stenoses by noninvasive coronary angiography using multislice computed tomography determines a good lomg-term prognosis in patients with chest pain.

Abstract Background The long-term prognosis of patients with hepatitis B virus–related acute-on-chronic liver failure (HBV-ACLF) is not well characterised. We assessed long-term outcomes and the associated risk factors of HBV-ACLF patients in southern China. Methods We retrospectively analysed clinical data, adverse events, and clinical endpoint events of HBV-ACLF patients treated at our department between January 2014 and December 2018. Results A total of 616 (52.3%) patients with cirrhosis and 561 (47.7%) patients without cirrhosis were included. In 973 (83%) patients, the disease was associated only with HBV, while 204 (17%) patients had two or more aetiological factors. The proportion of patients receiving antiviral treatment for HBV was low (20.3%). Further analyses indicated that patients without cirrhosis had a significantly lower 90-day liver transplantation–free mortality and higher 5‐year survival rate than those with cirrhosis (59.5% vs. 27.6%; 62% vs. 36%; P < 0.05). Remarkably, self-withdrawal of nucleos(t)ide analog (NA) was an independent risk factor for short-term prognosis. Age, cirrhosis at admission, and platelet level were closely related to long-term prognosis of HBV-ACLF patients. Conclusion The proportion of HBV-ACLF patients receiving antiviral treatment is very low in south China. Cirrhosis at admission has a significant effect on both short-term and long-term prognosis. No significant improvement in the short-term prognosis of HBV-ACLF patients was observed compared with previous studies. More comprehensive access to antiviral treatment and long-term surveillance of HBV patients are key imperatives to reduce the incidence of HBV-ACLF and improve the prognosis. Trial Registration The trial was registered at ClinicalTrials.gov (CT.gov identifier: NCT04231565) on May 13, 2020: https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0009OZY&selectaction=Edit&uid=U00036P1&ts=2&cx=27seqt

Abstract Background Acute respiratory infections (ARI) cause considerable morbidity and mortality worldwide, especially in children. Unfortunately, there are limited multi-center data on common viral respiratory infections in south China. Methods A total of 4403 nasal swabs were collected from children in 10 cities in Guangdong, China in 2019. Seven respiratory viruses, influenza A virus (IFA), influenza B virus (IFB), respiratory syncytial virus (RSV), adenoviruses (ADV) and parainfluenza virus types 1–3 (PIV1, PIV2 and PIV3), were detected by direct immunofluorescence antibody assay. The personal information and clinical characteristics were recorded and analyzed. Results The results showed that at least one virus was detected in 1099 (24.96 %) samples. The detection rates of RSV, IFA, ADV, PIV3, PIV1 and PIV2 were 7.13 % (314/4403), 5.31 % (234/4403), 4.02 % (177/4403), 3.04 % (134/4403), 1.70 % (75/4403) and 1.16 % (51/4403), respectively. The detection rate of RSV was highest in 0–6-month-old children at 18.18 % (106/583), while the detection rate of IFA was highest in 12–18-year-old children at 20.48 % (17/83). The total detection rates in winter and spring were 35.67 % (219/614) and 34.56 % (403/1166), higher than those in summer, 17.41 % (284/1631), and autumn, 19.46 % (193/992). Conclusions RSV and IFA were the main respiratory viruses in children. With increasing age the detection rate of RSV decreased in children, but the trends for the detection rates of IFA and IFB were the opposite. This study provided the viral etiology and epidemiology of pediatric patients with ARI in Guangdong, China.

Objective To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment. Methods A daily headache diary was completed during the 12-week, double-blind treatment phase of a placebo-controlled trial comparing erenumab 70 mg, 140 mg, and placebo, and weeks 1–12, 21–24, 37–40, and 49–52 of the open-label treatment phase. Chronic migraine to episodic migraine reversion rates were assessed over the double-blind treatment phase; persistent reversion to episodic migraine over 24 weeks (double-blind treatment phase through the first 12 weeks in the open-label treatment phase), long-term persistent reversion to episodic migraine over 64 weeks (double-blind treatment phase plus open-label treatment phase); delayed reversion to episodic migraine through the first 12 weeks of the open-label treatment phase among patients remaining in chronic migraine during the double-blind treatment phase. Results In the double-blind treatment phase, 53.1% (95% confidence interval: 47.8–58.3) of 358 erenumab-treated completers had reversion to episodic migraine; monthly reversion rates to episodic migraine were typically higher among patients receiving 140 mg versus 70 mg. Among 181 completers (receiving erenumab for 64 weeks), 98 (54.1% [95% confidence interval: 46.6–61.6]) had reversion to episodic migraine during the double-blind treatment phase; of those, 96.9% (95% confidence interval: 91.3–99.4) had persistent reversion to episodic migraine, 96.8% (95% confidence interval: 91.1–99.3) of whom had long-term persistent reversion to episodic migraine. Delayed reversion to episodic migraine occurred in 36/83 (43.4% [95% confidence interval: 32.5–54.7]) patients; of these, 77.8% (95% confidence interval: 60.9–89.9) persisted in reversion through week 64. Conclusions Patients with reversion to episodic migraine at week 12 will likely persist as episodic migraine with longer-term erenumab; others may achieve delayed reversion to episodic migraine. Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02066415

Abstract Funding Acknowledgements Type of funding sources: None. Background The specific and well-known design features of leadless pacing system (Micra Transcatheter Pacing System, M-TPS) have suggested his use in patients that previously underwent transvenous lead extraction (TLE) for any reason. The study aimed to investigate feasibility and long-term outcomes of M-TPS implant in patients underwent TLE. Methods Patients undergone M-TPS implantation in our Institution from May 2014 to September 2022 were included in the study. All patients fulfilled standard criteria for PM implantation (VVI or VDD mode). Follow-up (FU) was scheduled at discharge, after 1 month and every 6 months thereafter and electrical parameters were checked. Major complications were defined as life-threatening events, requiring surgical intervention or any event causing significant hemodynamic instability or resulting in death. Study population was divided between "naïve pacing" and "post-extraction" patients. Results We enrolled 193 patients (76.7% males), 57 (29.5%) received M-TPS implantation after TLE, needed because of infection in 91.4% of cases. Indications for pacing were permanent AF with bradycardia in 107 (55.5%) patients, complete AVB in 59 (30.5%), symptomatic sinus node dysfunction in 20 (10%), and advanced AVB or bifascicular bock in 7 (4%). There were no statistically significant differences between groups for demographics characteristics and primary PM implant indications, except mean age at implant that was significantly inferior in the post-extraction group [80 (IQR 75-84) vs 78 (IQR 72-83), p=0.04]. Implant procedure was successful in all and no complications were recorded. No differences between groups in procedure duration [40 (IQR 30-50) vs 45 (30-65) min, p=0.34], fluoroscopy time [9 (6-14) vs 9 (6-11) min, p=0.31] and single device delivery (64.9% vs 67.9%, p=0.35) were observed. The mean FU was 12 (1-36) months, maximum 8 years. Pacing variables at implantation [pacing threshold 0.5 (0.38-0.63) vs 0.5 (0.38-0.88) V/0.24 ms, p=0.15; impedance 720 (600-837) vs 675 (615-825) Ohm, p=0.51; R wave amplitude 9 (6.25-12.87) vs 8.2 (5.65-12) mV, p=0.47], discharge [pacing threshold 0.38 (0.38-0.63) vs 0.38 (0.38-0.63) V/0.24 ms, p=0.27; impedance 685 (580-770) vs 610 (560-750) Ohm, p=0.16; R wave amplitude 10.25 (7.2-14.5) vs 9.3 (6.5-16.5) mV, p=0.6], and at 6 months [pacing threshold 0.5 (0.38-0.5) vs 0.5 (0.38-1.25) V/0.24 ms, p=0.64; impedance 580 (520-680) vs 570 (510-640) Ohm, p=0.63; R wave amplitude 11.9 (8.2-16.4) vs 11.7 (9-20) mV, p=0.68; battery voltage 3.09 (3.05-3.11) vs 3.09 (3.04-3.13) V, p=0.71] did not show differences. Conclusion M-TPS is an efficacious and safe alternative to conventional PM, with the main advantage of the absence of transvenous leads and a surgically created subcutaneous pocket, avoiding all the related complications. These devices are a reliable alternative after TLE, with similar electrical performances than those observed in patients who did not previously received pacing.

Abstract Objective To identify redundant clinical trials evaluating statin treatment in patients with coronary artery disease from mainland China, and to estimate the number of extra major adverse cardiac events (MACEs) experienced by participants not treated with statins in those trials. Design Cross sectional study. Setting 2577 randomized clinical trials comparing statin treatment with placebo or no treatment in patients with coronary artery disease from mainland China, searched from bibliographic databases to December 2019. Participants 250 810 patients with any type of coronary artery disease who were enrolled in the 2577 randomized clinical trials. Main outcome measures Redundant clinical trials were defined as randomized clinical trials that initiated or continued recruiting after 2008 (ie, one year after statin treatment was strongly recommended by clinical practice guidelines). The primary outcome is the number of extra MACEs that were attributable to the deprivation of statins among patients in the control groups of redundant clinical trials—that is, the number of extra MACEs that could have been prevented if patients were given statins. Cumulative meta-analyses were also conducted to establish the time points when statins were shown to have a statistically significant effect on coronary artery disease. Results 2045 redundant clinical trials were identified published between 2008 and 2019, comprising 101 486 patients in the control groups not treated with statins for 24 638 person years. 3470 (95% confidence interval 3230 to 3619) extra MACEs were reported, including 559 (95% confidence interval 506 to 612) deaths, 973 (95% confidence interval 897 to 1052) patients with new or recurrent myocardial infarction, 161 (132 to 190) patients with stroke, 83 (58 to 105) patients requiring revascularization, 398 (352 to 448) patients with heart failure, 1197 (1110 to 1282) patients with recurrent or deteriorated angina pectoris, and 99 (95% confidence interval 69 to 129) unspecified MACEs. Conclusions Of more than 2000 redundant clinical trials on statins in patients with coronary artery disease identified from mainland China, an extra 3000 MACEs, including nearly 600 deaths, were experienced by participants not treated with statins in these trials. The scale of redundancy necessitates urgent reform to protect patients.

The manuscripts preserved acts as valuable treasure of knowledge which can be utilized for the wellbeing of present generation as well as to pass on to the next generation. A thorough study on Deepika and Gudartha Deepika commentaries on Lolimbaraja's Vaidya jeevana, present in the form of manuscript in oriental research institute libraries has been brought much information that is new for present understanding. The present study focuses on treatment aspects of various diseases and preparation of yogas with easy available drugs in present clinical practice and better development of Ayurvedic practices. The study is based on the technical method of critical edition in order to update & conserve the medical knowledge dealt in Deepika and Gudartha Deepika commentaries on Lolimbaraja's Vaidya jeevana. Objective: 1. To collect and decipher two important commentaries on Lolimbarajas vaidya Jeevana 2. To collate and critically edit the two important commentaries on Lolibarajs Vaidya Jeevana to know their contributions. Methodology: The study is based on seven plus five (total 12) manuscripts and all were in Devanagari script and their details are as below. 1. R-1 to R 7 are - Obtained from BORI, Pune : Acession numbers as - 1093/ 1886-92, 463/ 1895-98, 353/ 1879-80, 948/ 1891-95, 178/ 1882-83, 618/ Vi¾-1, 306/ Vi¾.1 2. H-1 to H 4 are -Obtained from BORI, Pune; Accession numbers as- 462/1895-98, 913/ 1887-91, 635/ 1895-1902, 238.B/ A 1883-84 and IX 3. H-5 - Obtained from Zen library, Arrah, Bihar; Accession number 76/42. Digitization of manuscripts, editing and analysis of mutual relationship among collected copies of Manuscripts, transliteration of all extant of copies selected for Critical edition and Critical Edition with English Translation of the Text is being done. Conclusion By observing all internal and external evidences, Deepika by Rudrabhatta and Gudartha Deepika by Harinatha Goswami are the well known commentaries on Lolimbaraja’s Vaidya jeevana pertaining to early and late 17th CAD respectively. These all contributions enhance the richness of Ayurveda in modern era. KEYWORDS: Critical edition, Deepika, Rudrabhatta, Gudartha Deepika, Goswami Harinatha, Vaidya Jeevana, etc.

Introduction: Readmission within 30 days of hospitalization (30dRA) is increasingly used as a metric for quality of care. Transcatheter aortic valve replacement (TAVR) is also increasing, but 30dRA following TAVR is not well-understood. Hypothesis: The purpose of this study is to define the incidence, etiology, and resource utilization of 30dRA following TAVR. Methods: We used the ICD-9-CM code for TAVR (35.05) to identify patients who underwent TAVR and survived to discharge in 2012, in the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project’s State Independent Databases for 4 geographically distinct states: Florida, Massachusetts, New York, and Washington. The patients were divided into 2 groups: those with and without a 30dRA. Patients with a 30dRA for rehabilitation on the day of discharge were excluded. Approximately 8% of 30dRA were not captured because they occurred in the following year. Results: The incidence of 30dRA following TAVR was 20.2% (244/1210). The most common principal diagnoses for readmission were heart failure (21%), infection (17%), bleeding (11%), and dysrhythmia (7%). A total of 4.2% of patients died during the 30dRA. More than 60% required skilled care following discharge, and only 20% had a routine discharge to home or self-care. The Centers for Medicare and Medicaid Services (CMS) were the primary payer for 93.4% of 30dRA following TAVR. The mean length of stay for a 30dRA was 7.0 +/- 6.6 days. The mean charges for a 30dRA were $61,657 +/- $73,000. On univariate analysis, the number of chronic comorbidities (9.9 +/- 2.8 vs. 9.3+/- 2.8; P=0.002), length of index hospitalization (10.3 +/- 7.4 vs. 8.9 +/- 6.9; P=0.01), and non-routine discharge (83.1% vs. 72.6% P<0.001) were associated with 30dRA. There was no significant difference in the mean age (83 years), gender makeup (50% female), racial makeup (19% non-White), and primary payer between patients who did and did not have a 30dRA. Conclusions: More than one in five patients undergoing TAVR is readmitted within 30 days of the procedure, most commonly for heart failure and infection. Future research should be directed toward identifying patients at risk for post-TAVR heart failure and infection prior to discharge, to reduce 30dRA.

Abstract Funding Acknowledgements Type of funding sources: None. Background The need for cardiac pacing progressively increases with age and the elderly constitute a special subset of patients, being often very fragile and at a greater risk for procedural complications. Leadless pacing systems appear to be a safe and effective option, being devoid of most complications associated with traditional transvenous pacing systems. Purpose This study aimed to analyze a single-center experience with M-TPS (Micra Transcatheter Pacing System) implantation in terms of safety and efficacy in a long-term follow-up. Methods Between May 2014 and November 2022, 193 patients underwent M-TPS implantation in our Center, all patients fulfilled standard criteria for pacemaker implantation with indication to receive either VVI or VDD pacing. We divided the study population into two groups according to age (group 1 &lt; 79 y vs group 2 &gt;= 80 y) and analyzed procedural outcomes, electrical performance of the system at follow-up (FU), rate of procedural major complications and of device-related events at FU. Results In 95/193 cases (69 males, 73%) M-TPS was implanted in patients &gt; 80 y. There were no statistically significant differences between groups in baseline characteristics. Implant procedure was successful in all cases and no device-related events were registered during FU. Patients were followed-up for an average of 18 months, up to 7 years. No differences were observed between groups in procedure duration, single device delivery (group 1 vs group 2: 62.1 vs 69.6%, p=0.17), fluoroscopy time [10 (IQR 6-14) vs 8.5 (IQR 6-12.5) minutes, p=0.27], electrical performance at implant: pacing threshold [0.44 (0.38-0.63) vs 0.5 (0.38-0.75) V/0.24 ms, p=0.39]; impedance [710 (610-840) vs 700 (600-810) Ohm, p=0.56]; R wave amplitude [9.3 (6 -13.5) vs 8.2 (6 -11.9) mV, p=0.68] and at 6 months follow-up : pacing threshold [0.5 (0.38-0.5) vs 0.38 (0.38-0.5) V/0.24 ms, p=0.25]; impedance [580 (500-640) vs 570 (530-680) Ohm, p=0.38]; R wave amplitude [13.2 (9.5-17) vs 9.7 (7.8-16.7) mV, p=0.17]. The only statistically significant difference was found in the percentage of ventricular pacing (Vp%), which was higher in group 2 [5.3 (IQR 0.5-35) vs 38% (IQR 14-83), p=0.001] and stayed higher at a 12 months follow-up [11 (1-53) vs 60% (10-94)], p=0.001). High pacing threshold (&gt;= 1mV@0.24ms) at implant was present in thirty-one patients (14 vs 19%, p=0.43). Conclusions As the population ages the incidence of rhythm disturbances raises, increasing the need for cardiac pacing. It is imperative to find a therapeutic solution that suits the elderly offering them high efficacy and a low rate of complications. MTP-S implant is an effective and safe procedure in elderly patients with similar electrical performance and outcomes compared with younger patients at long-term follow-up. While initially thought for patients that could not undergo traditional pacing interventions, MTP-S is now emerging as a valid substitute.

Информация об анодировании спеченных порошков (CП) ниобия ограничена изучением роста барьерных пленок. Формирование наноструктурированной анодной оксидной пленки (АОП) на поверхности частиц порошка должно привести к заметному увеличению удельной поверхности образца и росту химической активности материала. В соответствии с вышесказанным, исследование анодного наноструктурирования спеченных порошков ниобия является актуальной задачей, открывая перспективы создания новых функциональных наноматериалов. Цель статьи – изучение процесса анодирования спеченных порошков Nb во фторсодержащем водном электролите 1 М Н2SO4+1% HF.Объектами исследования являлись образцы из спеченного порошка Nb с удельной поверхностью Sуд = 800 см2/г. Анодирование проводилось в электролите 1 М Н2SO4 + 1% HF при различных значениях плотности тока ja. Морфология поверхности до и после анодирования изучалась методами сканирующей электронной микроскопии (СЭМ) и атомной силовой микроскопии (АСМ). Для исследования фазового состава применялся метод дифракции рентгеновских лучей. Выполнено изучение кинетики роста анодных оксидных пленок (АОП) на поверхности спеченных порошков СП Nb в гальваностатическом режиме. Определены оптимальные условия анодирования для получения кривых зависимости напряжения от времени Ua(t), характерных для образования самоорганизованных пористых анодных оксидных пленок АОП. Установлено, что анодирование при значениях плотности тока ja = 0.10–0.20 мA/cм2 вызывает формирование на поверхности частиц спеченных порошков СП оксидной пленки Nb2O5 с регулярно-пористым слоем, прилежащим к металлу, поверх которого располагается кристаллический микроконусный слой. Микроконусы (высота до 0.6 мкм, эффективный диаметр основания до 2 мкм) состоят из разветвленных волокон диаметром ~18–30 нм, смыкающихся на вершине. Впервые установлено, что анодирование спеченных порошков ниобия в водном фторсодержащем электролите вызывает формирование на поверхности микрочастиц порошка оксидной пленки с верхним кристаллическим микроконусным слоем. Предложенный метод обработки поверхности перспективен для создания биосовместимыхпорошковых имплантатов. ЛИТЕРАТУРА Одынец Л. Л., Орлов В. М. Анодные оксидные пленки. Л.: Наука; 1990. 200 с. Яковлева Н. М., Кокатев А. Н., Чупахина Е. А., Степанова К. В., Яковлев А. Н., Васильев С. Г., Шульга А. М. Наноструктурирование поверхности металлов и сплавов. Ч. 1. Наноструктурированные анодно-оксидные пленки на Al и его сплавах. Конденсированные среды и межфазные границы, 2015;17(2): 137–152. Режим доступа: https://journals.vsu.ru/kcmf/article/view/56 Яковлева Н. М., Кокатев А. Н., Степанова К. В., Яковлев А. Н., Чупахина Е. А., Шульга А. М., Васильев С. Г. Наноструктурирование поверхности металлов и сплавов. Ч. 2. 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IntroductionThe Internet (especially in the so-called Web 2.0 phase), digital media and file-sharing networks have thrust copyright law under public scrutiny, provoking discourses questioning what is fair in the digital age. Accessible hardware and software has led to prosumerism – creativity blending media consumption with media production to create new works that are freely disseminated online via popular video-sharing Web sites such as YouTube or genre specific music sites like GYBO (“Get Your Bootleg On”) amongst many others. The term “prosumer” is older than the Web, and the conceptual convergence of producer and consumer roles is certainly not new, for “at electric speeds the consumer becomes producer as the public becomes participant role player” (McLuhan 4). Similarly, Toffler’s “Third Wave” challenges “old power relationships” and promises to “heal the historic breach between producer and consumer, giving rise to the ‘prosumer’ economics” (27). Prosumption blurs the traditionally separate consumer and producer creating a new creative era of mass customisation of artefacts culled from the (copyrighted) media landscape (Tapscott 62-3). Simultaneously, corporate interests dependent upon the protections provided by copyright law lobby for augmented rights and actively defend their intellectual property through law suits, takedown notices and technological reinforcement. Despite a lack demonstrable economic harm in many cases, the propertarian approach is winning and frequently leading to absurd results (Collins).The balance between private and public interests in creative works is facilitated by the doctrine of fair use (as codified in the United States Copyright Act 1976, section 107). The majority of copyright laws contain “fair” exceptions to claims of infringement, but fair use is characterised by a flexible, open-ended approach that allows the law to flex with the times. Until recently the defence was unique to the U.S., but on 2 January Israel amended its copyright laws to include a fair use defence. (For an overview of the new Israeli fair use exception, see Efroni.) Despite its flexibility, fair use has been systematically eroded by ever encroaching copyrights. This paper argues that copyright enforcement has spun out of control and the raison d’être of the law has shifted from being “an engine of free expression” (Harper & Row, Publishers, Inc. v. Nation Enterprises 471 U.S. 539, 558 (1985)) towards a “legal regime for intellectual property that increasingly looks like the law of real property, or more properly an idealized construct of that law, one in which courts seeks out and punish virtually any use of an intellectual property right by another” (Lemley 1032). Although the copyright landscape appears bleak, two recent cases suggest that fair use has not fallen by the wayside and may well recover. This paper situates fair use as an essential legal and cultural mechanism for optimising creative expression.A Brief History of CopyrightThe law of copyright extends back to eighteenth century England when the Statute of Anne (1710) was enacted. Whilst the length of this paper precludes an in depth analysis of the law and its export to the U.S., it is important to stress the goals of copyright. “Copyright in the American tradition was not meant to be a “property right” as the public generally understands property. It was originally a narrow federal policy that granted a limited trade monopoly in exchange for universal use and access” (Vaidhyanathan 11). Copyright was designed as a right limited in scope and duration to ensure that culturally important creative works were not the victims of monopolies and were free (as later mandated in the U.S. Constitution) “to promote the progress.” During the 18th century English copyright discourse Lord Camden warned against propertarian approaches lest “all our learning will be locked up in the hands of the Tonsons and the Lintons of the age, who will set what price upon it their avarice chooses to demand, till the public become as much their slaves, as their own hackney compilers are” (Donaldson v. Becket 17 Cobbett Parliamentary History, col. 1000). Camden’s sentiments found favour in subsequent years with members of the North American judiciary reiterating that copyright was a limited right in the interests of society—the law’s primary beneficiary (see for example, Wheaton v. Peters 33 US 591 [1834]; Fox Film Corporation v. Doyal 286 US 123 [1932]; US v. Paramount Pictures 334 US 131 [1948]; Mazer v. Stein 347 US 201, 219 [1954]; Twentieth Century Music Corp. v. Aitken 422 U.S. 151 [1975]; Aronson v. Quick Point Pencil Co. 440 US 257 [1979]; Dowling v. United States 473 US 207 [1985]; Harper & Row, Publishers, Inc. v. Nation Enterprises 471 U.S. 539 [1985]; Luther R. Campbell a.k.a. Luke Skyywalker, et al. v. Acuff-Rose Music, Inc. 510 U.S 569 [1994]). Putting the “Fair” in Fair UseIn Folsom v. Marsh 9 F. Cas. 342 (C.C.D. Mass. 1841) (No. 4,901) Justice Storey formulated the modern shape of fair use from a wealth of case law extending back to 1740 and across the Atlantic. Over the course of one hundred years the English judiciary developed a relatively cohesive set of principles governing the use of a first author’s work by a subsequent author without consent. Storey’s synthesis of these principles proved so comprehensive that later English courts would look to his decision for guidance (Scott v. Stanford L.R. 3 Eq. 718, 722 (1867)). Patry explains fair use as integral to the social utility of copyright to “encourage. . . learned men to compose and write useful books” by allowing a second author to use, under certain circumstances, a portion of a prior author’s work, where the second author would himself produce a work promoting the goals of copyright (Patry 4-5).Fair use is a safety valve on copyright law to prevent oppressive monopolies, but some scholars suggest that fair use is less a defence and more a right that subordinates copyrights. Lange and Lange Anderson argue that the doctrine is not fundamentally about copyright or a system of property, but is rather concerned with the recognition of the public domain and its preservation from the ever encroaching advances of copyright (2001). Fair use should not be understood as subordinate to the exclusive rights of copyright owners. Rather, as Lange and Lange Anderson claim, the doctrine should stand in the superior position: the complete spectrum of ownership through copyright can only be determined pursuant to a consideration of what is required by fair use (Lange and Lange Anderson 19). The language of section 107 suggests that fair use is not subordinate to the bundle of rights enjoyed by copyright ownership: “Notwithstanding the provisions of sections 106 and 106A, the fair use of a copyrighted work . . . is not an infringement of copyright” (Copyright Act 1976, s.107). Fair use is not merely about the marketplace for copyright works; it is concerned with what Weinreb refers to as “a community’s established practices and understandings” (1151-2). This argument boldly suggests that judicial application of fair use has consistently erred through subordinating the doctrine to copyright and considering simply the effect of the appropriation on the market place for the original work.The emphasis on economic factors has led courts to sympathise with copyright owners leading to a propertarian or Blackstonian approach to copyright (Collins; Travis) propagating the myth that any use of copyrighted materials must be licensed. Law and media reports alike are potted with examples. For example, in Bridgeport Music, Inc., et al v. Dimension Films et al 383 F. 3d 400 (6th Cir. 2004) a Sixth Circuit Court of Appeals held that the transformative use of a three-note guitar sample infringed copyrights and that musicians must obtain licence from copyright owners for every appropriated audio fragment regardless of duration or recognisability. Similarly, in 2006 Christopher Knight self-produced a one-minute television advertisement to support his campaign to be elected to the board of education for Rockingham County, North Carolina. As a fan of Star Wars, Knight used a makeshift Death Star and lightsaber in his clip, capitalising on the imagery of the Jedi Knight opposing the oppressive regime of the Empire to protect the people. According to an interview in The Register the advertisement was well received by local audiences prompting Knight to upload it to his YouTube channel. Several months later, Knight’s clip appeared on Web Junk 2.0, a cable show broadcast by VH1, a channel owned by media conglomerate Viacom. Although his permission was not sought, Knight was pleased with the exposure, after all “how often does a local school board ad wind up on VH1?” (Metz). Uploading the segment of Web Junk 2.0 featuring the advertisement to YouTube, however, led Viacom to quickly issue a take-down notice citing copyright infringement. Knight expressed his confusion at the apparent unfairness of the situation: “Viacom says that I can’t use my clip showing my commercial, claiming copy infringement? As we say in the South, that’s ass-backwards” (Metz).The current state of copyright law is, as Patry says, “depressing”:We are well past the healthy dose stage and into the serious illness stage ... things are getting worse, not better. Copyright law has abandoned its reason for being: to encourage learning and the creation of new works. Instead, its principal functions now are to preserve existing failed business models, to suppress new business models and technologies, and to obtain, if possible, enormous windfall profits from activity that not only causes no harm, but which is beneficial to copyright owners. Like Humpty-Dumpty, the copyright law we used to know can never be put back together.The erosion of fair use by encroaching private interests represented by copyrights has led to strong critiques leveled at the judiciary and legislators by Lessig, McLeod and Vaidhyanathan. “Free culture” proponents warn that an overly strict copyright regime unbalanced by an equally prevalent fair use doctrine is dangerous to creativity, innovation, culture and democracy. After all, “few, if any, things ... are strictly original throughout. Every book in literature, science and art, borrows, and must necessarily borrow, and use much which was well known and used before. No man creates a new language for himself, at least if he be a wise man, in writing a book. He contents himself with the use of language already known and used and understood by others” (Emerson v. Davis, 8 F. Cas. 615, 619 (No. 4,436) (CCD Mass. 1845), qted in Campbell v. Acuff-Rose, 62 U.S.L.W. at 4171 (1994)). The rise of the Web 2.0 phase with its emphasis on end-user created content has led to an unrelenting wave of creativity, and much of it incorporates or “mashes up” copyright material. As Negativland observes, free appropriation is “inevitable when a population bombarded with electronic media meets the hardware [and software] that encourages them to capture it” and creatively express themselves through appropriated media forms (251). The current state of copyright and fair use is bleak, but not beyond recovery. Two recent cases suggest a resurgence of the ideology underpinning the doctrine of fair use and the role played by copyright.Let’s Go CrazyIn “Let’s Go Crazy #1” on YouTube, Holden Lenz (then eighteen months old) is caught bopping to a barely recognizable recording of Prince’s “Let’s Go Crazy” in his mother’s Pennsylvanian kitchen. The twenty-nine second long video was viewed a mere twenty-eight times by family and friends before Stephanie Lenz received an email from YouTube informing her of its compliance with a Digital Millennium Copyright Act (DMCA) take-down notice issued by Universal, copyright owners of Prince’s recording (McDonald). Lenz has since filed a counterclaim against Universal and YouTube has reinstated the video. Ironically, the media exposure surrounding Lenz’s situation has led to the video being viewed 633,560 times at the time of writing. Comments associated with the video indicate a less than reverential opinion of Prince and Universal and support the fairness of using the song. On 8 Aug. 2008 a Californian District Court denied Universal’s motion to dismiss Lenz’s counterclaim. The question at the centre of the court judgment was whether copyright owners should consider “the fair use doctrine in formulating a good faith belief that use of the material in the manner complained of is not authorized by the copyright owner, its agent, or the law.” The court ultimately found in favour of Lenz and also reaffirmed the position of fair use in relation to copyright. Universal rested its argument on two key points. First, that copyright owners cannot be expected to consider fair use prior to issuing takedown notices because fair use is a defence, invoked after the act rather than a use authorized by the copyright owner or the law. Second, because the DMCA does not mention fair use, then there should be no requirement to consider it, or at the very least, it should not be considered until it is raised in legal defence.In rejecting both arguments the court accepted Lenz’s argument that fair use is an authorised use of copyrighted materials because the doctrine of fair use is embedded into the Copyright Act 1976. The court substantiated the point by emphasising the language of section 107. Although fair use is absent from the DMCA, the court reiterated that it is part of the Copyright Act and that “notwithstanding the provisions of sections 106 and 106A” a fair use “is not an infringement of copyright” (s.107, Copyright Act 1976). Overzealous rights holders frequently abuse the DMCA as a means to quash all use of copyrighted materials without considering fair use. This decision reaffirms that fair use “should not be considered a bizarre, occasionally tolerated departure from the grand conception of the copyright design” but something that it is integral to the constitution of copyright law and essential in ensuring that copyright’s goals can be fulfilled (Leval 1100). Unlicensed musical sampling has never fared well in the courtroom. Three decades of rejection and admonishment by judges culminated in Bridgeport Music, Inc., et al v. Dimension Films et al 383 F. 3d 400 (6th Cir. 2004): “Get a license or do not sample. We do not see this stifling creativity in any significant way” was the ruling on an action brought against an unlicensed use of a three-note guitar sample under section 114, an audio piracy provision. The Bridgeport decision sounded a death knell for unlicensed sampling, ensuring that only artists with sufficient capital to pay the piper could legitimately be creative with the wealth of recorded music available. The cost of licensing samples can often outweigh the creative merit of the act itself as discussed by McLeod (86) and Beaujon (25). In August 2008 the Supreme Court of New York heard EMI v. Premise Media in which EMI sought an injunction against an unlicensed fifteen second excerpt of John Lennon’s “Imagine” featured in Expelled: No Intelligence Allowed, a controversial documentary canvassing alleged chilling of intelligent design proponents in academic circles. (The family of John Lennon and EMI had previously failed to persuade a Manhattan federal court in a similar action.) The court upheld Premise Media’s arguments for fair use and rejected the Bridgeport approach on which EMI had rested its entire complaint. Justice Lowe criticised the Bridgeport court for its failure to examine the legislative intent of section 114 suggesting that courts should look to the black letter of the law rather than blindly accept propertarian arguments. This decision is of particular importance because it establishes that fair use applies to unlicensed use of sound recordings and re-establishes de minimis use.ConclusionThis paper was partly inspired by the final entry on eminent copyright scholar William Patry’s personal copyright law blog (1 Aug. 2008). A copyright lawyer for over 25 years, Patry articulated his belief that copyright law has swung too far away from its initial objectives and that balance could never be restored. The two cases presented in this paper demonstrate that fair use – and therefore balance – can be recovered in copyright. The federal Supreme Court and lower courts have stressed that copyright was intended to promote creativity and have upheld the fair doctrine, but in order for the balance to exist in copyright law, cases must come before the courts; copyright myth must be challenged. 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