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Clinical Advances in Hematology &... Nov 2021The emerging molecular and prognostic characterization of diffuse large B-cell lymphoma (DLBCL) has challenged the rituximab, cyclophosphamide, doxorubicin, vincristine,... (Review)
Review
The emerging molecular and prognostic characterization of diffuse large B-cell lymphoma (DLBCL) has challenged the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment paradigm in recent years, with the identification of several DLBCL subtypes associated with significantly inferior survival after standard R-CHOP therapy. Efforts to improve upon the R-CHOP backbone have included dose intensification as well as the addition of new agents; the infusional dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) regimen has been identified as a potential replacement for R-CHOP in high-risk DLBCL. In this review, we provide a historical perspective on the R-CHOP and DA-R-EPOCH regimens and summarize the clinical trial literature regarding the efficacy of each regimen in various risk groups of DLBCL. Further, we propose clinical management scenarios in which DA-R-EPOCH may be preferred, including some for patient populations in which the use of R-CHOP vs DA-R-EPOCH is controversial.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lymphoma, Large B-Cell, Diffuse; Prednisone; Rituximab; Treatment Outcome; Vincristine
PubMed: 34807015
DOI: No ID Found -
Journal of Neuromuscular Diseases 2022Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle... (Review)
Review
Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle strength, improve timed motor function, delay loss of ambulation, improve pulmonary function, reduce the need for scoliosis surgery, delay onset of cardiomyopathy, and increase survival. Both have been used off-label for many years (choice dependent on patient preference, cost, and geographic location) before FDA approval of deflazacort for DMD in 2017. In this review, we compare deflazacort and prednisone/prednisolone in terms of their key pharmacological features, relative efficacy, and safety profiles in patients with DMD. Differentiating features include lipid solubility, pharmacokinetics, changes in gene expression profiles, affinity for the mineralocorticoid receptor, and impact on glucose metabolism. Evidence from randomized clinical trials, prospective studies, meta-analyses, and post-hoc analyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone. Regarding side effects, weight gain and behavior side effects appear to be greater with prednisone/prednisolone than with deflazacort, whereas bone health, growth parameters, and cataracts appear worse with deflazacort.
Topics: Humans; Muscular Dystrophy, Duchenne; Prednisolone; Prednisone; Pregnenediones; Prospective Studies
PubMed: 35723111
DOI: 10.3233/JND-210776 -
JAMA May 2023Implantation failure remains a critical barrier to in vitro fertilization. Prednisone, as an immune-regulatory agent, is widely used to improve the probability of... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Implantation failure remains a critical barrier to in vitro fertilization. Prednisone, as an immune-regulatory agent, is widely used to improve the probability of implantation and pregnancy, although the evidence for efficacy is inadequate.
OBJECTIVE
To determine the efficacy of 10 mg of prednisone compared with placebo on live birth among women with recurrent implantation failure.
DESIGN, SETTING, AND PARTICIPANTS
A double-blind, placebo-controlled, randomized clinical trial conducted at 8 fertility centers in China. Eligible women who had a history of 2 or more unsuccessful embryo transfer cycles, were younger than 38 years when oocytes were retrieved, and were planning to undergo frozen-thawed embryo transfer with the availability of good-quality embryos were enrolled from November 2018 to August 2020 (final follow-up August 2021).
INTERVENTIONS
Participants were randomized (1:1) to receive oral pills containing either 10 mg of prednisone (n = 357) or matching placebo (n = 358) once daily, from the day at which they started endometrial preparation for frozen-thawed embryo transfer through early pregnancy.
MAIN OUTCOMES AND MEASURES
The primary outcome was live birth, defined as the delivery of any number of neonates born at 28 or more weeks' gestation with signs of life.
RESULTS
Among 715 women randomized (mean age, 32 years), 714 (99.9%) had data available on live birth outcomes and were included in the primary analysis. Live birth occurred among 37.8% of women (135 of 357) in the prednisone group vs 38.8% of women (139 of 358) in the placebo group (absolute difference, -1.0% [95% CI, -8.1% to 6.1%]; relative ratio [RR], 0.97 [95% CI, 0.81 to 1.17]; P = .78). The rates of biochemical pregnancy loss were 17.3% in the prednisone group and 9.9% in the placebo group (absolute difference, 7.5% [95% CI, 0.6% to 14.3%]; RR, 1.75 [95% CI, 1.03 to 2.99]; P = .04). Of those in the prednisone group, preterm delivery occurred among 11.8% and of those in the placebo group, 5.5% of pregnancies (absolute difference, 6.3% [95% CI, 0.2% to 12.4%]; RR, 2.14 [95% CI, 1.00 to 4.58]; P = .04). There were no statistically significant between-group differences in the rates of biochemical pregnancy, clinical pregnancy, implantation, neonatal complications, congenital anomalies, other adverse events, or mean birthweights.
CONCLUSIONS AND RELEVANCE
Among patients with recurrent implantation failure, treatment with prednisone did not improve live birth rate compared with placebo. Data suggested that the use of prednisone may increase the risk of preterm delivery and biochemical pregnancy loss. Our results challenge the value of prednisone use in clinical practice for the treatment of recurrent implantation failure.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR1800018783.
Topics: Female; Humans; Pregnancy; Abortion, Spontaneous; Fertilization in Vitro; Live Birth; Prednisone; Pregnancy Rate; Premature Birth; Placebos; Abortion, Habitual; Embryo Implantation; Double-Blind Method; Administration, Oral; Adult; Embryo Transfer; Pregnancy Outcome
PubMed: 37129654
DOI: 10.1001/jama.2023.5302 -
Journal of Clinical Oncology : Official... Jul 2019Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303.
PURPOSE
Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma.
PATIENTS AND METHODS
Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety.
RESULTS
Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% 10.7%, respectively), febrile neutropenia (35.0% 17.7%, respectively), mucositis (8.4% 2.1%, respectively), and neuropathy (18.6% 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm.
CONCLUSION
In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Prednisone; Progression-Free Survival; Vincristine; Young Adult
PubMed: 30939090
DOI: 10.1200/JCO.18.01994 -
CMAJ : Canadian Medical Association... Nov 2021
Topics: Aged; Aged, 80 and over; Diagnosis, Differential; Female; Giant Cell Arteritis; Glucocorticoids; Humans; Incidence; Male; Medical History Taking; Middle Aged; Polymyalgia Rheumatica; Prednisone
PubMed: 34810164
DOI: 10.1503/cmaj.210541 -
JAMA Apr 2022Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage.
OBJECTIVE
To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy.
DESIGN, SETTING, AND PARTICIPANTS
Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019).
INTERVENTIONS
Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66).
MAIN OUTCOMES AND MEASURES
The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017.
RESULTS
Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]).
CONCLUSIONS AND RELEVANCE
Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01603407.
Topics: Child; Child, Preschool; Female; Glucocorticoids; Humans; Male; Muscular Dystrophy, Duchenne; Prednisone; Pregnenediones
PubMed: 35381069
DOI: 10.1001/jama.2022.4315 -
The Cochrane Database of Systematic... Feb 2022Focal segmental glomerulosclerosis (FSGS) can be separated into primary, genetic or secondary causes. Primary disease results in nephrotic syndrome while genetic and... (Review)
Review
BACKGROUND
Focal segmental glomerulosclerosis (FSGS) can be separated into primary, genetic or secondary causes. Primary disease results in nephrotic syndrome while genetic and secondary forms may be associated with asymptomatic proteinuria or with nephrotic syndrome. Overall only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome with treatment. FSGS progresses to kidney failure in about half of the cases. This is an update of a review first published in 2008.
OBJECTIVES
To assess the benefits and harms of immunosuppressive and non-immunosuppressive treatment regimens in adults with FSGS.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies to 21 June 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials (RCTs) and quasi-RCTs of any intervention for FSGS in adults were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non-immunosuppressive agents were assessed.
DATA COLLECTION AND ANALYSIS
At least two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
MAIN RESULTS
Fifteen studies (560 participants) were included. No studies specifically evaluating corticosteroids compared with placebo or supportive therapy were identified. Studies evaluated participants with steroid-resistant FSGS. Five studies (240 participants) compared cyclosporin with or without prednisone with different comparators (no specific treatment, prednisone, methylprednisolone, mycophenolate mofetil (MMF), dexamethasone). Three small studies compared monoclonal antibodies (adalimumab, fresolimumab) with other agents or placebo. Six single small studies compared rituximab with tacrolimus, cyclosporin plus valsartan with cyclosporin alone, MMF with prednisone, chlorambucil plus methylprednisolone and prednisone with no specific treatment, different regimens of dexamethasone and CCX140-B (an antagonist of the chemokine receptor CCR2) with placebo. The final study (109 participants) compared sparsentan, a dual inhibitor of endothelin Type A receptor and of the angiotensin II Type 1 receptor, with irbesartan. In the risk of bias assessment, seven and five studies were at low risk of bias for sequence generation and allocation concealment, respectively. Four studies were at low risk of performance bias and 14 studies were at low risk of detection bias. Thirteen, six and five studies were at low risk of attrition bias, reporting bias and other bias, respectively. Of five studies evaluating cyclosporin, four could be included in our meta-analyses (231 participants). Cyclosporin with or without prednisone compared with different comparators may increase the likelihood of complete remission (RR 2.31, 95% CI 1.13 to 4.73; I² = 1%; low certainty evidence) and of complete or partial remission (RR 1.64, 95% CI 1.10 to 2.44; I² = 19%) but not of partial remission (RR 1.36, 95% CI 0.78 to 2.39, I² = 22%). In Individual studies, cyclosporin with prednisone versus prednisone may increase the likelihood of partial (49 participants: RR 7.96, 95% CI 1.09 to 58.15) or complete or partial remission (49 participants: RR 8.85, 95% CI 1.22 to 63.92) but not of complete remission. The remaining individual comparisons may make little or no difference to the likelihood of complete remission, partial remission or complete or partial remission compared with no treatment, methylprednisolone, MMF, or dexamethasone. Individual study data and combined data showed that cyclosporin may make little or no difference to the outcomes of chronic kidney disease or kidney failure. It is uncertain whether cyclosporin compared with these comparators in individual or combined analyses makes any difference to the outcomes of hypertension or infection. MMF compared with prednisone may make little or no difference to the likelihood of complete remission (33 participants: RR 1.05, 95% CI 0.58 to 1.88; low certainty evidence), partial remission, complete or partial remission, glomerular filtration rate, or infection. It is uncertain whether other interventions make any difference to outcomes as the certainty of the evidence is very low. It is uncertain whether sparsentan reduces proteinuria to a greater extent than irbesartan.
AUTHORS' CONCLUSIONS
No RCTs, which evaluated corticosteroids, were identified although the KDIGO guidelines recommend corticosteroids as the first treatment for adults with FSGS. The studies identified included participants with steroid-resistant FSGS. Treatment with cyclosporin for at least six months was more likely to achieve complete remission of proteinuria compared with other treatments but there was considerable imprecision due to few studies and small participant numbers. In future studies of existing or new interventions, the investigators must clearly define the populations included in the study to provide appropriate recommendations for patients with primary, genetic or secondary FSGS.
Topics: Adult; Cyclosporine; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic
PubMed: 35224732
DOI: 10.1002/14651858.CD003233.pub3 -
Cancer Cell Dec 2021In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for...
In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL.
Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Piperidines; Prednisone; Rituximab; Vincristine
PubMed: 34739844
DOI: 10.1016/j.ccell.2021.10.006 -
Journal of Clinical Oncology : Official... Apr 2023To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD).
METHODS
Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety.
RESULTS
Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients.
CONCLUSION
There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.
Topics: Humans; Child; Prednisone; Bronchiolitis Obliterans Syndrome; Progression-Free Survival; Piperidines; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method
PubMed: 36608310
DOI: 10.1200/JCO.22.00509 -
Blood Advances Apr 2023Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial...
Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.
Topics: Humans; Aged; Aged, 80 and over; Dasatinib; Prednisone; Treatment Outcome; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36322825
DOI: 10.1182/bloodadvances.2022008216