Articoli di riviste sul tema "Mission 3MI"

Abstract. In this paper, we introduce a spectral surface reflectivity climatology based on observations made by TROPOMI on board the Sentinel-5P satellite. The database contains the directionally dependent Lambertian-equivalent reflectivity (DLER) of the Earth's surface for 21 wavelength bands ranging from 328 to 2314 nm and for each calendar month. The spatial resolution of the database grid is 0.125° × 0.125°. A recently developed cloud shadow detection technique is implemented to avoid dark scenes due to cloud shadow. In the database, the anisotropy of the surface reflection is described using a third-order parameterisation of the viewing angle dependence. The viewing angle dependence of the DLER is analysed globally and for a selection of surface type regions. The dependence is found to agree with the viewing angle dependence found in the GOME-2 surface DLER database. Differences exist, related to the actual solar position. On average, the viewing angle dependence in TROPOMI DLER is weaker than for GOME-2 DLER, but still important. Validation of the new database was first performed by comparison of the non-directional TROPOMI surface LER with heritage LER databases based on GOME-1, OMI, SCIAMACHY, and GOME-2 data. Agreement was found within 0.002–0.02 in the UV-VIS (below 500 nm), up to 0.003 in the NIR (670–772 nm), and below 0.001 in the short-wave infrared (SWIR) (2314 nm). These performance numbers are dominated by the performance over ocean, but they are in most cases also representative for land surfaces. For the validation of the directional TROPOMI surface DLER, we made use of comparison with the MODIS surface bi-directional reflectance distribution function (BRDF) for a selection of surface type regions. In all cases the DLER performed significantly better than the traditional LER, and we found good agreement with the MODIS surface BRDF. The TROPOMI surface DLER database is a clear improvement on previous surface albedo databases and can be used as input not only for satellite retrievals from TROPOMI observations, but also for retrievals from observations from other polar-orbiting satellite instruments provided that their equator crossing time is close to that of TROPOMI. The algorithm that is introduced in this paper can be used for the retrieval of surface reflectivity climatologies from other polar satellite missions as well, including Ocean and Land Colour Instrument (OLCI) on the Sentinel-3 satellites, Sentinel-5, and Multi-viewing Multi-channel Multi-polarisation imager (3MI) on the MetOp-SG-A1 satellite to be launched in 2025, as well as the future CO2M mission.

<p>Pakis people who live at the valley of Mount Merbabu is the representative of syncretic Javanese Muslims. As Muslims, they carry out the Islamic shari'ah. But as Javannese people, they perform Javanese cultural traditions such as shamanism. They practice it as a way to solve their life problems, such as to cure diseases, to find lost things, and to win the competition in the selection of certain positions. By using a qualitative approach, the study found a character positive change as a result of consistently da’wah efforts by the preachers. They have implemented a kind of cultural da’wah, as a strategy to encourage the society to change their shamanism tradition gradually. The preachers realize that this tradition is dominant in the society, so that if they used a structural strategy of da’wah, social upheavals could happen among the society in which finally would fail the da’wah mission.</p><p align="center"><strong>***</strong></p>Masyarakat Desa Pakis yang hidup di kaki Gunung Merbabu, merupakan reperesentasi umat Islam Jawa dengan karakter sinkretik. Mereka beragama Islam dan menjalankan syari’at-Nya, tetapi sebagai orang Jawa mereka melaksanakan tradisi dan budaya Jawa seperti perdukunan. Perilaku berdukun dilakukan masyarakat untuk menjalani kehidupan sehari-hari dan cara untuk menyelesaikan problem yang mereka hadapi. Seperti usaha untuk menyembuhkan penyakit, mencari benda-benda yang hilang, memenangkan persaingan dalam pemilihan jabatan tertentu. Dengan pendekatan kualitatif, penelitian ini menemukan gejala perubahan karakter itu yang positif sebagai hasil nyata dari upaya dakwah yang dilakukan secara konsisten dan berkesinambungan.Para da’i menerapkan dakwah kultural, sebagai strategi untuk mendorong perubahan perilaku masyarakat dari berdukun secara perlahan. Da’i juga menyadari bahwa budaya berdukun cukup dominan di masyarakat,sehingga jika digunakan strategi struktural dikhawatirkan akan menimbulkan kegoncangan sosial di masyarakat. Pada akhirnya dakwah yang dilakukan akan menemukan kegagalan.

Skeletal muscle atrophy is evident after muscle disuse, unloading, or spaceflight and results from decreased protein content as a consequence of decreased protein synthesis, increased protein breakdown or both. At this time, there are essentially no human data describing proteolysis in skeletal muscle undergoing atrophy on Earth or in space, primarily due to lack of valid and accurate methodology. This particular study aimed at assessing the effects of short-term unloading on the muscle contractile proteolysis rate. Eight men were subjected to 72-h unilateral lower limb suspension (ULLS) and intramuscular interstitial levels of the naturally occurring proteolytic tracer 3-methylhistidine (3MH) were measured by means of microdialysis before and on completion of this intervention. The 3MH concentration following 72-h ULLS (2.01 ± 0.22 nmol/ml) was 44% higher ( P < 0.05) than before ULLS (1.56 ± 0.20 nmol/ml). The present experimental model and the employed method determining 3MH in microdialysates present a promising tool for monitoring skeletal muscle proteolysis or metabolism of specific muscles during conditions resulting in atrophy caused by, e.g., disuse and real or simulated microgravity. This study provides evidence that the atrophic processes are evoked rapidly and within 72 h of unloading and suggests that countermeasures should be employed in the early stages of space missions to offset or prevent muscle loss during the period when the rate of muscle atrophy is the highest.

104 Background: Modalities of use of androgen deprivation therapy (ADT), like triptorelin, in real life, at the era of new strategies in advanced stages, lack of recent data. Our purpose here was to describe main reasons of choice of formulation and route (F&R) of triptorelin treatment (Tt) declared by the physician. Patient comorbidities, cancer aggressiveness and physician habits may influence their choices. Methods: Initiated in 2020, a prospective, multicenter, non-interventional study is ongoing in France (TALISMAN, NCT04593420). Patients with histologically confirmed PCa, eligible for ≥ 12-month triptorelin Tt within its label were enrolled. Interim analysis of baseline data was planned when 50% of 786 planned patients were enrolled. Modalities of use, including F&R of triptorelin prescribed [monthly intramuscular (1mIM), every 3 months subcutaneous (3mSC) or intramuscular (3mIM), every 6 months intramuscular (6mIM)], were described. Results: 509 patients were included in the interim analysis. Overall population was presented at ASCO-GU22. Subgroups of F&R are presented here. Main F&R prescribed was 3mSC (70.7%). Main baseline parameters in F&R subgroups are presented (except for 1mIM, 4 patients (0.8%)). 31 patients had missing F&R data and were not included in subgroups. 62.1% of patients overall received at least one concomitant systemic Tt for comorbidity at baseline (58.2% in 3mIM, 61.7% in 3mSC and 6mIM). 18.6% and 13.0% of patients overall received, respectively, platelet aggregation inhibitor and anticoagulant; they were 20.9% and 13.8% in 3mSC, 7.3% and 5.5% in 3mIM, 18.5% and 11.1% in 6mIM. Conclusions: Main reason of choice of F&R of triptorelin was physician preferred F&R (47.7%); noticeable reasons included anticoagulants for the choice of 3mSC, planned total duration of Tt for 3mIM and 6mIM, and potential impact on compliance for 6mIM. As the covid pandemic may change the management of patients with prostate cancer, longer acting formulations may become more attractive. Clinical trial information: NCT04593420 . [Table: see text]

This article discusses the education and teaching of the Qur’an in schools. In order to produce a generation that excels in ethics, akhlaqul karimah. So each school has different visions and missions, with these differences there is a common thread that can be applied simultaneously, namely the application of learning the Qur'an. This study will discuss the methods used in learning the Qur’an, common problems, and solutions to the problems of learning the Qur’an in schools. The model for writing this article is by using a descriptive-analytic methodology, based on library research. The results of this study are that there must be continuity between teachers, students, schools, parents, the environment, and their relatives. So that it will be born from every school of generations who have good morals with the basis of the Qur'an as a guide to their lives. It will also bring the souls of the students closer to the Qur'an, which is expected to bring peace, prosperity, and happiness not only in this world, but also in the hereafter.

With increasing Li coverage on Cu(110), (n×1)(4≤n≤8) structures follow the (1×2) missing-row structure at room temperature. We determine the (4×1) structure by a dynamical low-energy electron diffraction (LEED) analysis with symmetrized automated tensor LEED. This completes the solution of the complex surface structures formed on low-index planes of copper single crystal by Li deposition. Every fourth Cu row in the [001] direction is substituted by Li atoms and the remaining Cu rows are covered by Li adatoms. Features of this structure, denoted as Cu (110)-(4×1)-3 Li , are very similar to those of the previously determined Cu (001)-(3×3)-5 Li , Cu (001)-(4×4)-10 Li and Cu (111)-(2×2)-3 Li structures.

Osteoarthritis (OA) is a degenerative joint disease manifested by movement limitations and chronic pain. Endocannabinoid system (ECS) may modulate nociception via cannabinoid and TRPV1 receptors. The purpose of our study was to examine alterations in the spinal and joint endocannabinoid system during pain development in an animal model of OA. Wistar rats received intra-articular injection of 3mg of sodium monoiodoacetate (MIA) into the knee joint. Animals were sacrificed on day 2, 7, 14, 21, 28 after injection and lumbar spinal cord, cartilage and synovium were collected. Changes in the transcription levels of the ECS elements were measured. At the spinal level, gene expression levels of the cannabinoid and TRPV1 receptors as well as enzymes involved in anandamide synthesis and degradation were elevated in the advanced OA phase. In the joint, an important role of the synovium was demonstrated, since cartilage degeneration resulted in attenuation of the changes in the gene expression. Enzymes responsible for anandamide synthesis and degradation were upregulated particularly in the early stages of OA, presumably in response to early local joint inflammation. The presented study provides missing information about the MIA-induced OA model and encourages the development of a therapy focused on the molecular role of ECS.

<div><p><em>Former Prime Minister Shri Lal Bahadur Shastri had given slogan of “ Jai Jawan, Jai Kisan”, Now the Prime Minister Shri Narendra Modi call to farmers to fill the granaries of nation, the farmers left no stone unturned to live up to his aspirations. He appeal each and every farmer , if they have five acre field, then use at least one acre land for cultivation of pulses and legumes so that India need not import it and pulses, which are basic source of protein are available to the poor at affordable price. In Andhra Pradesh </em><em>(13 districts)</em><em> the area under pulses is 13, 73,544 hectares in 2010-11 which accounted for 23.62 per cent in total food crops area, whereas the same in 2014-15 is 10,42,300 hectares which accounted for 20.03 per cent of total food crops area. Under the National Food Security Mission </em><em>(NFSM) pulses being implemented in all the 13 districts of the state. An amount of Rs. 2378.04 lakhs was spent under NFSM- pulses up to 15-11-2015. </em><em>An intensive analysis of data, the compound annual growth rates are very meager for area, production and productivity of pulses in Andhra Pradesh. The area, production and productivity growth rates of pulses are 0.0039, 0.026 and 0.022 respectively. The change in the growth rate of area was completely decelerated in all three periods (i.e. original, 3MA and 5MA). The same trend exhibits in production in original series. The main source of pulses growth due to yield. It is the time for the policy makers and government to concentrate on pulses production through spreading it to irrigated areas.</em></p></div>

Wandering is a symptom present in a variety of psychiatric disorders.A case of a patient manifesting wandering in the scope of a brief psychotic disorder is described in this presentation.A 28-year-old male patient was transferred in the Acute Ward of the Psychiatric Hospital of Petra Olympus from the emergency ward of the General Hospital of Katerini.He was exhausted, filthy, and full of scratches, mentioning that while being with his girlfriend in a remote area, they were verbally attacked by strangers. Panicked, he ran away (this being the last thing he could clearly recall). from that point on, he was wandering in the forest disorientated and feeling threatened. He accidentally approached his village and sought for help.Upon his admission he had a good self, place orientation but he was disorientated in time and couldn't define the time period he had been wandering. (His relatives mentioned that he was missing for three days, confirming the incident he described). He presented persecutory ideas, auditory hallucinations and he was extremely anxious since he strongly believed that his life was in danger.He was free of psychiatric history, being functional till the day of the incident. His lab results were normal as well as his neurological examination, EEG and brain-CT. the test for substance use was also negative. He received medication with risperidone (3mg/day) and diazepam (15mg/day). Few days upon his admission he was free of symptoms and was dismissed within 10 days with diagnosis: Brief Psychotic Disorder on risperidone (2mg/day).

9024 Background: Ipilimumab, a fully human monoclonal Ab directed against the CTLA-4 receptor on T-cells, has shown significant improvement in OS for patients with metastatic melanoma in randomized phase III trials. Eosinophilia in peripheral blood of those patients has been observed, but its clinical significance as a prognostic factor has not been assessed. Methods: We report on a retrospective multi-center analysis of 123 patients who received ipilimumab in three centers between 2010 and 2013. Patients treated had AJCC unresectable stage III or stage IV melanoma of any origin and received ipilimumab in first- and second-line setting at the approved standard dosage of 3mg/kg (4 times q21d). Four patients were excluded due to missing baseline values in eosinophil count (EC). Results: Median OS for patients in final analysis (n=119) was 9.57 months. Based on cut-offs assessed by ROC curves, OS was estimated by Kaplan-Meier curves. Baseline absolute eosinophil count (AEC) ≥ 0.1 (109/l) was significantly associated with improved OS (p= 0.002) with 6-, 12- and 18-month survival rates of 79%, 60% and 48% compared to rates of 48%, 37% and 19% for pts with baseline AEC below 0.1. Baseline relative eosinophil counts (REC) of ≥ 1.75% showed an even stronger significance (p<0.0001) with 6-, 12- and 18-months survival rates of 79% vs. 52%, 60% vs. 40% and 51% vs. 17.1% respectively. Conclusions: This retrospective analysis elucidates the possible association of baseline EC with OS of patients treated with Ipilimumab. Improvement of OS was highly significant in both analyses considering AEC (p= 0.002) and REC (p<0.0001). Since easily detectable biomarkers could be of great potential value, further effort on understanding the potential role of eosinophil granulocytes as possible effector cells in the immune-mediated response to anti CTLA-4 abs should be undertaken.

BackgroundCorresponding with improved survival among patients with breast cancer, the awareness of the long-term effects of cancer treatments has increased. CANcer TOxicities (CANTO) aims to identify predictors of development and persistence of long-term toxicities in patients treated for stages I–III breast cancer and to characterise their incidence, as well their impact. In this paper, we describe the methodology used in this study and provide a first characterisation of the study population.MethodsCANTO (NCT01993498) is a French prospective, longitudinal cohort study enrolling patients with invasive cT0-cT3cN0-3M0 breast cancer of 26 French cancer centres. Patients are assessed at diagnosis, 3–6 (M0), 12 (M12), 36 (M36) and 60 (M60) months after completion of primary surgery, chemotherapy or radiotherapy whichever comes last. CANTO collects clinical, treatment, toxicity data, an extensive list of validated patient-reported outcomes (focusing on quality of life, psychological and behavioural questionnaires) and ad hoc socioeconomic questionnaires. Blood collection is performed at diagnosis, M0, M12, M36 and M60. Biologic sub-studies are ongoing (eg, microbiotic and cognitive sub-study).ResultsEnrolment started in 2012; by October 2018, 12 012 patients had been enrolled. Data collected have a low missing completion rate (<5% for key clinical variables, <20% for patient-reported outcomes). Blood, serum and plasma samples are stored in over 96% of patients. Among the first 5801 patients enrolled in CANTO, 76.7% of patients had hormone receptor positive and human epidermal growth factor 2 negative tumours; 73.1% of patients had breast conserving surgery; 90.4% received adjuvant radiotherapy, 53.4% (neo) adjuvant chemotherapy, 11.3% adjuvant trastuzumab and 80.3% adjuvant hormonotherapy.ConclusionsCANTO represents a unique opportunity to explore important medical, biological and psychosocial outcomes on breast cancer survivor population.

Abstract. Our examination of the 20 years of magnetospheric magnetic field data from ISEE, AMPTE/CCE and Polar missions has allowed us to quantify how the ring current flows and closes in the magnetosphere at a variety of disturbance levels. Using intercalibrated magnetic field data from the three spacecraft, we are able to construct the statistical magnetic field maps and derive 3-dimensional current density by the simple device of taking the curl of the statistically determined magnetic field. The results show that there are two ring currents, an inner one that flows eastward at ~3 RE and a main westward ring current at ~4–7 RE for all levels of geomagnetic disturbances. In general, the in-situ observations show that the ring current varies as the Dst index decreases, as we would expect it to change. An unexpected result is how asymmetric it is in local time. Some current clearly circles the magnetosphere but much of the energetic plasma stays in the night hemisphere. These energetic particles appear not to be able to readily convect into the dayside magnetosphere. During quiet times, the symmetric and partial ring currents are similar in strength (~0.5MA) and the peak of the westward ring current is close to local midnight. It is the partial ring current that exhibits most drastic intensification as the level of disturbances increases. Under the condition of moderate magnetic storms, the total partial ring current reaches ~3MA, whereas the total symmetric ring current is ~1MA. Thus, the partial ring current contributes dominantly to the decrease in the Dst index. As the ring current strengthens the peak of the partial ring current shifts duskward to the pre-midnight sector. The partial ring current is closed by a meridional current system through the ionosphere, mainly the field-aligned current, which maximizes at local times near the dawn and dusk. The closure currents flow in the sense of region-2 field-aligned currents, downward into the ionosphere near the dusk and upward out of the ionosphere near the dawn. Key words. Magnetospheric physics (current systems; storms and substorms; magnetospheric configuration and dynamics)

BackgroundSubcutaneous (SC) CT-P13 is the first and only subcutaneous formulation of infliximab (IFX) approved by the EMA.1 In the pivotal study (NCT03147248), non-inferiority of SC IFX to intravenous (IV) was demonstrated in rheumatoid arthritis (RA) patients using 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) improvement at Week 22, with a statistically significant treatment difference of 0.27 (95% CI 0.02, 0.52) favoring the SC versus the IV arm.2,3 At Week 30, numerical differences in efficacy outcomes were shown between SC and IV IFX favoring SC IFX. IV group patients switched to SC IFX by Week 30, and the difference between the groups was reduced at Week 54.2ObjectivesTo investigate whether there was a statistically significant difference between SC and IV IFX at Weeks 30 and 54 in the phase 3 pivotal study of CT-P13 SC using conservative missing imputation methods.MethodsPatients with active RA who had an inadequate response to MTX received IV IFX 3mg/kg at Weeks 0 and 2 for induction and were randomized at a 1:1 ratio to receive SC IFX 120mg every 2 weeks or IV 3mg/kg every 8 weeks thereafter for maintenance. Patients who were randomized to receive IV IFX switched to SC at Week 30. In this post-hoc analysis, non-responder imputation (NRI) and last observation carried forward (LOCF) methods were used to investigate whether the difference in efficacy outcomes between SC and IV IFX at Weeks 30 and 54 was statistically significant. Assessments included EULAR (CRP/ESR)/ACR response; remission rate and low disease activity (LDA) rate based on DAS28 (CRP/ESR), Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI); Boolean remission rate; and the proportion of patients achieving a minimal clinically important difference (MCID) in Health Assessment Questionnaire (HAQ).ResultsOf the 343 randomized patients, 165 patients who received SC IFX and 174 patients who received IV IFX from the efficacy population were included in the analysis. There was a statistically significant difference in SC IFX compared to IV treated patients at Week 30 using both NRI and LOCF methods in almost all the clinical variables. However, the difference in efficacy outcomes between SC IFX and IV was reduced at Week 54 after the IV group switched to SC. This supports the improved efficacy of SC IFX at Week 30. Some of the key results (EULAR [CRP] responses, LDA rates based on DAS28 [CRP], CDAI, and SDAI) were presented in Figure 1. Analysis using LOCF and NRI methods yielded consistent results across most of the efficacy outcomes.Figure 1.Comparison of clinical outcomes between SC IFX and IV IFX in patients with active rheumatoid arthritis.*P<0.05.P-value for difference in proportion between SC and IV treatment group was obtained by asymptotic Wald test.Low disease activity based on DAS28 (CRP) (< 3.2), CDAI (eatment group AI (≤ 11.0).ConclusionStatistical analyses using conservative missing imputation methods showed significantly greater improvements in clinical outcomes with SC IFX compared to IV at Week 30 in patients with RA. Between-group differences was reduced at Week 54, suggesting improved responses after switching from IV to SC.References[1]Remsima summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/remsima-epar-product-information_en.pdf. Published 2021. Accessed 10 January 2022.[2]Westhovens R, Wiland P, Zawadzki M, et al. Efficacy, pharmacokinetics and safety of subcutaneous versus intravenous CT-P13 in rheumatoid arthritis: a randomized phase I/III trial. Rheumatology (Oxford). 2021;60(5):2277-2287.[3]Combe B, Allanore Y, Alten R, et al. Comparative efficacy of subcutaneous (CT-P13) and intravenous infliximab in adult patients with rheumatoid arthritis: a network meta-regression of individual patient data from two randomised trials. Arthritis Res Ther. 2021;23(1):119.Disclosure of InterestsArnaud Constantin Speakers bureau: Abbvie, Amgen, Boehringer, Celltrion, Galapagos, Janssen, Lilly, Novartis, Sanofi, UCB, Consultant of: Abbvie, Amgen, Boehringer, Celltrion, Galapagos, Janssen, Lilly, Novartis, Sanofi, UCB, Roberto Caporali Speakers bureau: Abbvie, Amgen, BMS, Celltrion, Galapagos, Lilly, Pfizer, Fresenius-Kabi, MSD, UCB, Roche,Janssen, Novartis, Sandoz, Consultant of: Abbvie, Amgen, BMS, Celltrion, Galapagos, Lilly, Pfizer, MSD, UCB, Janssen, Novartis, Sandoz, Christopher John Edwards Speakers bureau: Abbvie, Astra Zeneca, Celltrion, Chugai, Fresenius, Galapagos, Gilead, GSK, Lilly, Janssen, Pfizer, Roche, Consultant of: Abbvie, Astra Zeneca, Chugai, Galapagos, Gilead, GSK, Lilly, Janssen, Pfizer, Roche, Grant/research support from: Celltrion, Pfizer, Abbvie, Joao Eurico Fonseca Speakers bureau: Abbvie, Ache, Janssen, Lilly, Medac, Novartis, Pfizer, Consultant of: Abbvie, Celltrion, Janssen, Lilly, Pfizer, Grant/research support from: Abbvie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Florenzo Iannone Speakers bureau: Abbvie, BMS, Celltrion, Galapagos, MSD, Eli-Lilly, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, BMS, Celltrion, Galapagos, MSD, Eli-Lilly, Janssen, Pfizer, Grant/research support from: BMS, MSD, Edward Keystone Speakers bureau: Amgen, AbbVie, Celltrion, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi Genzyme, Consultant of: AbbVie, Amgen, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc, Janssen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis, Grant/research support from: Amgen, Merck, Pfizer Pharmaceuticals, Hendrik Schulze-Koops Consultant of: Celltrion, Taeksang Kwon Employee of: Celltrion Healthcare, Seungmin Kim Employee of: Celltrion Healthcare, Sangwook Yoon Employee of: Celltrion Healthcare, Dong-Hyeon Kim Employee of: Celltrion Healthcare, Gahee Park Employee of: Celltrion Inc., DaeHyun Yoo Speakers bureau: Celltrion, Celltrion Healthcare

Introduction: Emicizumab is a subcutaneously administered, bispecific, humanized monoclonal antibody that bridges factor (F)IXa and FX to restore the function of missing activated FVIII in persons with hemophilia A (PwHA). This study (NCT03361137) was designed to evaluate the safety and efficacy of emicizumab prophylaxis in PwHA with or without FVIII inhibitors undergoing minor surgical procedures without additional prophylaxis with bypassing agents (BPAs; for patients with FVIII inhibitors) or FVIII (for patients without FVIII inhibitors). Methods: This Phase IV, multicenter, single-arm, open-label study enrolled PwHA of any age, with or without FVIII inhibitors, who were scheduled to undergo minor surgical procedures. Patients were required to have received a minimum of four loading doses of emicizumab (3mg/kg once weekly for 4 weeks) prior to surgical procedure; subsequent maintenance doses of emicizumab were 1.5mg/kg once weekly, 3mg/kg every 2 weeks, or 6mg/kg every 4 weeks. Patients were required to be adherent to emicizumab prophylaxis. Treatment with emicizumab was scheduled to continue for at least 1 month after surgery. No other prophylactic treatment with coagulation factor was permitted. Outcome measures included incidence of excessive bleeding intra-operatively and until discharge from surgery, use of BPAs or FVIII to control bleeding (intra- and post-operatively), incidence of adverse events (AEs), and the percentage of patients with complications requiring hospitalization or return to surgery. Excessive bleeding was defined as a rating of fair to poor on the hemostatic rating scale and translates to an intra- and/or post-operative blood loss of ≥25% over expectation for a patient without hemophilia prior to discharge from surgery. Patients were followed for 28 days following discharge from surgery. Results: Between June 28, 2018 and March 13, 2020, 14 PwHA undergoing minor surgeries were enrolled (with FVIII inhibitors n=11; without FVIII inhibitors n=3); one PwHA with FVIII inhibitors enrolled but did not have surgery and discontinued prematurely, therefore the surgery analysis population comprised 13 patients (with FVIII inhibitors n=10; without FVIII inhibitors n=3). The majority (78.6%) of those enrolled were &lt;18 years of age and all surgeries were either central venous access device (CVAD) removal (n=11) or dental procedures (n=2; Table 1). Of the 10 patients with FVIII inhibitors, one CVAD removal led to excessive bleeding during surgery with a need for BPA therapy, two patients undergoing CVAD removal received BPA therapy during surgery but had no reported excessive bleeding, three (two CVAD removals, one dental extraction) had post-operative bleeding that required use of a BPA (Table 2). Seven patients with FVIII inhibitors had zero bleeds after discharge from surgery. None of the three PwHA without FVIII inhibitors had excessive bleeding necessitating FVIII treatment during surgery or until discharge; two CVAD removals resulted in zero bleeds post-operatively and one dental extraction led to a post-operative bleed that did not require treatment. No serious AEs, thromboembolic events (TEs), thrombotic microangiopathies (TMAs) or deaths were reported during the study. Overall, 10 AEs occurred in five patients with FVIII inhibitors (headache n=3, limb injury, procedural pain, pyrexia, constipation, device occlusion, adhesiolysis, and hematoma, all n=1); no AEs were reported in patients without FVIII inhibitors. There were no AEs leading to dose modification, interruption or withdrawal of treatment, and no patient in either group had surgical complications requiring hospitalization or a return to surgery. The study was terminated early due to low enrollment and the limited variety of surgery types. Conclusions: In this study of mostly pediatric PwHA with and without FVIII inhibitors receiving emicizumab prophylaxis, minor surgeries were safely performed. The majority of surgeries were performed without additional prophylactic coagulation factor, however the small sample size should be considered here. There were no serious AEs, TEs, TMAs, or deaths. These findings are consistent with results from previous studies of patients undergoing minor surgery while receiving emicizumab prophylaxis. Disclosures Escobar: National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dunn:Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Spire: Honoraria; ATHN: Research Funding; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy. Quon:Octapharma: Honoraria; Bayer: Honoraria; Biomarin: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Shire/Takeda: Speakers Bureau; Orthopaedic Institute for Children: Current Employment. Trzaskoma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Lee:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ko:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Carpenter:Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding; Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria.

Background Sickle cell disease (SCD) is associated with a high frequency of chronic kidney disease, which is an independent risk factor for mortality in this population. SCD-associated nephropathy (SCAN) is an emerging concern, characterized by significant albuminuria and progressive deterioration of renal function with a prevalence of up to 26% to 68% in SCD adult patients (Falk 1992, Powars 2005, Yeruva 2016, Ataga 202). Because of rapid decline of estimated glomerular filtration rate (eGFR) is a frequent finding in this population (Derebail 2019, Ataga KI 2021), early diagnosis of SCAN and identification of associated clinical and biologic risk factors are crucial for initiating kidney-protective therapy at early stages of renal impairment. Albuminuria serves as a relevant biomarker for detecting early glomerular damage in SCD patients (Audard 2017). To date, Hydroxycarbamide (HU) remains the cornerstone treatment for managing SCD patients, and its efficacy is primarily attributed to its ability to increase fetal hemoglobin (HbF) levels (Segal 2008). Several observational studies conducted in adult SCD patients have shown that HU may have renal protective effects, making it a promising therapeutic option, but until now, randomized clinical trials confirming this hypothesis are missing (Bartolucci 2015, Laurin 2014). Method SIKAMIC (SIklos on Kidney Function and AlbuMInuria Clinical Trial) is an international (France and Africa), phase IIb, double-blind, randomized, placebo-controlled study. The main objective is to assess the effect of HU on albuminuria levels in SCD adult patients after 6 months of treatment. Eligible patients are of the SS or Sβ0 genotype with a mean albuminuria value (assessed by albumin-to-creatinine ratio: ACR) above 3 and less than 100 mg/mmol, on three urine samples taken one day apart. Patients should not have received HU treatment within the previous 6 months and should not be taking conventional kidney-protecting measures (ACE inhibitors or ARA2) and having blood transfusion in the last 3 months. Patient with an eGFR rate &lt; 60 and ≥ 140 ml/min/1,73m² are excluded from the study. Patients receive either HU at a dosage of 15mg/kg/day or placebo for 6 months, and responders (patient achieving at least a 30% decrease of the ACR baseline at 6 months) have the option to continue the study for an additional six months. Recruitment started in August 2019 in France and in October 2021 in Africa and was extended until June 2023 due to challenge in finding HU-Naïve patients. The end of the study is planned in June 2024 with safety monitoring conducted by an Independent Data Monitoring Committee throughout. Results During the recruitment period, 179 patients were screened, 99 were randomized, 34 in France, 65 in Africa (Senegal: 31, Mali: 23, Ivory Coast: 11) ( Figure 1). The main reason for screen failure was mean ACR &lt; 3mg/mmol. Two patients were excluded from the analysis due to non-compliance with exclusion criteria. Among the 97 patients analyzed, 32 completed the study by June 30, 2023, while 46 were still ongoing treatment, and 19 withdrew before the end of the 6 months follow-up period. The study includes a higher proportion of women (68%), which can be attributed to challenges faced in conducting semen analysis in African countries and the hesitancy to initiate HU treatment without prior semen analysis. The mean age at enrolment was 29.7 ± 9.2 years. Recruitment significantly improved after opening African sites. The study encountered several difficulties, primarily stemming from the challenge of finding HU-naïve patients in France and the high rate of screen failure attributed to non-expected ACR measurement variability and eGFR outside the accepted limits. No safety issues were reported, with 15 well-known adverse events related to HU occurring in 11 patients. Results of the study are expected by the end of 2024. Conclusion This study is the first randomized placebo-controlled study investigating the effect of HU on albuminuria in SCD patients. By employing a complex and robust study design, with ACR measurements at multiple time points, the study will provide valuable insights into the impact of HU on albuminuria levels. Moreover, the collaboration with African countries has highlighted the significance of considering country-specific factors and fostering partnerships to address the unique challenges faced by patients in these regions.

Abstract Introduction Emicizumab - a bispecific humanized monoclonal antibody given subcutaneously - bridges FIXa and FX to restore the function of missing FVIIIa. It is approved for routine prophylaxis in people with hemophilia A (PwHA) with inhibitors of all ages. Previous data from the HAVEN 2 study of emicizumab in pediatric PwHA with inhibitors <12 years (data cut-off May 8, 2017) showed once-weekly (QW) dosing provided effective bleed control and was well tolerated (Young et al. Blood 2017). We present the primary analysis of the study, including analyses of the bi-weekly (Q2W) and monthly (Q4W) dosing regimens. Methods HAVEN 2 (NCT02795767) enrolled PwHA with inhibitors aged <12 years (or 12-17 years if <40kg) previously treated with episodic or prophylactic bypassing agents (BPAs) to receive emicizumab prophylaxis for ≥52 weeks. A loading dose of 3mg/kg emicizumab was given QW for 4 weeks followed by a maintenance dose of 1.5mg/kg QW, 3mg/kg Q2W or 6mg/kg Q4W (cumulative dose identical for all regimens). Efficacy analyses included annualized bleed rates (ABRs) for all bleed endpoints and an intra-individual comparison with ABR on prior BPAs from a prospective non-interventional study (NIS; NCT02476942). Safety assessments included records of adverse events (AEs), serious AEs (SAEs), AEs of interest and immunogenicity. Pharmacokinetics (PK) across dosing regimens was also analyzed. Results Eighty-eight patients were enrolled (n=68 QW; n=10 Q2W; n=10 Q4W), 18 of whom were aged ≤2 years old. At clinical cut-off (April 30, 2018), the median (range) emicizumab exposure for each cohort was 57.2 (17.1-92.1), 20.1 (18.1-24.1), and 18.1 (8.1-24.1) weeks, respectively; 59 patients in the QW cohort completed 52 weeks on study; 3 patients discontinued due to switching to commercial emicizumab (n=2 QW) or lack of efficacy (n=1 Q4W). In the QW, Q2W, and Q4W cohorts, the ABR in treated patients aged <12 years was 0.3 (95% confidence interval [CI]: 0.17-0.50), 0.2 (0.03-1.72), and 2.2 (0.69-6.81) for treated bleeds, respectively. Zero treated bleeds were reported in 50/65 (76.9%), 9/10 (90.0%), and 6/10 (60.0%) patients, respectively. Across cohorts, all patients experienced ≤3 treated bleeds (Table 1). Overall, 30 treated bleeds were reported (n=22 QW; n=1 Q2W; n=7 Q4W): 19 occurring in a joint (n=12 QW; n=1 Q2W; n=6 Q4W), 4 in a muscle (n=3 QW; n=1 Q4W), and 7 classified as 'other' (n=7 QW). The majority (25/30; 83.3%) of treated bleeds were traumatic and 5/30 (16.7%) were spontaneous. An intra-individual comparison of 18 patients <12 years old in the QW cohort who had participated in the NIS (15 and 3 on prior prophylactic and episodic BPAs, respectively) showed a 99% (95% CI: 97.7-99.4) reduced risk of treated bleeds with emicizumab compared with prior BPAs (Figure 1). Emicizumab was safe and well tolerated. No thromboembolic or thrombotic microangiopathy events or deaths occurred. The most common AEs are listed in Table 2. Seventeen patients experienced 21 SAEs. Four patients tested positive for anti-drug antibodies (ADA), two of whom had ADA with neutralizing potential based on reduced emicizumab levels; one discontinued emicizumab treatment and the other had no bleeds as of the clinical cut-off date. Mean steady-state trough concentrations of emicizumab were maintained at therapeutic levels across all regimens (Figure 2). Trough plasma concentrations increased with loading doses until Week 5, then were maintained at approximately 50, 45-50 and 38μg/mL with QW, Q2W and Q4W dosing, respectively. As of the data cut-off, 21 minor surgical procedures had been carried out, 14 (66.7%) of which were central venous access device (CVAD) removals. Conclusions To our knowledge, HAVEN 2 is the largest prospective study in pediatric PwHA with inhibitors to date, and demonstrates that emicizumab prophylaxis is well tolerated and can prevent or substantially reduce bleeds in this population. Meaningful efficacy and PK were maintained with less frequent dosing, with no new safety signals, suggesting the potential for reduced treatment burden in the pediatric population. Additionally, the large number of CVAD removals suggests that prophylactic emicizumab may offer a new and effective standard of care for hemophilia that is also more convenient and less invasive, and may offer the potential for flexible treatment regimens based on patient needs. Disclosures Young: Genentech/Roche: Consultancy, Honoraria, Research Funding; Novo Nordisk: Honoraria; Shire: Honoraria. Liesner:Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Roche: Research Funding; Sobi: Speakers Bureau. Sidonio:Uniqure: Honoraria; CSL Behring: Honoraria; Shire: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; Kedrion/Grifols: Research Funding; Bioverativ: Honoraria, Research Funding; Biomarin: Honoraria; Novo Nordisk: Honoraria. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jimenez-Yuste:NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; CSL Behring: Consultancy; Octapharma: Consultancy, Research Funding; Grifols: Consultancy, Research Funding. Mahlangu:Alnylam: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Biomarin: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Kruse-Jarres:Grifols: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Terumo BCT: Other: CPC Clinical Research; Novo Nordisk: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; Bayer: Consultancy; CSL Behring: Consultancy. Chang:Genentech: Employment, Equity Ownership. Uguen:F.Hoffmann-LaRoche: Employment. Doral:Genentech: Employment. Schmitt:F. Hoffmann-La Roche: Employment, Equity Ownership. Levy:Genentech/Roche: Employment, Equity Ownership. Shima:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Mancuso:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biotest: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion: Consultancy; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Breeding of wheat adapted to new climatic conditions and resistant to diseases and pests is hindered by a limited gene pool due to domestication and thousands of years of human selection. Annual goatgrasses (Aegilops spp.) with M and U genomes are potential sources of the missing genes and alleles. Development of alien introgression lines of wheat may be facilitated by the knowledge of DNA sequences of Aegilops chromosomes. As the Aegilops genomes are complex, sequencing relevant Aegilops chromosomes purified by flow cytometric sorting offers an attractive route forward. The present study extends the potential of chromosome genomics to allotetraploid Ae. biuncialis and Ae. geniculata by dissecting their M and U genomes into individual chromosomes. Hybridization of FITC-conjugated GAA oligonucleotide probe to chromosomes suspensions of the two species allowed the application of bivariate flow karyotyping and sorting some individual chromosomes. Bivariate flow karyotype FITC vs. DAPI of Ae. biuncialis consisted of nine chromosome-populations, but their chromosome content determined by microscopic analysis of flow sorted chromosomes indicated that only 7Mb and 1Ub could be sorted at high purity. In the case of Ae. geniculata, fourteen chromosome-populations were discriminated, allowing the separation of nine individual chromosomes (1Mg, 3Mg, 5Mg, 6Mg, 7Mg, 1Ug, 3Ug, 6Ug, and 7Ug) out of the 14. To sort the remaining chromosomes, a partial set of wheat-Ae. biuncialis and a whole set of wheat-Ae. geniculata chromosome addition lines were also flow karyotyped, revealing clear separation of the GAA-rich Aegilops chromosomes from the GAA-poor A- and D-genome chromosomes of wheat. All of the alien chromosomes represented by individual addition lines could be isolated at purities ranging from 74.5% to 96.6% and from 87.8% to 97.7%, respectively. Differences in flow karyotypes between Ae. biuncialis and Ae. geniculata were analyzed and discussed. Chromosome-specific genomic resources will facilitate gene cloning and the development of molecular tools to support alien introgression breeding of wheat.

Objectives: The purpose of this study was to determine the longitudinal concentrations of several synovial fluid biomarkers after cartilage transplantation and potential correlations with patient reported outcomes. Methods: After institutional IRB approval, patients undergoing osteochondral allograft (OCA) transplantation or autochondrocyte implantation (ACI) were consented and enrolled into a prospective study involving intraoperative synovial fluid aspiration of the operative knee, as well as postoperative aspirations of the operative knee at standardized clinic follow-up timepoints: 2 weeks, 6 weeks, 6 months, and 1 year postoperatively. For this analysis, patients undergoing cartilage transplantation (OCA or ACI) with preoperative aspiration and at least one successful postoperative aspiration were included. Exclusion criteria for aspirations from the analysis included subsequent surgical procedure or articular injections on the index knee within 1 year of the transplant. The synovial fluid samples were analyzed for the following inflammatory biomarkers with Multiplex ELISA: CCL5, MMP-1, EGF, VEGF, IL1a, FGF2, CCL2, BMP2, and Aggrecan (ACAN). The samples were digested 1:1 with 3mg/mL hyaluronidase prior to execution of the assay in accordance with the manufacturer’s protocol. A minimum of 3uL was required for analysis. Patients prospectively completed Knee Injury and Osteoarthritis Outcome Score (KOOS), including Activities of Daily Living (ADL), Pain, Quality of Life (QoL), Sports, Symptoms, and Joint Replacement (JR) subscores, preoperatively and at 6 months and 1 year postoperatively. All statistical analyses were performed on RStudio and STATA. Non-parametric tests were utilized to avoid assumptions of normality. Skillings-Mack tests were utilized as a non-parametric alternative for a repeated-measures ANOVA in the setting of sporadic missing values (i.e., dry aspirations). Post-hoc pairwise Wilcoxon ranksum tests with Bonferroni corrections for multiple comparisons were performed for significant tests. Univariate linear regressions were performed to determine correlations between cytokine changes and patient-reported outcomes. A minimum of 10 observations per predictor was considered sufficient for the analysis. All testing was two-sided, and significance was set at p<0.05. Results: A total of 63 aspirations from 19 patients were evaluated. Postoperatively, successful aspirations were able to be performed on 13 patients at 2 weeks (68%), 17 patients at 6 weeks (89%), 9 patients at 6 months (47%), and 5 patients at 1 year (26%) (Table 1). One patient underwent a subsequent procedure on the index knee (lysis of adhesions) 10 weeks after cartilage transplantation, thereby excluding their 6 month and 1-year aspirations from analysis. Across all timepoints, there were significant differences in MMP-1 (p=0.003), ACAN (p<0.001), and FGF2 (p=0.026). Specifically, ACAN was significantly elevated at 2 (p<0.001) and 6 weeks (p<0.001), and MMP- 1 was the greatest at 6 weeks relative to transplant (p<0.001), 6 months (p=0.01), and 1 year (p=0.04). In contrast, FGF2 was significantly lower at 2 weeks compared to transplant levels (p=0.02). There were no significant differences across timepoints for CCL5 (p=0.88), VEGF (p=0.068), CCL2 (p=0.071), BMP2 (p=0.067), IL-1a (p=0.13), or EGF (p=0.01, p>0.05 for all pairwise comparisons after Bonferroni correction) (Figure 1). A subanalysis was performed for cytokines which demonstrated at least 5 “pro-inflammatory” responses (positive fold-change) and at least 5 “anti-inflammatory” responses (negative fold-change), with a minimum of 10 observations with associated patient-reported outcomes at 6 and/or 12 months postoperatively. From the 2-week aspiration samples, CCL5 (5 increase/7 decrease), IL-1a (5/7), and CCL2 (6/7) met the inclusion criteria. Increase in IL-1a demonstrated significant linear associations with worse postoperative KOOS ADL (p=0.048), Pain (p=0.01), Quality of Life (p=0.01), and Symptoms (p=0.01) scores at 6 months (Table 2, Figure 2). Similarly, an increase in CCL-2 postoperatively was associated with worse KOOS ADL (p=0.04) and Pain (p=0.04) scores at 6 months. No significant linear associations between cytokine changes at 6 weeks and later PROMs were identified. Conclusions: Following cartilage transplantation of the knee, the synovial fluid profile may demonstrate early postoperative increases in MMP-1 and ACAN and a decrease in FGF-2. An early pro-inflammatory response with IL-1a within the first two postoperative weeks may be linearly associated with worse short-term patient-reported outcomes compared to an early decrease. [Table: see text] [Table: see text]