Literatura científica selecionada sobre o tema "Accomodation support"

Abstract Hemophagocytic Lymphohistiocytosis (HLH) is characterized by pathologic immune activation which occurs either as a familial disorder or as an acquired condition. The diagnosis of HLH requires the presence of five out of nine criteria: fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, hyperferritinemia, low or absent natural killer cell activity and high level of soluble interleukin-2 receptor. Here we present a 6-month-old girl with parents from Southern Italy. She suffered from hepatosplenomegaly and a recurrent high fever for 3 months' duration. On admission, she showed neurological symptoms including irritability and neck stiffness. Blood analysis revealed bicytopenia, namely anemia and thrombocytopenia. The first bone marrow aspirate was indicative for neither malignancies nor HLH. At this time, additional investigations indicated macrophage activation syndrome with elevated ferritin value (11.741ng/ml), soluble interleukin-2 receptor (CD25) levels (16.018U/ml), hypertriglyceridemia (582mg/dl) supportive of the diagnosis of HLH. Because of the worsening of her clinical condition, a second bone marrow aspirate and biopsy was performed 5 days later when the child became pancytopenic. The second bone marrow aspirate still did not show morphological signs of HLH, but microorganisms were detected in at least one macrophage, which were consecutively diagnosed as Leishmania amastigotes within macrophages by positive Leishmanial polymerase chain reaction from bone marrow specimen. Consistent with the diagnosis of visceral Leishmaniasis Amphotericin B (liposomal) therapy was initiated which resulted in dramatic resolution of fever, splenomegaly, ferritin levels, and recovery of blood counts within 96 hours. Familial hemophagocytic lymphohistiocytosis (FHL) manifests as acute illness with prolonged fever, cytopenias and hepatosplenomegaly. Onset typically occurs within the first months of life. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months. Acquired HLH is typically associated with T-/NK-cell lymphomas and autoimmune diseases but also with infections including EBV, malaria and Leishmaniasis. Even in non-endemic areas, our case of vertically transmitted Leishmaniasis highlights the importance of recognizing infectious etiologies of HLH compared with hereditary forms of HLH in early infancy to initiate appropriate therapy to prevent life-threatening complications. Disclosures Russo: Novo Nordisk: Other: conference fee, travel and accomodation support ; Octapharma: Other: conference fee, travel and accomodation support. Lammle:Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support ; Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support .

Abstract Introduction. Prekallikrein (PK) and high-molecular-weight kininogen (HK) deficiencies are ultra-rare, autosomal-recessive defects of the contact system caused by biallelic mutations in the KLKB1 and KNG1 genes, respectively. Since affected subjects do not manifest a bleeding phenotype, a correct diagnosis is essential to prevent the administration of prohemostatic agents or plasma and to avoid delay of surgery. We describe a new case of PK deficiency identified at UMC Mainz. In addition, we performed a systematic review of the literature in order to i) collect blood material for genetic studies of reported PK deficient cases lacking this information, and ii) perform a comprehensive individual patient analysis for studying the clinical course and diagnostic criteria (analysis ongoing). Methods. MEDLINE and EMBASE were searched without time and language restrictions. Reference lists of retrieved articles, abstract books of hematology congresses, theses, and grey literature were manually reviewed. All the authors of recent articles on PK deficient cases not assessed for genetic defects, were contacted in order to retrieve blood samples. Clotting activities of PK and HK (PK:C and HK:C) were measured using PK and HK deficient plasmas, respectively. PK and HK antigens (PK:Ag and HK:Ag) were determined by ELISA. Routine aPTT and coagulation factor measurements were performed using an ACL TOP (IL). Genetic testing was performed by Sanger-, Pyrosequencing and/or NGS. Results. Our patient was a 69-year-old woman of African descent referred for preoperative evaluation of an isolated aPTT prolongation. Diagnosis of PK deficiency was based on absent PK:C and PK:Ag (≤1% of normal, each). The homozygous KLKB1 mutation p.Ser151Phefs*34 was found, which was not yet described as a cause of PK deficiency, but had been detected in the African sub-collective (MAF 1.3%) of the 1000 Genomes cohort. A total of 1,913 studies were identified by systematic literature review. Eleven studies with genetic data were found. Blood from 4 unrelated European families without previous genetic testing was analysed, including 3 index cases and 5 relatives. The KLKB1 mutation p.Cys548Tyr was found in 2 families with one index patient being homozygous. This data and the literature suggest that p.Cys548Tyr may be the most frequent KLKB1 mutation in Caucasians, associated with lacking PK:C but low amount of PK:Ag. One patient erroneously diagnosed with PK deficiency based on (incomplete) normalization of aPTT with increased preincubation time and low PK:C (7%) was found to carry compound heterozygous mutations in KNG1 (c.1038+1G>A and c.1165C>T, p.Arg389*) but no mutations in KLKB1. His low PK:C was explained by severe HK deficiency. Conclusions. PK deficiency may not be as rare as previously thought, especially in subjects of African origin. Incomplete normalization of severely prolonged aPTT upon prolonged preincubation and low PK levels are not sufficient for the diagnosis of PK deficiency. Our latter case and data from literature suggest that patients with HK deficiency usually present with moderately low PK levels: therefore, PK:C, PK:Ag, HK:C, and HK:Ag should be determined for proper diagnosis. Disclosures Kremer Hovinga: Shire: Other: Member of Advisory Board, Research Funding; Ablynx: Other: Member of Advisory Board. Lammle:Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support ; Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support .

The article presents the qualification of types of accommodation support in the Armed Forces of Ukraine (AFU) in accordance to which the military personnel and their family members are to be supported by newly built accommodation, liberated accommodation, acquired accommodation, service accommodation or a monetary compensation for a premise fit for living. The essence of the financial mechanism of accommodation support in the Armed Forces of Ukraine has been analyzed, which is basically comprised of the funds of the state budget according to the types of generic and special funds. It has been demonstrated that the existing financial mechanism is not perfect, limited in resources accompanied by a large number of bureaucratic obstacles, does not satisfy the modern request for accommodation support within the AFU. According to date provided at the 1-st of January 2021 the overall amount of military personnel accountable for accommodation is at 47,2 thousand, whilst at the same time in the years 2020 and 2021 at the costs of the budget it is only possible to build 4000 apartments a year, which is obviously not sufficient to meet the requirements of the Armed Forces of Ukraine as such. The main reason for the insufficient support of military personnel in terms of accommodation are the limited financial resources that are available to build or to buy (accommodation). Following the detailed analyses of the budget expenditures for the finance support in terms of the program of construction (acquiring) accommodation for military personnel in the years 2011-2020 it has been stipulated, that even the assets of the special fund have not been used completely in the course of the years 2011-2017 and the level of using the budget assets for the accommodation support within the AFU in an overall perspective was within the framework of 27-81 %. It has also been pointed out that the reason for the incomplete using of the budget assets is the systematic delay of approval of the passports of the budget approval of construction (acquiring) accommodation for servicemen. The article suggests the introduction of innovative approaches to support the military personnel with accommodation, namely mortgage lending, financial leasing and investment for housing construction on land plots of the Ministry of Defense of Ukraine. It is also suggested to implement the experience of NATO member state countries that happen to present service premises to military personnel situated on the territory of the unit (garrison) for temporary use, presenting monetary support to hire accommodation, interest-free loans or loans on preferential terms for the purchase or construction of accommodation.

Functioning adults with disabilities in GermanyIn Germany, the issue of prevention of social exclusion of people with disabilities is treated as the primary task of public policy. This article presents German solutions for adults with disabilities thanks to they are integrated into professional and social life. Among these solutions are own budget, job’s assistant, work in the professional workshop, support in accomodation, tax breaks, subsidies for rehabilitation equipment.

Archaeological research in Losari Temple site also implicates how the site should be developed. There are three frameworks: research framework, educational framework, and tourism framework. Research framework is related to Losari Temple and how its information or its data may support archaeological research or other disciplines. A framework for education is related to how the information may support educational program. In the framework for tourism there are four most important aspects: how to preserve the site, how to present the information, how to manage the access and accomodation, and how to promote the object.

Introduction. Ibrutinib, a small molecule inhibitor of Bruton's tyrosine kinase (BTK), has proven to be an efficient treatment for chronic lymphocytic leukemia (CLL). A distinct characteristic of ibrutinib therapy is transient lymphocytosis. Recently, we have demonstrated that CLL patients with high levels of CD49d show reduced lymphocytosis and inferior nodal response under ibrutinib due to residual activity of BCR-induced inside-out activation of the CD49d/CD29 integrin VLA-4 (Tissino E et al. J Exp Med. 2018;215(2):681-697). Here, we used Tcl1 transgenic (tg) mice as a model to further validate the observation of VLA-4 activation under ibrutinib and to study involved signaling pathways and the effect of VLA-4 inhibition in vivo. Methods. Surface receptor expression analysis of various receptors was performed by flow cytometry. The phosphorylation of signaling molecules was measured by phosflow and western blotting. VLA-4 affinity state was determined by a real-time kinetic assay described in Chigaev A et al. J Biol Chem. 2001;276(52):48670-8. To analyze the distribution of individual VLA-4 molecules on the cell surface, immunofluorescence approaches and superresolution microscopy (STORM, Abbelight) were employed. Mouse treatment studies were performed upon transplantation of TCL1-tg splenocytes to wild-type C57BL/6J mice using the small molecule VLA-4 inhibitor firategrast in drinking water. Tumor infiltration of different organs was measured by flow cytometry. Results. Analyzing the surface expression of CD49d and other homing receptors, we found that TCL1-tg mice correspond with the CD49d-high CLL cohort. We found that both CLL cells from TCL1-tg mice and human CD49d-high CLL show similar CD49d expression levels as the corresponding healthy B cells (human: N = 116 CD49d-high CLL and 32 healthy donor, P = 0.8717; mouse: N = 12 per group, P = 0.6845). Next, we analyzed the impact of BCR pathway inhibitors on the phosphorylation of signaling molecules involved in the BCR pathway after activation by anti-IgM (aIgM) in TCL1-tg leukemic cells. Ibrutinib and idelalisib showed specific patterns of inhibition of BTK and PI3K, respectively. The combination of ibrutinib and idelalisib proved to be the most efficient in reducing the phosphorylation of BTK, SYK, ERK1/2 and Akt upon IgM activation, compared to the phosphorylation of stimulated cells without inhibition (N = 6, P = 0.0003, 0.0305, 0.0039, 0.0019, respectively). IgM stimulation induced VLA-4 high affinity as well as a reorganization of VLA-4 molecules on the cell surface, forming areas of high VLA-4 density. BCR-induced inside-out activation of VLA-4 remained functional upon treatment with ibrutinib (N = 5, cnt vs aIgM P = 0.0017, cnt vs ibrutinib+aIgM P = 0.0499), while idelalisib reduced VLA-4 activation more effectively (N = 5, cnt vs aIgM P = 0.0014, cnt vs idelalisib+aIgM P = 0.0803), suggesting a pivotal role of PI3K in the transmission of the exogenous antigen signal to the integrin. Finally, to analyze the potential of VLA-4 blockage in a tumor setting similar to VLA-4-high CLL patients, we treated wild-type C57BL/6J mice (N = 6 mice per group), which were transplanted with TCL1-tg splenocytes, with the CD49d inhibitor firategrast. This treatment reduced the tumor load in spleen and bone marrow. Conclusion. We found that the TCL1-tg mouse model is adequate to study the activity of the BCR-VLA-4 axis in CLL. Using this model, we show that a) BCR stimulation induces both, an increase in VLA-4 affinity as well as avidity (clustering), b) that PI3K is an essential transmitter between BCR and VLA-4, and c) that VLA-4 inhibition alters tumor infiltration patterns in vivo. Synergies of VLA-4 blockage with established therapy options as a possible way of reducing microenvironment-induced resistance development are currently been investigated. Disclosures Egle: Celgene: Honoraria, Other: Advisory board and Travel support. Greil:Eisai: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria; Genentech: Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Janssen-Cilag: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Boehringer Ingelheim: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding.

Background In myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML), achievement of morphologic complete response (CR) is a prerequisite for potential cure. In AML, CR is deemed the major outcome associated with improved overall survival (OS); patients (pts) without CR are considered non-responders, and hematologic improvement (HI) without bone marrow blast (BMB) clearance is considered treatment (trt) failure (Cheson 2003). Evidence suggests that these definitions may not be applicable to older pts treated with hypomethylating agents (HMA), and that achievement of CR may not be necessary for prolonged OS (Pleyer 2013, 2014, 2015; Schuh 2015; Bloomfield 2018). IWG response criteria for HI do not differentiate between pts who qualify for response (QFR) vs those that do not. Pts with 'normal' blood counts at trt start are per definition HI non-responders. This may obscure potential survival benefits of responding pts. Aims 1) Assess the impact of HI irrespective of BMB clearance and excluding immortal time bias via landmark analyses. 2) Differentiate between pts who QFR, and those with 'normal' baseline values (not-QFR) defined according to IWG prerequisites for CR. 3) Introduce 3 new categories of HI: peripheral blood blasts (PBB), elevated white blood cells (WBC), and PB-CR (defined as Hb ≥11 g/dl, ANC ≥1.0 G/l, WBC <15 G/l, PB blasts: 0%) in analogy to the concept of complete hematologic response in chronic myelogenous leukemia. Methods 1301 consecutive pts with azacitidine (AZA) trt were analyzed (NCT01595295). Data cut-off 26.07.19. HI was assessed according to IWG criteria (Cheson 2006) and the definitions specified in 3) above. More recent proposals of revision for low-risk MDS pts included in trials (Platzbecker 2018) remain largely idem. Human errors in HI assessment for each AZA cycle and lineage were excluded by automated computational calculation from electronic case report form (eCRF) data. Landmark analyses were performed at 3 months (mo) (HI requires ≥8 weeks response duration) and 6 mo (91, 92 and 88% of MDS, CMML and AML pts respond by cycle 6 [Silverman 2011; Pleyer 2013, 2014]). Statistics were performed by Unidata Geodesign GmbH using DeployR Open 8.0.0. Results In total, 462, 113, and 720 pts had MDS, CMML and AML (n=6 unknown). At AZA start, median age was 73 (range 23-93) years. One, 2 or 3 cytopenias were present in 25, 41 and 29% of pts and 46% were transfusion dependent. 55% received AZA 1st line (26% of whom received prior growth factors or iron chelators). Median AZA dose was 889 mg/cycle and 73 mg/m2/day. Median time to 1st response was 3.0 mo and 95% of pts responded by cycle 6. During AZA trt 1091 BM evaluations (BME) were performed in 599 (46%) pts. At the 3 (6) mo landmark, 44% (47%) of pts with BME achieved CR or CR with incomplete blood count recovery (CRi). Early mortality was 5.6 and 10.3% at 30 and 60 days. Of 932 (598) pts that met the 3 (6) mo landmark, a total of 39% (25%) had no BME. The impact of HI on OS became smaller the later the landmark (Tables 1 and 2). The impact of response on OS was 0.4-4.4 mo longer and significance at the 6 mo landmark was retained using IWG criteria with (Table 1) vs without (Table 2) differentiating between pts who did or did not QFR. Pts who did not QFR had similar or better OS compared with responders. At the 3 mo landmark, proposed additional response parameters HI-PBB, HI-elevated WBC and PB-CR were assoc. with a survival benefit of +7.4, +5.0 and +12.9 mo (Table 1, Fig 1A-C). Conclusions 1) The impact of HI on OS is overestimated without landmark analyses. Median time to 1st response was 3.0 mo and ≥8 weeks response duration required. We therefore suggest using a 3 mo landmark when assessing HI. 2) Using IWG criteria for HI assessment underestimates the impact of response, as non-responders are diluted by pts who do not QFR. Distinguishing QFR/not-QFR seems necessary. 3) Proposed additional HI categories (HI-PBB, HI-elevated WBC, PB-CR) add value to current response criteria. It is often the case that BME are not performed in elderly pts in real-world settings (Dinmohamed 2015; current study). Achievement of HI in any lineage and especially PB-CR might be used as a surrogate for response in pts unable or unwilling to undergo BME for response assessment. This large and growing database is suitable to allow future validation of potential novel response criteria. Disclosures Pleyer: Celgene: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Agios: Other: Advisory board; Abbvie: Other: Advisory board. Pfeilstocker:Novartis: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva (Ratiopharm): Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding. Heibl:Daiichi Sankyo: Honoraria; Pfizer: Honoraria; Mundipharma: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sill:Astex: Other: Advisory board; Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria. Petzer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Personal fees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vallet:MSD: Honoraria; Pfizer: Honoraria; Roche Pharmaceuticals: Consultancy. Geissler:Abbvie: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Roche: Honoraria; Ratiopharm: Honoraria. Sperr:Novartis: Honoraria; Celgene: Consultancy, Honoraria. Leisch:Novartis: Honoraria, Other: Travel support; Celgene: Other: Travel support; Bristol-Myers-Squibb: Honoraria. Egle:Celgene: Honoraria, Other: Advisory board and Travel support. Melchardt:MSD: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Novartis: Honoraria; Cephalon: Research Funding. Piringer:Amgen: Research Funding; Roche: Other: Travel support; Merck: Other: Travel support; Bayer: Research Funding. Zebisch:Roche: Honoraria; Novartis: Honoraria, Other: Advisory board; Celgene: Honoraria; AbbVie: Other: Advisory board. Machherndl-Spandl:Celgene: Other: Advisory board. Wolf:Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Keil:Bionorica: Honoraria, Research Funding; Roche: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Merck: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Greil:Ratiopharm: Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Sandoz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML, CMML with <10% BM blasts and IPSS low-risk MDS in the EU

Abstract Background: Patients (pts) aged 80 years or older, albeit making up ≥ 20% of CLL pts, are still underrepresented in clinical trials and treatment outcomes in this cohort remain understudied. We conducted an analysis of pts aged 80 years or older in 6 phase II and III studies of the German CLL Study Group (GCLLSG) in the frontline-setting to elucidate outcomes of targeted treatments with regard to relevant clinical endpoints including overall survival and causes of death. Methods: We pooled data of pts aged 80 years or older at the time of first-line treatment, with at least one administration of a targeted agent as first-line treatment (ibrutinib, idelalisib, or venetoclax) within the following GCLLSG trials: CLL14 (treatment with venetoclax + obinutzumab [GVe]), CLL2-GIVe (venetoclax + obinutuzumab + ibrutinib) and the so-called BXX-studies (CLL2-BIG, CLL2-BAG, CLL2-BIO, CLL2-BCG; treatment with optional bendamustine debulking and either ibrutinib + obinutuzumab, venetoclax + obinutuzumab, ibrutinib + ofatumumab or idelalisib + obinutuzumab). Demographic, laboratory, and genetic data were pooled. Data on treatment exposure and safety (standardized mortality ratios and secondary malignancies) were analyzed accordingly. Kaplan-Meier curves for progression free survival (PFS), overall survival (OS) and time to next treatment (TTNT) were plotted. Results: A total of 716 pts (66 pts each from CLL2-BIG, CLL2-BAG, CLL2-BIO, 45 from CLL2-BCG, 41 from CLL2-GIVe and 432 from CLL14) were analyzed. Of these, 33 (5%) matched the selection criteria for our analysis. The median observation time was 51.8 months. Median age of pts at the time of treatment initiation was 82 years (range 80-89), 18 (55%) pts were male (Table 1). 22 (71%) pts had relevant comorbidities with a cumulative illness rating scale (CIRS) of &gt;6 and 30 (91%) pts having impaired renal function with a GFR &lt;70 mL/min (19 [58%] &lt;50 ml/min). The majority of pts presented with advanced disease with 20 (61%) having a documented Binet stage C and 20 (69%) of 29 pts with an evaluable CLL-IPI risk score being categorized into the high or very high risk group. The type of first-line treatment received was GVe in 27 (82%), bendamustine + ibrutinib + obinutuzumab in 3 (9%), bendamustine + ibrutinib + ofatumumab in 1 (3%) and GIVe in 2 (6%) of pts. 16 pts (48%) discontinued treatment prematurely, in 4 cases because of pts wish, 3 because of progressive disease, 7 pts died (5 due to adverse event, 1 due to cardiac failure and for 1 pt the cause of death is unknown) and 2 discontinued because of reasons classified as "other". The overall response rate was 73%, with 36% CR and 36% PR. Within our sub-cohort, undetectable minimal residual disease (uMRD) rate was 73% in peripheral blood and 39% in bone marrow. Time-to-event analyses showed a median PFS of 49 months (pts &lt;80y: not reached) and a median OS of not reached and 4-year OS of 68% (pts &lt;80y: 4y OS of 92%) (Figure 1). Median TTNT was not reached, with only 2 events in this analysis. There were 11 documented deaths (33%) in our analysis, with adverse events being the most frequent cause of death in 5 cases. Of these, 2 were due to sepsis and 1 each due to heart failure, pulmonary embolism and renal failure. Other reasons not attributed to AEs were progressive disease, infection, respiratory insufficiency and cardiac arrest as well as cardiac failure in 1 case each. For one pt the cause of death is unknown. There were 9 secondary malignancies in 7 pts reported with basal cell carcinoma being the most frequent in 44% of cases. The standardized mortality ratio was 0.78 (95% CI 0.39-1.4) with 11 observed deaths vs. 14 expected deaths compared to the average mortality in this age group. Conclusions: Our analysis demonstrates that this patient population is indeed underrepresented in clinical trials, but anti-leukemic treatment with targeted agents appears feasible and effective in ≥80-year-old pts with CLL, even in presence of coexisting conditions or organ function impairment. Very old pts treated with targeted agents have a comparable survival to an age- and sex-matched population, suggesting that initiating treatment in elderly and potentially frail pts is beneficial. Dedicated studies are warranted for this clinical setting. Hence, our ongoing phase II CLL-Frail trial is evaluating BTK-inhibition for very old (≥80y) or frail pts with CLL (NCT04883749). Figure 1 Figure 1. Disclosures Simon: Gilead: Other: Travel support. Fink: Celgene: Research Funding; AbbVie: Other: travel grant; AstraZeneca: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Cramer: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding; F. Hoffmann-LaRoche: Honoraria, Other: Travel support, Research Funding; AbbVie: Honoraria, Other: Travel support; Gilead: Other: Travel support, Research Funding. Von Tresckow: AbbVie: Honoraria, Other: advisory board, travel grant; Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Janssen: Honoraria, Other: Reasearch support, travel grant; Roche: Honoraria, Other: Reasearch support, travel grant. Goede: Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support. Wendtner: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Eichhorst: University Hospital of Cologne: Current Employment; Consultant Department I for Internal Medicine: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Fischer: Roche: Honoraria, Other: Travel Grants; Abbvie: Honoraria. Hallek: Abbvie: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Sawaf: Janssen: Honoraria, Research Funding; Gilead: Honoraria; Beigene: Honoraria, Research Funding; AstraZeneca: Honoraria; Adaptive: Honoraria; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

Background The anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (r/r cHL) due to high overall response rates (ORR) with a favorable safety profile. However, complete responses (CR) are rare, and patients eventually develop progressive disease. Treatment options in this situation are very limited and usually regarded palliative. Innovative therapies for patients with progressive r/r cHL or insufficient response to anti-PD1 antibodies are hence an unmet clinical need. Radiotherapy (RT) is highly effective and potentially curative in cHL. Local RT results in immunogeneic cell-death at times leading to immune-mediated systemic effects termed abscopal response (AR). Case reports in different cancers including cHL highlight this effect of local therapies potentially enhanced by systemic immunotherapies. Combining the approved systemic anti-PD1 treatment with local RT to a single cHL lesion might hence work synergistically and result in improved tumor control with limited additional toxicity. It thereby would constitute a viable therapeutic option for patients with r/r cHL and could in the future also be incorporated in earlier lines of therapy. However, prospective data regarding this treatment strategy is lacking and will be generated with the recently activated herein presented GHSG AERN trial. Study Design & Methods AERN is an investigator-sponsored, prospective, international, multicenter, single-arm, two-stage phase II trial (NCT03480334) conducted at 10 European trial sites in Austria, Germany, United Kingdom, Netherlands and Norway. Patients with r/r cHL on active anti-PD1 therapy &gt;18 years of age without serious concomitant diseases or organ dysfunction are eligible for enrollment. Patients either have to present with progressive disease (PD) or stable disease (SD) &gt;6 months as best response to the ongoing anti-PD1 antibody. After registration for the screening phase, eligibility will be verified by a centralized GHSG review facility who will also define a single target lesion for RT to ensure at least one cHL lesion outside the 10% RT isodose for evaluation of the primary endpoint (abscopal response rate after 6x nivolumab, ARR-6). All patients will receive 240mg nivolumab at 2-weekly intervals and 20 Gy RT to the target lesion at 2 Gy fractions on ten consecutive working days starting day 6 of nivolumab treatment. Nivolumab will be discontinued in case of inacceptable toxicity or further disease progression and continued for a maximum of 18 months within the AERN trial. During the first stage of the trial, 9 qualified patients will be treated and their response to treatment will be centrally evaluated after the first 6 nivolumab doses. If no AR is observed in stage I, the trial will be terminated for futility. Otherwise 20 additional patients will be enrolled into the second stage for a total trial population of 29 r/r cHL patients. The null hypothesis H0: ARR-6 &lt; 5% will be tested against a one-sided alternative at a confidence level of α = 5%, and at least 4 AR need to be observed for the rejection of H0. Secondary endpoints include e.g. ORR, overall ARR, CR rate, PFS and OS but also feasibility aspects, (S)AEs and quality of life (QoL) measures. To understand the underlying mechanisms of efficacy but also resistance or toxicity a comprehensive set of correlative studies will be conducted. Baseline and sequential blood samples as well as tumor biopsies and rectal swabs for microbiome analyses will be taken during AERN in patients with separate informed consent. This allows detailed evaluation of serological, cellular, functional, histological and genetic parameters to elucidate synergies between anti-PD1 and RT. Ultimately the correlative studies should help to further refine anti-PD1 based combination therapies, ideally beyond the setting of r/r cHL. In summary AERN, to our knowledge, is the first prospective trial formally evaluating the postulated abscopal effect in r/r cHL. The trial addresses an unmet clinical need in r/r cHL patients with insufficient or lost response to anti-PD1 antibodies. AERN additionally will provide proof-of-concept for a synergy of local RT with checkpoint inhibition substantiated by comprehensive correlative studies in blood, tumor tissue and microbiome. Recruitment has started but preliminary data regarding safety or efficacy are not yet available. Figure Disclosures Bröckelmann: MSD Sharpe & Dohme: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding. Greil:Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Sanofi Aventis: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sandoz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria. Zijlstra:Janssen: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Illidge:Div of Cancer Sciences, Faculty of Biology, Medicine and Health, Univ of Manchester, National Institutes of Health and Research Biomedical Research Center, Manchester Academic Health Sciences, Christie Hospital National Health Service Foundation Trust: Employment; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses.

A b s t r a c tThis research was conducted to find out more about the potential of tourist attractions and their development in the Kaliurang Yogyakarta tourist area which is located in Sleman Regency, Yogyakarta Special Region with its stunning natural potential. Qualitative methods are used in this study. Data were collected through interviews, questionnaires, and also observation. With the 5A approach in the tourism component (Atraction, Accomodation, Accessibility, Awareness, and Ancillary Services), Kaliurang actually already has these elements, but it is necessary to develop other additional public facilities such as public transportation facilities to locations that are not yet available, providing at least one ATM machines, as well as the nearest health service post around the tourist area, which are currently far enough away to support tourism activities at this location, therefore synergy is needed between the Sleman Tourism Office and the management and local residents.A b s t r a kPenelitian ini dilakukan untuk mengetahui lebih lanjut tentang potensi daya tarik wisata dan pengembangannya di daerah wisata Kaliurang Yogyakarta yang terletak di Kabupaten Sleman, Daerah Istimewa Yogyakarta dengan potensi alamnya yang mempesona. Metode kualitatif digunakan dalam penelitian ini. Data dikumpulkan melalui wawancara, kuisioner, dan juga observasi. Dengan pendekatan 5A dalam komponen pariwisata (Atraction, Accomodation, Accesibility, Awareness, dan Ancillary Services), Kaliurang sebenarnya sudah memiliki unsur-unsur tersebut, namun perlu adanya pengembangan fasilitas umum tambahan lainnya seperti sarana angkutan umum menuju lokasi yang belum tersedia, disediakannya minimal satu mesin ATM, serta pos layanan kesehatan terdekat di sekitar kawasan wisata yang saat inikeberadaannya cukup jauh guna menunjang kegiatan wisata di lokasi ini, oleh karena itu diperlukan sinergitas antara Dinas Pariwisata Sleman dengan pihak pengelola maupun penduduk setempat.

Le Logement d'abord se présente comme une voie alternative pour mettre fin au sans-abrisme. Ses promoteurs cherchent à réorienter le système d'assistance aux personnes sans-abri afin qu'elles puissent vivre directement dans un logement personnel stable, avec un soutien adapté à leurs choix et besoins. Cette nouvelle doctrine circule depuis les années 1990 dans les pays occidentaux où elle fait l'objet de débats, d'adaptations et de réappropriations qui alimentent un corpus doctrinal qui n'est pas figé. En France, elle inspire une stratégie nationale pour refonder le système d'hébergement en privilégiant l'accès au logement au plus tôt. Elle s'incarne aussi dans des dispositifs expérimentaux tels que le programme Un chez soi d'abord qui accompagne en logement des personnes sans-abri avec un long parcours de rue et des troubles psychiatriques sévères.La recherche interroge la consistance de ce programme de changement et son issue, ainsi que la place respective du logement social et de l'hébergement dans ce système d'action en reconfiguration. Elle s'appuie sur une enquête ethnographique de quatre ans (2017-2020) auprès des acteurs impliqués dans le déploiement du Logement d'abord dans la métropole lyonnaise, en lien avec les acteurs et institutions actifs au niveau national et supranational.. Le Logement d'abord est abordé comme une nouvelle catégorie d'action publique à interroger et un processus d'innovation institutionnel à enquêter. Pour prendre tout son sens, il est resitué dans le champ plus vaste des politiques sociales de l'habitat auxquelles il participe.La première partie de la thèse présente une socio-histoire de l'émergence du Logement d'abord en France et dans les différents pays où la doctrine se forge, circule et oriente l'action publique. Elle décrit les modalités de formation de cette doctrine à partir de ses foyers d'inspiration nord-américain et finlandais, en montrant l'interpénétration des niveaux d'action publique, le rôle des réseaux de promotion à l'international et le renforcement mutuel des processus de diffusion. En Europe, la doctrine évolue ainsi d'une approche ciblée visant les situations jugées les plus complexes, à une approche extensive et transformative pour mettre fin au sans-abrisme. Sa diffusion participe d'un mouvement de contestation des différentes formes d'emprise institutionnelle qui traverse l'ensemble de l'offre sociale et médico-sociale.La deuxième partie de la thèse se centre sur la démarche engagée dans la métropole lyonnaise. Elle analyse le contexte socio-institutionnel qui conduit à un arbitrage politique local en faveur du Logement d'abord, ainsi que les inflexions apportées à l'ambition initiale au fil de l'action. Les épreuves de la mise en œuvre conduisent à des hybridations entre hébergement et logement qui transforment la proposition initiale. Loin de conduire au retrait de l'hébergement, le Logement d'abord en renouvelle plutôt les contours et les formes. Le processus d'innovation institutionnel se poursuit sous la bannière d'une politique de l'hospitalité afin de dépasser les limites d'une acceptation trop restrictive du logement et du droit à l'habiter. La troisième partie de la thèse traite des apprentissages et des déplacements qui résultent de ces explorations. Au travers de deux expérimentations, elle donne à voir les coopérations entre institutions nécessaires pour qu'une vie autonome soit possible, en logement ordinaire ou dans des formes alternatives d'habitat, non pas sous la responsabilité d'une seule institution mais avec le soutien d'une pluralité d'entre elles. Elle met aussi en évidence les limites d'une action publique supplétive qui ne permet pas de compenser durablement des institutions en retrait faute de moyens
Housing First is presented as an alternative way to end homelessness. Its promoters seek to reorient the system of assistance to homeless people so that they can live directly in stable personal housing, with support adapted to their choices and needs. This new doctrine has been circulating since the 1990s in Western countries, where it has been debated, adapted and re-appropriated, feeding a non-fixed doctrinal corpus. In France, it inspires a national strategy to overhaul the temporary accommodation system, prioritizing access to ordinary housing as quickly as possible. This is also embodied in experimental projects such as the program Un chez soi d'abord, which provides housing for homeless people with long street histories and psychiatric disorders.The research questions the coherence of this change program, its outcome as well as the respective place of social housing and accommodation in this reconfigured action system. It is based on a four-year (2017-2020) ethnographic survey of actors involved in the deployment of Housing First in the Lyon metropolitan area, in conjunction with actors and institutions active at national and supranational levels. Housing First is approached as a new category of public action to question and an institutional innovation process to investigate. To be fully meaningful, it needs to be seen in the wider context of the social housing policies to which it contributes.The first part of the thesis presents a socio-history of the emergence of Housing First in France and in the different countries where the doctrine is forged, circulates and guides public action. It describes the way in which it was formed from its North American and Finnish sources of inspiration, showing the interpenetration of levels of public action, the role of international promotion networks and the mutual reinforcement of diffusion processes. In Europe, the doctrine is evolving from a approach targeting situations deemed to be the most complex, to a global and transformative approach to ending homelessness. Its diffusion is part of a movement to protest the different forms of institutional control which permeate the entire social and medico-social offer. The second part of the thesis focuses on the approach adopted in the Lyon metropolitan area. It analyzes the socio-institutional context that led to a local political decision in favor of Housing First, as well as the changes made to the initial ambition. The difficulties of implementation lead to hybridizations between accommodation and housing which transform the initial proposal. Far from leading to the withdrawal of accommodation, Housing First is leading to a renewal of its contours and forms. The process of institutional innovation continues under the banner of a policy of hospitality to overcome the limits of an overly restrictive acceptance of housing and the right to inhabitThe third part of the thesis deals with the learning and changes that result from these explorations. Through two experiments, it shows the cooperation between institutions necessary to make independent living possible, in ordinary housing or in alternative forms of housing, not under the responsibility of a single institution but with the support of several between them. It also highlights the limits of supplementary public action, which is not enough to compensate in the long term for institutions that are failing due to a lack of resources

The aim of this master‘s thesis is to design a sports hall including an accommodation facility in Hradec Králové. Sports hall is situated in a town district called Věkoše. It is tree-storey building equipped with combined pillar‘s and wall‘s support system. Building is founded on solid slab and propped piles. Pillars are made of steel, walls are made of ceramic bricks and curved roof is made of gluelam beams and roof trusses with aluminum cover system Kalzip. There are two single ply flat roofs. Also basement is a part of the building. For spectators two separated auditoriums with steel support system are designed. The accommodation for twenty people was split into ten rooms. It is designed as barrier free building for both sportsmen and audience.

Forced migration trend around the world is increasing. UNHCR estimated that more than 65 million people are forcibly displaced in 2015, representing about 26% of all international migrants. In relation to forced migration, secondary cities are also impacted, with many of such cities attract forcibly displaced migrants who view them as more accessible and 'friendly' compared to primary cities. Many secondary cities support the needs of migrants as a first point of entry, shelter, asylum and informal employment. In Indonesia, UNHCR recorded almost 14,000 person-ofconcerns in 2015. They are present in about 13 cities, with at least four is considered secondary cities. Although small, the number of forced migrants in Indonesia is expected to increase slowly along with the increasing trend of forced migration around the world. The study explores the capacity of secondary cities in Indonesia in accommodating the influx of refugees and asylum seeker, with Makassar as a case study, using a simplified City Resilience Framework developed by Arup International Development (2015) as a framework. By understanding the system and how it affects displaced people, it is expected that the focus for future improvement that contributes to the city resilience can be identified.