scholarly journals Studying the Impact of Presence of Alpha Acid Glycoprotein and Protein Glycoprotein in Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate in State of Qatar

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4846-4846
Author(s):  
Nader I Al-Dewik ◽  
Andrew Jewell ◽  
Mohamed A. Yassin ◽  
Hisham Morsi

Abstract Background Despite the efficacy of Imatinib Mesylate (IM) in treating Chronic Myeloid Leukemia (CML), a high degree of resistance has already been noted. Alpha acid glycoprotein (AGP) may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target while Protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. In our cohort of patients with the highest rate of resistance to IM globally, we investigated if the level of AGP and PGP could be correlated with CML resistance/response to IM? and if so, could they be employed as biological markers for CML resistance to treatment? Methods To answer these questions, the 26 CML patients who were enrolled into our previous study between November 2006 and December 2011 were investigated for AGP and PGP levels at diagnosis and during treatment. Serum samples were analyzed to determine AGP level via an Immunoturbidimetric assay and up-regulation of PGP level was determined via Flow cytometry analysis of Peripheral Blood (PB) and Bone Marrow (BM) samples. Results A total of 100 serum, 40 BM & 100 PB samples were collected from the 26 CML patients (22 CP & 4 AP) treated at the National Center for Cancer Care and Research (NCCCR) in Qatar. Samples from 10 healthy volunteers were collected as a control. AGP results At Diagnosis 11/22 CP patients had elevated AGP (mean 1.5 ±0.11 g/l) while 3/4 AP patients had elevated AGP (mean 1.8 ±0.3 g/l). During follow-up The mean AGP values among the 14/26 patients who failed IM treatment were (1.05 ±0.09 g/l) while the values for the 12 patients who responded to the treatment were not significantly different (1.1 ±0.06 g/l) (p =) > 0.05. The 10/14 resistant patients who were previously reported to have mutations/Additional Chromosomal Abnormalities (ACAs) as underlying mechanisms of resistance, showed a mean AGP level of 1.06 (±0. 09) while the 4/14 patients with no mutations/ACAs showed no significant difference (AGP leve1.04 ±0.08) (p =) > 0.05. The mean value of the 10 healthy individuals who were enrolled as a control group was 0.71 ±0.04 g/l. The mean AGP levels were 1.2 (±0.12), 1.61 (±0.38), 1.05 (±0.09), 1.1 (±0.06), and 0.71(±0.04) g/l for 22/26 CP, 4/26 AP, 14/26 failed treatment, 12/26 optimal responders and controls respectively and the differences between patients groups and the control group on other hand were significant (p) 0.001, 0.03, 0.003, and 0.005 respectively. There was no a significant difference or correlation between AGP levels amongst the different groups of patients and there was no significant correlation between AGP and other biomarkers such as Platelets (PLTs), White Blood Cells (WBCs), Absolute Basophils (Abs. Baso) and Lactate Dehydrogenase (LDH) of CML patients in the responders group. However, the group who failed treatment showed a strong correlation between elevated AGP and LDH (p = 0.0001), WBCs (p=0.002) and Abs. Baso (p=0.03) PGP results On the other hand, the mean PGP level was 1.25 (±0.06), 1.17 (±0.02), 1.21 (±0.03), 1.2 (±0.04) for AP, CP, responders and resistant patients respectively. Flow cytometric analysis showed no significant difference in the fluorescence intensities of the blast cells incubated with CD 243 and the blast cells incubated with isotypic control among the different groups of patients. Discussion and Conclusion With a significant difference in AGP levels between patients and controls in our cohort of CML cases, combining AGP with others markers showed significant correlations during different disease stages that may be employed as a warning sign for resistance of CML to Tyrosine Kinase Inhibitors (TKIs). PGP expression, on the other hand did not differ in patients presenting in chronic phase or accelerated phase and showed no specific pattern for those who resist or respond to IM treatment. However, neither AGP nor PGP could be employed as an independent marker for disease progression as the noticed resistance in our CML patients could not be correlated to AGP or PGP levels and regardless of response or resistance to treatment, there was no significant pattern of AGP or PGP expression. Disclosures Al-Dewik: Qatar National Research Fund (QNRF): Other: sponsorship.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4368-4368
Author(s):  
Kursat Ozdilli ◽  
Fatma Oguz ◽  
Yeliz Duvarci ◽  
Hulya Bilgen ◽  
Sema Anak ◽  
...  

Abstract Cytokines are necessary for normal hematopoiesis in the bone marrow and provide a means of fine-tuning bone marrow function in response to stimulation. Several of cytokines generated during both innate and adaptive immune responses stimulate the growth and differantiation of bone marrow progenitor cells. The vast majority of polymorphism found in cytokine genes and their reseptors are located in non coding regions. Cytokine gene polymorphism may be implicated in the pathogenesis of infections, autoimmun disease and malignancies via their effect on cytokine production and regulation. It is known that leukemic cells proliferate under the influence of cytokines. Our aim is to analyze cytokine gene profiles in patients with chronic myeloid leukemia (CML)in order to clarify the pathogenesis of CML. Genomic DNA from 26 CML patients were analysed. Genotyping was performed by polymerase chain reaction with sequence specific primers (PCR-SSP) using “ One lamda” kit in 26 childhood CML patients 60 unrelated healthy individuals. Genotype frequencies between CML patients and controls were compared using Chi-Square Yates, Fisher’s Exact Tests. In this study; 26 CML patients with a mean age of 15,6±5,3 and 60 healthy controls with a mean age of 18,2±5,4 were investigated. In CML patients the frequencies of TGF-b(TC/GG) genotype (in chi-square p=0,01,odds ratio(OR)=3,46, 95% confidence interval (CI) 1,3–9,04) and IL-10 (GCC/ATA) genotype (in chi-square p=0,04,OR=3,3, 95% CI 0,9–11,1 were found higher in patients with CML compared to the control group. On the other hand IL-6 (CC) genotype (in chi-square p=0,012,OR=0,17, 95% CI 0,4–0,76 frequency was found higher in the control group compared to the patients with CML. As a conclusion higher frequency in TGF-b(TC/GG) and IL-10(GCC/ATA) genotype polymorphism were significantly higher in the patients with CML so it may predispose to CML. On the other hand IL-6 (CC) genotype might be the preventive factor for CML. The present study is rather significant that it is the study which assessed the relation of the cytokines in patients with CML compared to the control group taken from the genetic pool of The Turkish population, we believe studies like this will eventually help to understand the pathogenesis of CML and the role cytokines play in CML,but larger groups of studies must be done in future.


2015 ◽  
Vol 7 ◽  
pp. BIC.S31427
Author(s):  
Nader I. Ai-Dewik ◽  
Andrew P. Jewell ◽  
Mohammed A. Yassin ◽  
Hisham M. Morsi

Despite the efficacy of imatinib mesylate (IM) in treating chronic myeloid leukemia (CML), there is a high degree of resistance. Alpha-1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP) may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment.


2021 ◽  
Vol 10 (12) ◽  
pp. 2637
Author(s):  
Mª. Ángeles del Buey-Sayas ◽  
Elena Lanchares-Sancho ◽  
Pilar Campins-Falcó ◽  
María Dolores Pinazo-Durán ◽  
Cristina Peris-Martínez

Purpose: To evaluate and compare corneal hysteresis (CH), corneal resistance factor (CRF), and central corneal thickness (CCT), measurements were taken between a healthy population (controls), patients diagnosed with glaucoma (DG), and glaucoma suspect patients due to ocular hypertension (OHT), family history of glaucoma (FHG), or glaucoma-like optic discs (GLD). Additionally, Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated IOP (IOPcc) were compared between the different groups of patients. Methods: In this prospective analytical-observational study, a total of 1065 patients (one eye of each) were recruited to undergo Ocular Response Analyzer (ORA) testing, ultrasound pachymetry, and clinical examination. Corneal biomechanical parameters (CH, CRF), CCT, IOPg, and IOPcc were measured in the control group (n = 574) and the other groups: DG (n = 147), FHG (n = 78), GLD (n = 90), and OHT (n = 176). We performed a variance analysis (ANOVA) for all the dependent variables according to the different diagnostic categories with multiple comparisons to identify the differences between the diagnostic categories, deeming p < 0.05 as statistically significant. Results: The mean CH in the DG group (9.69 mmHg) was significantly lower compared to controls (10.75 mmHg; mean difference 1.05, p < 0.001), FHG (10.70 mmHg; mean difference 1.00, p < 0.05), GLD (10.63 mmHg; mean difference 0.93, p < 0.05) and OHT (10.54 mmHg; mean difference 0.84, p < 0.05). No glaucoma suspects (FHG, GLD, OHT groups) presented significant differences between themselves and the control group (p = 1.00). No statistically significant differences were found in the mean CRF between DG (11.18 mmHg) and the control group (10.75 mmHg; mean difference 0.42, p = 0.40). The FHG and OHT groups showed significantly higher mean CRF values (12.32 and 12.41 mmHg, respectively) than the DG group (11.18 mmHg), with mean differences of 1.13 (p < 0.05) and 1.22 (p < 0.001), respectively. No statistically significant differences were found in CCT in the analysis between DG (562 μ) and the other groups (control = 556 μ, FHG = 576 μ, GLD = 569 μ, OHT = 570 μ). The means of IOPg and IOPcc values were higher in the DG patient and suspect groups than in the control group, with statistically significant differences in all groups (p < 0.001). Conclusion: This study presents corneal biomechanical values (CH, CRF), CCT, IOPg, and IOPcc for diagnosed glaucoma patients, three suspected glaucoma groups, and a healthy population, using the ORA. Mean CH values were markedly lower in the DG group (diagnosed with glaucoma damage) compared to the other groups. No significant difference was found in CCT between the DG and control groups. Unexpectedly, CRF showed higher values in all groups than in the control group, but the difference was only statistically significant in the suspect groups (FHG, GLD, and OHT), not in the DG group.


2017 ◽  
Vol 7 (2) ◽  
pp. 67 ◽  
Author(s):  
Mehmet Fatih Ocal

Integrating the properties of computer algebra systems and dynamic geometry environments, Geogebra became an effective and powerful tool for teaching and learning mathematics. One of the reasons that teachers use Geogebra in mathematics classrooms is to make students learn mathematics meaningfully and conceptually. From this perspective, the purpose of this study was to investigate whether instruction with Geogebra has effect on students’ achievements regarding their conceptual and procedural knowledge on the applications of derivative subject. This study adopted the quantitative approach with pre-test post-test control group true experimental design. The participants were composed of two calculus classrooms involving 31 and 24 students, respectively. The experimental group with 31 students received instruction with Geogebra while the control group received traditional instruction in learning the applications of derivative. Independent samples t-test was used in the analysis of the data gathered from students’ responses to Applications of Derivative Test which was subjected to them before and after teaching processes. The findings indicated that instruction with Geogebra had positive effect on students’ scores regarding conceptual knowledge and their overall scores. On the other hand, there was no significant difference between experimental and control group students’ scores regarding procedural knowledge. It could be concluded that students in both groups were focused on procedural knowledge to be successful in learning calculus subjects including applications of derivative in both groups. On the other hand, instruction with Geogebra supported students’ learning these subjects meaningfully and conceptually.


2020 ◽  
Vol 26 (7) ◽  
pp. 1676-1682 ◽  
Author(s):  
Semih Başcı ◽  
Naim Ata ◽  
Fevzi Altuntaş ◽  
Tuğçe Nur Yiğenoğlu ◽  
Mehmet Sinan Dal ◽  
...  

Introduction In this study, we aim to report the outcome of COVID-19 in chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitor (TKI). Method The data of 16 laboratory-confirmed COVID-19 patients with CML receiving TKI and age, gender, and comorbid disease matched COVID-19 patients without cancer at a 3/1 ratio (n = 48), diagnosed between March 11, 2020 and May 22, 2020 and included in the Republic of Turkey, Ministry of Health database, were analyzed retrospectively. Results The rates of intensive care unit (ICU) admission, and mechanical ventilation (MV) support were lower in CML patients compared to the control group, however, these differences did not achieve statistical significance (p = 0.1, and p = 0.2, respectively). The length of hospital stay was shorter in CML patients compared with the control group; however, it was not statistically significant (p = 0.8). The case fatality rate (CFR) in COVID-19 patients with CML was 6.3%, and it was 12.8% in the control group. Although the CFR in CML patients with COVID-19 was lower compared to the control group, this difference did not achieve statistical significance (p = 0.5). When CML patients were divided into 3 groups according to the TKI, no significant difference was observed regarding the rate of ICU admission, MV support, CFR, the length of stay in both hospital and ICU (all p > 0.05). Conclusion This study highlights that large scale prospective and randomized studies should be conducted in order to investigate the role of TKIs in the treatment of COVID-19.


2020 ◽  
Vol 7 (2) ◽  
pp. 119-124
Author(s):  
Shinta Oktya Wardhani ◽  
Hani Susianti ◽  
Puji Rahayu ◽  
Yuyun Yueniwati

Background: The failure of imatinib therapy in patients with chronic myeloid leukemia (CML) is associated with the presence of leukemic stem cell (LSC), and the altered LSC level was reported to occur earlier in the progression of CML. Objective: The study aimed to assess the association between the level of LSC and treatment response among CML patients treated with imatinib mesylate. Methods: A cross-sectional study was conducted in Saiful Anwar Hospital. All participants were divided into two groups, response and non-response group. To assess the level of LSC, flow cytometry was conducted conforming with BD Bioscience. The association and effect estimates were determined using multiple logistic regression. Results and Discussion: A total of 29 response and non-response CML patients treated with imatinib therapy were recruited for our study. After six months of imatinib therapy, we found that elevated levels of leukocytes, thrombocytes, basophils, and blast cells were associated with treatment failure among CML patients treated with imatinib. Moreover, we also found that the LSC level was observed significantly higher in the non-response group compared to the response group among CML patients treated with imatinib. Conclusion: Our study reveals that the elevated level of LSC is considered as an important factor to predict the failure of imatinib therapy among CML patients.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2209-2209 ◽  
Author(s):  
Meaghan StCharles ◽  
Vamsi K Bollu ◽  
Elizabeth Hornyak ◽  
John Coombs ◽  
Christopher M Blanchette ◽  
...  

Abstract Abstract 2209 Poster Board II-186 Introduction: Imatinib mesylate (IM), an oral tyrosine kinase inhibitor, is now standard front line therapy for the treatment of patients with chronic myeloid leukemia (CML). As demonstrated in the IRIS trial, IM has a 7-year over-all survival rate of 86%. While treatment with IM is effective, adherence among patients receiving IM is suboptimal. Methods: A retrospective cohort study was performed using Medstat Marketscan employer-based data from Jan 1, 2004 through October 1, 2008 for the purposes of identifying key factors associated with patients who are non-adherent to IM. Patients included in the study were adult patients below age 65, with a diagnosis of CML (ICD-9 205.1x), received two or more prescriptions for IM treatment, and are continuously eligible in the health plan. Patients were required to have a 12-month follow-up data of their complete medical and pharmacy events from their first IM prescription in the study period. Independent variables examined included patient demographics, CML disease complexity, frequency of medical treatment received for adverse events, plan type (PPO/HMO), duration of time on IM, duration of time between CML diagnosis and initiation of IM, average daily dose of starting IM, use of chemotherapies prior to initiation of IM, comorbid conditions, bone marrow/stem cell treatment, and the average percent of patient copayment. Patient adherence to IM treatment was measured by calculating average medication possession ratio (MPR) over the 12-month period. Patients were categorized as adhering to the treatment if they maintained on average an MPR of >85%. A sensitivity analysis was performed utilizing an MPR cut-off of 80%. Descriptive and multivariate statistics were conducted. Logistic regression models were developed to determine the factors that influenced odds of achieving an 80% and 85%, adherence rates. Results: A total of 522 patients had a CML diagnosis and received two or more prescriptions of IM treatment. After applying the exclusion criteria, the final sample included data from 430 patients. The mean age of the patients was 49 years and majority were male (54%). Only 15% of patients received additional chemotherapy during the study period. The number of unique medications consumed by patients averaged 14. The mean MPR in this patient group was 80%, with only 60% of patients categorized as adherent based on MPR of >85%. The following factors were found to be significantly associated with patients who had an MPR of '85%: lower age (p<0.05), shorter exposure to IM (p<0.001), starting IM dose of ≤400 mg (p<0.005), longer time lag between CML diagnosis to IM prescription fill (p<0.0005), higher concomitant prescriptions (p<0.05), and higher percentage of copayment (p<0.01). Conclusions: Approximately 40% of patients receiving IM treatment were categorized as non-adherent to the treatment. Understanding the factors associated with failure to adhere to the treatment regimen will help physicians assess and educate patients receiving CML treatment. Our findings suggest that duration on IM treatment, time lag between CML diagnosis and IM index date, starting IM dose, and patient cost-sharing to be strong predictors of IM non-adherence, suggesting a need for monitoring of these areas within patients with CML. Persistent monitoring, ongoing dialogue, and appropriate IM dosing is crucial to achieving optimal patient adherence in patients with CML. Disclosures: StCharles: Novartis Pharmaceuticals Corporation: Research Funding. Bollu:Novartis Pharmaceuticals Corporation: Employment. Hornyak:Novartis Pharmaceuticals Corporation: Employment. Coombs:Novartis Pharmaceuticals Corporation: Employment. Blanchette:Novartis Pharmaceuticals Corporation: Research Funding. DeAngelo:Enzon Pharmaceuticals: Research Funding; Celgene: Speakers Bureau; Bristol-Meyers Squibb: Speakers Bureau; Novartis: Speakers Bureau.


2015 ◽  
Vol 12 (1) ◽  
pp. 110-118
Author(s):  
Baghdad Science Journal

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence Philadelphia chromosome (Ph) which was created by a reciprocal translocation between chromosomes 9 and 22 (t [9;22] [q34;q11]. The approval of the 2nd generation TKI ( Nilotinib) takes the treatment of CML patients into new erea with more efficiency and mild to moderate adverse effects. This study was aimed at evaluation of molecular cytogenetic response by (FISH) for Nilotinib in Iraqi patients with assessment for electrolytes disturbances of Nilotinb by measuring a panel of electrolyte (Na+, K+, Ca++, PO4--- and Mg++) , where thirty Iraqi patients with CML who have resistance or no response to Imatinib treatment, attending to Baghdad Teaching Hospital/Hematology Department, have been submitted to this study. Blood samples have been taken pre and post starting treatment with Nilotinib, FISH study was done only for CML patients, while 30 normal healthy control volunteers submitted to the same panel of electrolytes measurements (Na+, K+, Ca++, PO4--- and Mg++) in addition to pre and post treatment Nilotinib patients. The results show out of 30 patients (17) males and (13) females with male to female ratio 1.3:1, FISH results for patients (pre and post) treatment mean±SD were(58.7%±26.2 % and 45.7%±29.9%) obviously significant with good cytogenetic response in resistance CML for Imatinib. Sodium levels in mmol/L pre, post treatment and control mean±SD were (139.2±6.9 , 142.4±9.2 and 140.4±2.52) respectively, with no significant difference between each other with P value > 0.05 in all comparisons. Potassium levels mean±SD in mmol/L results for patients (pre, post) and control were (4.6±0.69, 4.3±0.68 and 4.46±0.76) respectively, with no significant difference between each other with P value > 0.05 in all comparisons. Calcium levels in mg/dL results for patients (pre, post) and control as mean±SD were (8.68 ±1.68, 8.1±1.72 and 9.12±0.38) respectively with no significant differences except between post treatment and control group with P value > 0.05 in all comparisons. Phosphate levels in mg/dL results for patients (pre, post) and control as mean±SD were (2.5±0.84, 2.95±1.04 and 3.4±0.49) respectively with significant difference with P value < 0.05 in all comparisons. Magnesium levels in mg/dL results for patients pre, post and control as mean±SD were (1.93±0.34, 2.06±0.44 and 2.1±0.34) respectively with no significant difference between each other with P value > 0.05 in all comparisons. This study sheds a light on the molecular cytogenetic response for CML patients who have already resistance to Imatinib and Nilotinib that has much more potent effect as approved by studies and this study has used FISH technique. This study emphasizes on the importance of evaluation of electrolyte panel for CML patients before starting Nilotinib study taking in to consideration if these patients are already receiving Imatinib which can also affect bone metabolism and calcium and phosphate levels.


2020 ◽  
Author(s):  
Mostafa Abdelnaem ◽  
Maha Ali Hassan ◽  
Mohamed Helmy Abdel Hafeez

Abstract BackgroundChildhood epilepsy can have a significant impact on family functioning with high rates of patent anxiety and depression being reported.ObjectivesTo demonstrate the frequency of depression, anxiety and distress among the parents of epileptic children.Patients and MethodsA cross sectional study design was carried out on 100 children and their parents attending the outpatient clinics in Minia University Hospital, arranged in two groups, Group (A) consisted of 50 epileptic children and their caregivers. On the other hand, Group (B) consisted of 50 age- and sex matched controls. Comprehensive Assessment was carried out. A well-prepared sheet had been used for the evaluation of subjects of the study. Twenty-one item Depression Anxiety Stress Scale (DASS-21), Hamilton Anxiety Scale (HAM - A) and Hamilton Rating Scale for Depression (HRSD) were used for interviewing the parents of the epileptic children to screen for depression, anxiety, stress in those parents. This process preceded by full explanation of all the previous tools.There was statistically significant difference between the parents of the epileptic group and the control group regarding DASS score, and HAM-A score. There was no statistically significance between the 2 groups regarding the HRSD. The parents group of generalized fits shows to have a higher score of DASS (9.5±4.7), HDRS (5.1±3.3). In contrast to the focal fits group. On the other hand, the parents of group of generalized fits shows to have lower score of HAM-A (6.7±4) in contrast to the focal fits group but not statistically significant.Compliant group shows to have higher score of HAM-A, HDRS score in contrast to non-compliant group. These correlations were not statistically significant.ConclusionsParents of the epileptic children had more anxiety, depression and stress than the control. Lower parental education was associated with more distress and anxiety.Ploy-therapy increased parent anxiety and depression. Compliance on treatment decreased parent distress but increased parent anxiety and depression.


Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1782-1789 ◽  
Author(s):  
Vivian G. Oehler ◽  
Ted Gooley ◽  
David S. Snyder ◽  
Laura Johnston ◽  
Allen Lin ◽  
...  

Abstract The impact of imatinib mesylate (IM) treatment for chronic myeloid leukemia (CML) on subsequent allogeneic transplantation is uncertain. To better understand this relationship, we retrospectively compared 145 patients with CML receiving IM for a minimum of 3 months before allogeneic hematopoietic cell transplantation (HCT) to 231 patients with CML who did not. IM treatment was associated with no increase in early hepatotoxicity or engraftment delay after HCT compared with the historical cohort. In addition, there was no statistically significant difference in the IM-treated cohort compared with the historical cohort with regard to overall survival, disease-free survival, relapse, and nonrelapse mortality. For chronic-phase (CP) patients, IM response prior to HCT was associated with post-HCT outcome. Patients who underwent transplantation in CP with a suboptimal response or a loss of response on IM had a statistically significant higher hazard of mortality when compared with CP patients who achieved a complete cytogenetic response (CCR) or major cytogenetic response (MCR) on IM (HR = 5.31, 95% confidence interval [CI] 1.13-25.05, P = .03). These data indicate that pre-HCT IM is not associated with increased transplant-related morbidity (TRM) or poorer outcomes. However, patients with a suboptimal or loss of IM response before HCT do worse, suggesting a more aggressive disease course for these patients.


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