Fire simulator exposure alters the innate epithelial response and inflammatory status in the airways of firefighters

2021 ◽  
Vol 59 (3) ◽  
pp. 267-276
Author(s):  
T.G. Cordeiro ◽  
J.B. do Amaral ◽  
V. Pavao ◽  
R.G. Cardoso ◽  
R.L. Voegels ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Oxygen Saturation ◽  
Mucociliary Clearance ◽  
Phase 1 ◽  
Phase 2 ◽  
Phase 3 ◽  
Peripheral Oxygen Saturation ◽  
By Products ◽  
Nasal Mucociliary Clearance

Background: Firefighters are often exposed to high temperatures and by-products of combustion, which can compromise their health. We aimed to evaluate the effect of fire exposure in fire simulators on the airways of firefighters at different time-points. Methodology: Thirty-seven male firefighters exposed to fire simulators were evaluated in three phases: pre-exposure, at the end of the first week, and 4 weeks after. Pulmonary function by spirometry, nasal mucociliary clearance; peripheral oxygen saturation, inflammatory markers in the nasal lavage and CC16 in the sputum, nasal obstruction, and quality of life (using the questionnaires NOSE and SNOT-22) were assessed. Results: Higher levels of IL-8, IL-10, and exhaled carbon monoxide were found more in phase 2 than in phase 1. Higher CC16 levels and lower peripheral oxygen saturation were observed in phase 3 as compared to phase 1. Lower levels of IL-2 and peripheral oxygen saturation were found in phase 3 than in phase 2. Higher nasal mucociliary clearance, as well as the worst quality of life and nasal obstruction, were observed in phases 2 and 3 as compared to phase 1. Conclusions: The firefighters' exposures to high temperatures and by-products of combustion in the fire simulators elicit an inflammatory process in the airways with impairment in the innate epithelial response of the upper airway lining. Furthermore, changes in O2 transport affected the professionals' quality of life negatively.

scholarly journals Fitusiran Treatment Impacts on Health-Related Quality of Life in Subjects with Hemophilia A and B with Inhibitors Assessed with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Sylvia Von Mackensen ◽  
Pratima Chowdary ◽  
Sarah Mangles ◽  
Qifeng Yu ◽  
Baisong Mei ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Hemophilia A ◽  
Phase 1 ◽  
Phase 2 ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Related Quality ◽  
Health Related ◽  
Dose Dependent

Background: Fitusiran, an investigational RNA interference treatment for people with hemophilia A or B (PwH), with or without inhibitors, has shown dose-dependent lowering of antithrombin, increase in thrombin generation, and decrease in bleeding frequency in clinical trials. The novel mechanism of action and long pharmacodynamic effect enables once-monthly subcutaneous administration. This sustained hemostatic protection and less burdensome administration may improve patient-reported outcomes (PRO). Objective: To evaluate changes in PRO in terms of patient-relevant improvements in health-related quality of life (HRQoL) in PwH with inhibitors (PwHI) on prophylactic fitusiran treatment. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a phase 2 open-label extension (OLE) study (NCT02554773) with monthly subcutaneous fixed doses of 50 mg or 80 mg. HRQoL was assessed using the Haem-A-QoL and the EuroQol 5 Dimensions (EQ-5D) questionnaires at baseline and at end of study in a cohort of 17 PwHI (Hemophilia A, n=15; Hemophilia B, n=2) from the phase 1 study. Results: Subjects previously treated on-demand or prophylactically had a mean (standard deviation [SD]) age of 34.6 (10.3) years and a mean (SD) number of bleeding episodes in the 6 months before baseline of 16.6 (10.7). Mean (SD) changes from baseline to end of study (day 84 or later) in Haem-A-QoL total (-9.2 [11.2]) and physical health (−12.3 [15.1]) domain scores suggest clinically meaningful improvement (lower scores indicate better HRQoL). Numeric reduction (i.e., improvement) in all other domains appeared to be dose-dependent (greater improvement in the 80 mg group) (Table 1). Changes in EQ-5D utility and EQ-VAS scores were not clinically meaningful. Further analyses in PwH with and without inhibitors from the phase 2 OLE will be presented. Conclusions: Fitusiran prophylaxis may improve HRQoL - particularly the Haem-A-QoL 'Physical health' domain (painful swelling, joint pain, pain with movement, difficulty walking, and time to get ready) as shown in a cohort of 17 PwHI . Additional analyses from ongoing OLE and phase 3 studies are planned to quantify the patient-relevant changes with fitusiran treatment in all hemophilia patients over time. Disclosures Von Mackensen: Sanofi, Bayer, Sobi, Chugai, Kedrion, Spark: Consultancy; Biotest, Sobi, CSL Behring: Honoraria; Novo Nordisk, Sobi: Research Funding. Chowdary:BioMarin: Honoraria; Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer and Sobi: Research Funding; Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi: Speakers Bureau; Bayer, Chugai, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Shire (Baxalta), Sobi, Spark: Membership on an entity's Board of Directors or advisory committees. Mangles:Roche, Takeda, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, Octapharma, Novo Nordisk, Shire and Roche/Chugai: Other: travel funding. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company. Dasmahapatra:Sanofi: Current Employment, Current equity holder in publicly-traded company.

Effect of Deviated Nasal Septum Type on Nasal Mucociliary Clearance, Olfactory Function, Quality of Life, and Efficiency of Nasal Surgery

2016 ◽  
Vol 27 (5) ◽  
pp. 1151-1155 ◽  
Author(s):  
Güler Berkiten ◽  
Tolgar Lütfi Kumral ◽  
Ziya Saltürk ◽  
Yavuz Atar ◽  
Güven Yildirim ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Nasal Septum ◽  
Mucociliary Clearance ◽  
Olfactory Function ◽  
Nasal Surgery ◽  
Deviated Nasal Septum ◽  
Nasal Mucociliary Clearance

Validation Study of the Heavy Menstrual Bleeding Questionnaire in Adolescents

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-45
Author(s):  
Meghan Pike ◽  
Ashley Chopek ◽  
Nancy Young ◽  
Koyo Usuba ◽  
Mark J. Belletrutti ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Heavy Menstrual Bleeding ◽  
Menstrual Bleeding ◽  
Measurement Tool ◽  
Phase 2 ◽  
Advisory Committees

Introduction Heavy menstrual bleeding (HMB) is a common problem among adolescent girls that affects many aspects of their lives. Estimating the effect of HMB on health-related quality of life (HRQoL) is important but challenging, as there is no instrument that measures menstrual bleeding-specific HRQoL for girls ages < 18 years. Aim To develop and assess the psychometric properties of a menstrual bleeding-specific HRQoL tool adapted for use by girls with HMB aged < 18 years. Methods HMB was defined using a pictorial bleeding assessment chart (PBAC) score >100 and/or hemoglobin >2 SD below age appropriate means. Phase 1 utilized a focus group of girls with HMB to review items of the Menstrual Bleeding Questionnaire (MBQ), validated for use in women ages ≥ 18 years, to generate new items and develop the Adolescent MBQ (aMBQ). In phase 2, participants were divided in two groups: those with and those without HMB. Each participant completed 3 questionnaires (aMBQ, Pediatric Quality of Life core module [PedsQL] and PBAC) at 2 time points. Validity of the aMBQ was measured by Spearman's correlation with the PedsQL. Reliability was calculated using an intra-class correlation (ICC) random effect model in those without HMB who repeated the 3 questionnaires within 30-60 days from baseline. Receiver Operating Characteristic (ROC) curve analysis assessed the ability of the aMBQ to distinguish between participants with and without HMB. Ethics approval and informed consent were obtained prior to participation. Results Phase 1 included 5 girls with previously diagnosed HMB. The MBQ was revised to be appropriate for adolescents by substituting 4 words/phrases that altered 8 of 20 questions (Table 1). With the addition of one new question, a 21-item aMBQ was developed with a score range of 0-77, with 77 representing the worst HRQoL. Phase 2 included 73 participants: 19 with HMB and 56 without HMB. Mean age of participants was 14.7 years (range 11-17 years). The validity of the aMBQ was confirmed by a moderate correlation with PedsQL (rho=-0.61). Test-retest reliability was substantial (ICC=0.71, p=0.03). An aMBQ score of >30 identified those with HMB with excellent discrimination (AUC=0.826, sensitivity 71.4%, specificity 88.0%). Conclusion The aMBQ is a valid and reliable measurement tool to assess HRQoL in adolescents with HMB that is easily implemented in the office setting. Furthermore, it may assist clinicians in identifying those with HMB and aid in the evaluation of treatment effectiveness both in clinical practice and research. Disclosures Belletrutti: Takeda Canada: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Canada: Membership on an entity's Board of Directors or advisory committees; Bayer Canada: Membership on an entity's Board of Directors or advisory committees; Roche Canada: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Matteson:ABOG: Honoraria, Other: Received stipend for being an oral boards examiner.; Myovant: Membership on an entity's Board of Directors or advisory committees; Bayer Ensure: Other: Co-Investigator for longitudinal research study and clinical trial. All funds go to site of research, Research Funding.

Carfilzomib Weekly Plus Melphalan and Prednisone in Newly Diagnosed Elderly Multiple Myeloma (IFM 2012-03)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3028-3028
Author(s):  
Xavier Leleu ◽  
Lionel Karlin ◽  
Brigitte Kolb ◽  
Mourad Tiab ◽  
Carla Araujo ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Board Of Directors ◽  
Safety Profile ◽  
Phase 1 ◽  
Maintenance Phase ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3

Abstract Background. New standards with increasing efficacy that are also characterized with improving the quality of life are needed for elderly myeloma patients. Although MPT and MPV regimens are remarkable in terms of efficacy, quality of life while on treatment with these 2 regimens remain an issue. The Carmysap twice weekly carfilzomib-based phase 2 study has demonstrated that Carfilzomib at the MTD of 36mg/m² might challenge bortezomib in the VMP standard. However, it has become routine practice to use bortezomib on a weekly schedule, with maintained efficacy and an improved safety profile. We sought to demonstrate that Carfilzomib Weekly plus Melphalan and Prednisone will prove strongly efficacious with acceptable safety profile and quality of life to newly diagnosed elderly multiple myeloma (eNDMM). Methods . IFM2012-03 (also called carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate during the phase 2 part of the study. The inclusion/exclusion criteria of interest were eNDMM (65 and older), with symptomatic and measurable disease, with absolute neutrophils ≥1 G/L, untransfused platelet count ≥75 G/L, hemoglobine ≥8.5 g/dL and clairance creatinine ≥ 30ml/min. We report herein the phase 1 part of the study which last cohort was completed at ASH abstract deadline. For the phase 1 part of the study, each cohort was 6 patients based, and started at 36mg/m² of carfilzomib on days 1, 8, 15, 22 using IV, 30 minutes infusion, route followed by a 13-day rest period per 35-days cycles, melphalan given at 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. The subsequent cohorts' doses for carfilzomib were 45, then 56 and finally 70mg/m². 9 cycles were planned as induction followed by a maintenance phase of weekly carfilzomib monotherapy given at 36mg/m² weekly for one year. The MTD was determined when ˃2 DLTs were observed. DLTs were considered during cycle 1 if any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle, grade ≥3 febrile neutropenia, grade ≥3 gastrointestinal toxicities, any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator, grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. Results. 26 NDMM patients recruited, 24 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45 then 56, and finally at 70mg/m² which cohort cycle 1 is up and running. The median age was 74 with 10 patients older than 75 and sex ratio M/F 65. There was a DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3). At ASH deadline, all patients from cohort 36 of carfilzomib have completed induction and maintenance up to cycle 6, 5/6 of cohort 45 have completed induction and started the maintenance phase, 5/6 of cohort 56 have completed cycle 6 of induction and pursue within the induction phase, and finally all patients from cohort 70 of carfilzomib are undergoing cycle 1. There are 22 SAE reported for a total of 171 cycles administered of carfilzomib +MP. So far, 3 patients (out of 24) have stopped treatment, including the 2 patients with DLTs, lysis syndrome and cardiac failure, and one patient that presented with pulmonary hypertension later in the disease course on cycle 5 of the 56mg/m² carfilzomib +MP cohort. And, an extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4, thrombocytopenia grade 4, and Dyspnea grade 3, respectively. Conclusion. The MTD of weekly carfilzomib in the combination to Melphalan and Prednisone could be determined at 70mg/m² in elderly NDMM, demonstrating the good safety profile of carfilzomib in this regimen and fragile population. The complete dataset of the entire study will be updated at ASH with response rate, survival and safety profile. Disclosures Leleu: Chugai: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Transfusion independence in patients with myelodysplastic syndromes treated with azacitidine

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6576-6576 ◽  
Author(s):  
L. R. Silverman ◽  
B. L. Peterson ◽  
J. F. Holland ◽  
R. M. Stone ◽  
B. L. Powell ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Platelet Transfusion ◽  
Randomized Study ◽  
Phase 2 ◽  
Phase 3 ◽  
Beneficial Effects ◽  
Transfusion Independence ◽  
Transfusion Requirements ◽  
Independence Results

6576 Background: Patients (pts) receiving red blood cell (RBC) transfusions are exposed to various side-effects such as intolerance reactions, iron overload, and alloimmunization risks. Reduction in RBC transfusions plus improvement in quality of life was demonstrated in pts with MDS treated with azacitidine in the phase 3 randomized study (9221) conducted by the CALGB (JCO 2002;20:2429). Azacitidine also demonstrated beneficial effects on platelets and neutrophils. To further explore transfusion results in 9221, we compared RBC and platelet transfusion requirements in pts treated with azacitidine across 3 CALGB studies (phase 2 intravenous [IV] 8421, phase 2 subcutaneous [SC] 8921, and Phase 3 SC 9221). Methods: Baseline was defined as 90 days immediately prior to randomization or crossover, as appropriate. Transfusion independence was defined as maintaining independence for ≥56 days (IWG criteria). Duration of transfusion independence was defined as the date of last transfusion to the date of the next transfusion or date of censoring. Proportions of pts who became RBC or platelet independent during the study were compared, as were the median durations of independence. Results: Compared with pts treated with IV azacitidine, a greater percent of pts treated with SC azacitidine achieved independence ( Table ), but the IV study (8421) enrolled only pts with advanced MDS. Differences of 10% in proportions of pts registered or randomized to SC azacitidine who achieved transfusion independence were noted in the phase 2 and 3 studies for RBCs (8921: 35%; 9221: 45%) and for platelets (8921: 43%; 9221: 53%). Median duration of RBC independence in 8921 was 221 days, which was within 6% of that observed for pts randomized to azacitidine in 9221 (235 days). Conclusions: These results provide further support that azacitidine has beneficial effect on erythropoiesis and thrombopoiesis. Patients with MDS treated with azacitidine may develop RBC or platelet transfusion independence. [Table: see text] [Table: see text]

scholarly journals Global open-label extension: 24-month data of patisiran in patients with hattr amyloidosis

2021 ◽  
Author(s):  
Wilson Marques Jr ◽  
David Adams ◽  
Alejandra González- Duarte ◽  
Elizabeth Mauricio ◽  
Thomas Brannagan ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Disease Progression ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Extension ◽  
Life Threatening

Introduction: Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, life- threatening disease. The efficacy and safety of patisiran has been demonstrated in Phase 3 (APOLLO) and Phase 2 Open-Label Extension (OLE) studies in patients with hATTR amyloidosis with polyneuropathy. Objective: To describe interim 24-month efficacy and safety analyses of the ongoing Global OLE study. Methods: International OLE study (NCT02510261) in eligible patients who completed parent studies, including APOLLO patients randomized to placebo (APOLLO/placebo, n=49) or patisiran (APOLLO/patisiran, n=137) and Phase 2 OLE patients (n=25). Results: As of 10/07/2019, 178/211 patients had 24-month assessments. Safety profile remained consistent with previous studies. After 24 months of additional patisiran treatment in the OLE, durable improvement was seen for mNIS+7 (mean change [SEM]) in APOLLO/patisiran (-4.9 [2.1]) and Phase 2 OLE (-5.9 [2.1]) groups vs. parent study baselines. Norfolk QOL-DN continued to show durable improvement in APOLLO/patisiran patients (-2.4 [2.4]) following additional 24- months treatment. In the Global OLE, APOLLO/placebo patients experienced halting of disease progression and quality of life (QOL) improvement compared to Global OLE baseline after 24 months of patisiran (mNIS+7: +0.1 [3.3], Norfolk QOL-DN: -4.1 [3.3]), although they had progressed relative to APOLLO baseline (mNIS+7: +26.3 [5.0], Norfolk QOL-DN: +15.8 [4.5]) given progression while on placebo in APOLLO. Conclusion: Patients with long-term exposure to patisiran continue to demonstrate durability of efficacy. Despite marked progression on placebo during APOLLO, previously untreated patients continue to exhibit halting of disease progression and QOL improvement following 24 months of patisiran. Patisiran continues to demonstrate a positive benefit:risk profile.

PENERAPAN MODEL QUANTUM LEARNING UNTUK MENINGKATKAN HASIL BELAJAR AUTOCAD SISWA KELAS X TEKNIK PEMESINAN SMK NEGERI 1 STABAT

2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Abdul Hasan Saragih
Keyword(s):  
Positive Response ◽  
Phase 1 ◽  
First Grade ◽  
Learning Model ◽  
Second Phase ◽  
Phase 2 ◽  
Phase 3 ◽  
The Third ◽  
Third Phase ◽  
Quantum Learning

This classroom research was conducted on the autocad instructions to the first grade of mechinary class of SMK Negeri 1 Stabat aiming at : (1) improving the student’ archievementon autocad instructional to the student of mechinary architecture class of SMK Negeri 1 Stabat, (2) applying Quantum Learning Model to the students of mechinary class of SMK Negeri 1 Stabat, arising the positive response to autocad subject by applying Quantum Learning Model of the students of mechinary class of SMK Negeri 1 Stabat. The result shows that (1) by applying quantum learning model, the students’ achievement improves significantly. The improvement ofthe achievement of the 34 students is very satisfactory; on the first phase, 27 students passed (70.59%), 10 students failed (29.41%). On the second phase 27 students (79.41%) passed and 7 students (20.59%) failed. On the third phase 30 students (88.24%) passed and 4 students (11.76%) failed. The application of quantum learning model in SMK Negeri 1 Stabat proved satisfying. This was visible from the activeness of the students from phase 1 to 3. The activeness average of the students was 74.31% on phase 1,81.35% on phase 2, and 83.63% on phase 3. (3) The application of the quantum learning model on teaching autocad was very positively welcome by the students of mechinary class of SMK Negeri 1 Stabat. On phase 1 the improvement was 81.53% . It improved to 86.15% on phase 3. Therefore, The improvement ofstudent’ response can be categorized good.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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