Online discussion forums are asynchronous communication tools that are widely used in Learning Management Systems. However, instructors and students face various difficulties, and instructors lack a ...guide on what strategies they can use to achieve a more participatory forum environment. This work aims to identify benefits and difficulties of using online discussion forums from the instructors’ point of view, and to provide a list of strategies and improvements that can mitigate the challenges and lead to a more participatory forum. We used coding procedures to analyze data collected through semi-structured interviews. The results of our exploratory analysis are relevant to the distance learning community and can inform instructors, developers, and researchers to help them improve the quality of mediation and use of forums.
Introduction/Objectives: Multiple myeloma is a disease of elderly and frail people, who are often predominantly ineligible for intensive therapies. The objective of this analysis is to report the ...efficacy and safety of elranatamab monotherapy by age and frailty in B-cell maturation antigen-naïve patients (pts) with relapsed or refractory multiple myeloma (RRMM) enrolled into cohort A of the ongoing phase 2 MagnetisMM -3 (NCT04649359) study. Materials and methods: Eligibility criteria, dosing and administration were previously reported (Bahlis et al, ASH 2022). Subgroups of pts within Cohort A (n = 123) were analyzed by age: <65 (n = 43) vs ≥65 years (n = 80) and frailty: non-frail (n = 84) vs frail (n = 39). A simplified frailty scale was used (Facon et al, Leukemia 2020). Results include data up through ≍12 months after last pt initial dose. Results: The median treatment duration was 8.2 vs 5.5 mo in the <65 vs ≥65 years, and 6.4 vs 5.6 mo in the non-frail and frail subgroups, respectively. Discontinuation occurred in 62.8% vs 67.5% of pts aged <65 vs ≥65 years and in 63.1% vs 71.8% of the non-frail vs frail groups, respectively. The most common reason for discontinuation in all subgroups was progressive disease, 51.2%, 32.5%, 42.9%, and 30.8% of <65, ≥65 years, non-frail, and frail subgroups, respectively. The objective response rate (ORR) (95% CI) was 58.1% (42.1%, 73.0%) vs 62.5% (51.0%, 73.1%) for pts aged <65 vs ≥65 years. Median duration of response was not reached in either age subgroup. The probability of maintaining response (95% CI) at 12 mo was 74.1% (51.0%, 87.5%) vs 73.8% (55.7%, 85.4%) for pts aged <65 vs ≥65 years. The ORR (95% CI) for non-frail pts was 63.1% (51.9%, 73.4%) vs 56.4% (39.6%, 72.2%) for frail pts. Median duration of response was not reached in either frailty subgroup. The probability of maintaining response at 12 mo (95% CI) was 76.0% (60.2%, 86.2%) vs 70.5% (41.9%, 86.9%) for non-frail vs frail pts. Any grade treatment-emergent adverse events (TEAEs) were reported in 100% of pts in the study. Grade 3/4 TEAEs were reported in 74.4%, 68.8%, 73.8% and 64.1% of pts in <65, ≥65, non-frail and frail subgroups, respectively. Infections (any grade; grade 3/4; grade 5) were reported in 72.1%, 32.6% and 4.7% vs 68.8%, 40.0% and 6.3% in <65 and ≥65 pts, respectively, and in 70.2%, 38.1% and 4.8% vs 69.2%, 35.9% and 7.7% in non-frail and frail pts, respectively. The rate of cytokine release syndrome was similar in patients with respect to age (<65, 58.1%; ≥65 years, 57.5%) and frailty groups (non-frail, 57.1%; frail, 59.0%). Immune effector cell-associated neurotoxicity syndrome was reported in 2.3%, 6.3%, 6.0% and 2.6% of pts in <65, ≥65, non-frail and frail subgroups, respectively. Discussion: Elranatamab is efficacious and has a manageable safety profile in elderly or frail pts with RRMM. Conclusions: Elranatamab may be a treatment option for those ineligible for more intensive myeloma therapies.
In this study hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) were used as polymeric carriers to improve controlled release performances of matrix tablets containing a ...soluble drug. The drug release behaviour of the systems containing these two polymers mixture and each material separately was investigated. To evaluate the effect of the dissolution medium pH, on the drug release performance, release tests were conducted at pH 1, 4.5 and 6.8. In vitro release studies demonstrated that the mixture of the two cellulose derivatives enables a better control of the drug release profiles at pH 4.5 and at 6.8 both in term of rate and mechanism. Texture analysis on the swollen tablets helps to understand drug release kinetic and mechanism. In fact, the results obtained confirm that a gel, which is characterized by high strength and consistence is less susceptible to erosion and chains disentanglement and the drug release mechanism is mainly governed by diffusion. On the contrary, gels, which show a low strength and texture, have low resistance to the fluid erosion action and the release of the active molecule is manly due to polymer relaxation and chains disentanglement moving the drug delivery kinetic towards an erosion/relaxation mechanism.
High molecular weight polyethylene oxides (PEOs) have recently been proposed as an alternative to hydroxypropylmethylcellulose (HPMC) in controlled release matrix tablets. In this study, we compared ...the performance of PEO and HPMC polymers when employed in the Geomatrix®
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Geomatrix® is a registered trademark of Skye Pharma AG, Muttenz, CH.
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technology, a versatile, well-known method to achieve extended release of drugs at a constant rate. Four core formulations were prepared, containing a soluble drug (diltiazem) and, alternatively, PEO or HPMC of two different viscosity grades. These formulations have the same composition except for the polymer employed. Similarly, four barrier formulations were also prepared, which only differ in the kind of polymer employed. Three-layer Geomatrix® systems were then prepared using these core and barrier formulations. The release profiles of the different three-layer systems obtained were compared, to verify if PEO could efficiently replace HPMC in this type of dosage form. The results show that slower release rates can be obtained from the plain matrices containing HPMC compared to PEO, moreover HPMC, used in the barrier formulations, is generally more efficient in controlling drug release rate in three-layer Geomatrix systems.
An influx of newcomers is critical to the survival, long-term success, and continuity of many Open Source Software (OSS) community-based projects. However, newcomers face many barriers when making ...their first contribution, leading in many cases to dropouts. Due to the collaborative nature of community-based OSS projects, newcomers may be susceptible to social barriers, such as communication breakdowns and reception issues. In this article, we report a two-phase study aimed at better understanding social barriers faced by newcomers. In the first phase, we qualitatively analyzed the literature and data collected from practitioners to identify barriers that hinder newcomers’ first contribution. We designed a model composed of 58 barriers, including 13 social barriers. In the second phase, based on the barriers model, we developed FLOSScoach, a portal to support newcomers making their first contribution. We evaluated the portal in a diary-based study and found that the portal guided the newcomers and reduced the need for communication. Our results provide insights for communities that want to support newcomers and lay a foundation for building better onboarding tools. The contributions of this paper include identifying and gathering empirical evidence of social barriers faced by newcomers; understanding how social barriers can be reduced or avoided by using a portal that organizes proper information for newcomers (FLOSScoach); presenting guidelines for communities and newcomers on how to reduce or avoid social barriers; and identifying new streams of research.
Aims: To characterize and select Lactobacillus strains for properties that would make them a good alternative to the use of antibiotics to treat human vaginal infections.
Methods and Results: Ten ...Lactobacillus strains belonging to four different Lactobacillus species were analysed for properties relating to mucosal colonization or microbial antagonism (adhesion to human epithelial cells, hydrogen peroxide production, antimicrobial activity towards Gardnerella vaginalis and Candida albicans and coaggregation with pathogens). The involvement of electrostatic interactions and the influence of bacterial metabolic state in the binding of lactobacilli to the cell surface were also studied. Adherence to epithelial cells varied greatly among the Lactobacillus species and among different strains belonging to the same Lactobacillus species. The reduction in surface negative electric charge promoted the binding of several Lactobacillus strains to the cell membrane whereas lyophilization reduced the adhesion capacity of many isolates. The antimicrobial activity of lactobacilli culture supernatant fluids was not directly related to the production of H2O2.
Conclusions: Three strains (Lactobacillus brevis CD2, Lact. salivarius FV2 and Lact. gasseri MB335) showed optimal properties and were, therefore, selected for the preparation of vaginal tablets. The selected strains adhered to epithelial cells displacing vaginal pathogens; they produced high levels of H2O2, coaggregated with pathogens and inhibited the growth of G. vaginalis.
Significance and Impact of the Study: The dosage formulation developed in this study appears to be a good candidate for the probiotic prophylaxis and treatment of human vaginal infections.
The aim of the present study is an investigation of the swelling behaviour of matrix systems containing a mixture of hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) with ...a model soluble drug to find the correlation between the morphological behaviour and the drug release performance. The swelling study was conducted on tablets containing only the drug and the two polymers mixture (MB) and on reference tablets containing each polymer and the same drug, at three different pHs. MB matrices show a similar swelling trend at pH 4.5 and 6.8, while they have different behaviour in acidic fluid. At pH 1 the gel layer formed by NaCMC is characterized by a rigid structure of a partially chemically crosslinked hydrogel while HPMC and MB matrices form a physical not crosslinked gel. At pH 4.5 and 6.8, all the systems show the typical morphological behaviour of a swellable matrix in which the macromolecular chains in the gel network are held together by weak bondings (physical gel). In these buffers, MB systems maintain a constant drug release rate coupling diffusion and erosion mechanism: the gel and infiltrated layers thicknesses are maintained constant and a zero-order release kinetics can be achieved.
Introduction/Objectives: To report the findings of extended follow-up and biweekly administration of elranatamab monotherapy in patients (pts) with relapsed/refractory multiple myeloma (RRMM) naïve ...to BCMA-directed therapies enrolled in Cohort A of MagnetisMM-3. Materials and methods: MagnetisMM-3 (NCT04649359) is an open-label, multicenter, registration phase 2 study evaluating the efficacy and safety of elranatamab monotherapy in pts with RRMM. Eligible pts were refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Pts received subcutaneous elranatamab in 28-d cycles with step-up doses of 12 mg on cycle 1 day 1 (C1D1) and 32 mg on C1D4 followed by 76 mg once-weekly beginning C1D8. Pts treated for 6 cycles and achieving partial response (PR) or better, lasting ≥2 mo, were switched to 76 mg once every two weeks (Q2W). Results: Overall, 123 pts received elranatamab. Median pt age was 68.0 y (range, 36-89); 63.4% of pts had an ECOG PS ≥1. The median number of prior lines of therapy was 5.0 (2-22), with 96.7% and 42.3% of pts having triple-class- and penta-drug refractory disease, respectively. At data cutoff (≍12 mo after last pt initial dose), the median follow up was 12.8 mo (0.2-22.7); 34.1% of pts remained on treatment. The most common reasons for treatment discontinuation were progressive disease (39.0%) and adverse events (AE; 13.8%). Objective response rate per blinded independent central review (BICR) was 61% (95% CI 51.8-69.6), with 39 (31.7%) pts with complete response (CR) or stringent CR (sCR); very good partial response (VGPR) and PR were achieved in 29 (23.6%) and 7 (5.7%) pts, respectively. MRD-negativity (threshold 10−−5) was achieved by 92.0% (n = 23/25) of evaluable pts. Median duration of response (mDOR) has not been reached (95% CI 12.9-NE), and DOR at 12 mo was 74.1% (95% CI 60.5-83.6). In pts with CR/sCR or VGPR, mDOR was not reached by 12 mo; in pts with PR, mDOR was 5.2 mo (95% CI 1.6-NE). There were 46 responders by BICR who switched to Q2W dosing ≥24 wk prior to the data cutoff; among these pts, 80.4% maintained/improved their response ≥24 wk after the switch. Median progression-free and overall survival have not been reached by 12 mo, and the respective rates (95% CI) at 12 mo were 57.1% (47.2-65.9) and 62.0% (52.8-70.0). Most common grade 3/4 treatment emergent AEs were hematologic; grade 3/4 nonhematologic events reported in ≥5% of pts were COVID-pneumonia (10.6%), hypokalemia (9.8%), pneumonia (7.3%), sepsis (6.5%), hypertension (6.5%), ALT increased (5.7 %), and SARS-COV-2 test positive (5.7%). Among pts who switched to Q2W dosing (n = 58), the incidence of grade 3/4 AEs decreased by >10% after the switch. Discussion: Elranatamab remains efficacious and well tolerated in pts with RRMM after >1 y of follow-up. Updated analysis with a median follow-up of ≍15 mo, the longest of all phase 2 BCMA-CD3 bispecific antibody studies, including the outcome of pts who switched to the Q2W dosing, will be presented. Conclusion: These results support continued elranatamab development for pts with MM.
Introduction/Objectives: To evaluate the efficacy and safety of elranatamab in a pooled analysis of patients (pts) enrolled in MagnetisMM trials with relapsed or refractory multiple myeloma (RRMM) ...who had prior exposure to B-cell maturation antigen (BCMA)-directed therapy. Materials and methods: Eligible pts received at least 1 proteasome inhibitor, 1 immunomodulatory drug, 1 anti-CD38 antibody, and 1 BCMA-directed therapy (antibody-drug conjugate ADC and/or chimeric antigen receptor CAR-T cells). The pooled analysis included pts in the MagnetisMM-1 trial (NCT03269136; n = 13) who received subcutaneous (SC) elranatamab 215-1000 μg/kg; MM-3 (NCT04649359; n = 64) and MM-9 (NCT05014412; n = 9) who received the recommended phase 2 dose of 76 mg SC once-weekly. Efficacy endpoints were evaluated by investigator per IMWG criteria. TEAEs were graded by CTCAE (MM-1, v4.03; MM-3 & MM-9, v5.0); CRS and ICANS were graded by ASTCT criteria. Results include data up through ≍10 months after last pt initial dose in all pooled studies. Results: In total, 86 pts were included. Median age was 66.0 y (range, 40-84); 47.7% male. At baseline, 69.8% had an ECOG PS ≥1; 24.4% had high risk cytogenetics; 54.7% had extramedullary disease. Pts received a median of 7.0 (3-19) prior lines of therapy, including BCMA-directed ADC (67.4%), CAR T-cells (41.9%); 9.3% received both. 96.5% and 54.7% of pts were triple-class and penta-drug refractory, respectively; among pts who received ADC and CAR-T cells respectively, 79.3% and 27.8% were refractory to ADC and CAR-T cells. After a median follow-up of 10.3 mo (0.3-32.3), median duration of treatment was 3.3 mo (0.03-30.4). At the cut-off date, 24.4% of pts remained on treatment; most common reason for permanent treatment discontinuation was progressive disease (44.2%). The overall response rate (ORR) was 45.3% (95% CI 34.6-56.5), with ≥CR achieved in 17.4% of pts. ORR for pts with prior BCMA-directed ADC and CAR-T cells was 41.4% (95% CI 28.6-55.1) and 52.8% (95% CI 35.5-69.6), respectively. Among responders, median time to objective response was 1.9 mo (0.3-9.3). Median duration of response (DOR) was not reached by 10 mo; the DOR rate at 9 mo was 72.4% (95% CI 54.7-84.2). DOR rate (95% CI) for pts with prior BCMA-directed ADC and CAR-T cells were 67.3% (43.1-83.0) and 78.9% (53.2-91.5) at 9 mo, respectively. Median progression-free survival was 4.8 mo (95% CI 1.9-7.7); median overall survival was not reached by 10 mo, with a rate of 60.1% (95% CI 48.9-69.6) at 9 mo. Most common (≥25% of pts) TEAEs were CRS (65.1% G3 1.2%), anemia (59.3% G3/4, 46.5%), neutropenia (44.2% G3/4, 40.7%), thrombocytopenia (40.7% G3/4, 29.1%), diarrhea (33.7% G3/4, 0%, and lymphopenia (32.6% G3/4, 30.2%). 5.8% (G3, 2.3%) of pts. Discussion: In pts with RRMM and prior exposure to BCMA-directed therapies, elranatamab was efficacious and well tolerated; no new safety signals were observed vs the BCMA-naïve population. Conclusions: These results support treatment with elranatamab in pts with RRMM post BCMA-directed therapy.
BackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesReport the pharmacokinetics (PK), safety and taste acceptability of tofacitinib ...following multiple oral doses in patients (pts) 2-<18 years (yrs) old with active juvenile idiopathic arthritis (JIA).MethodsData were obtained from an open-label, non-randomised, multicentre, Phase I study (NCT01513902) where JIA pts were given 5 mg adult equivalent (based on body weight) of tofacitinib (tablet or solution) twice daily (BID) for 5 days (Table). There were 3 cohorts (COH) based on pt age, COH1: 12-<18 yrs, COH2: 6-<12 yrs, and COH3: 2-<6 yrs, with a target enrolment per group of ≥8 JIA pts for N=≥24 evaluable pts completing the study. Pts were enrolled in a step-wise approach beginning with the older age COH first. Subsequent younger age COH were enrolled following confirmation of safety and PK from the previous COH. PK parameters of tofacitinib were calculated using non-compartmental analysis of plasma concentration (conc)-time data. Taste acceptability of the solution formulation was listed and categorically summarised (frequency and %).Results26 pts (COH1 N=8, COH2 N=9 and COH3 N=9) were included in this analysis. Pts' age ranged from 2–17 years; all were white race except for one; there were 17 females and 9 males. Baseline disease characteristics were similar across all COH. All exposure metrics including geometric mean (GM) area under the conc-time curves (AUCtau), maximum (Cmax), minimum (Cmin) and predose (Ctrough) conc were lower in COH2 relative to those in COH1; however, due to higher doses in COH3 (modified after interim analysis of COH1 and 2), the mean AUCtau in COH3 was comparable to COH1. GM apparent volume of distribution (Vz/F) decreased with age (COH1=104.9L, COH2=71.0L, COH3=51.4L). Average terminal half-life (t1/2) were COH1=2.62h, COH2=1.95h and COH3=1.77h. GM tofacitinib CL/F were 53%, 39% and 11% higher in COH1, COH2 and COH3 pts, respectively, vs adult RA pts (18.4L/h) receiving tofacitinib 5 mg BID. GM CL/F and V/F parameters were similar between males and females. Tofacitinib, administered over 5 days as multiple dose tablets or solution formulation, was well tolerated and taste for the solution formulation was found acceptable in children with active JIA. No serious adverse events or new safety signals were identified.ConclusionsPK results from this study established dosing regimens for pts aged ≥2 years to be used in the upcoming efficacy and safety studies of tofacitinib in JIA pts. Tofacitinib was well tolerated in this study in JIA pts. Overall, pts found the taste of the tofacitinib solution formulation to be acceptable.AcknowledgementStudy sponsored by Pfizer Inc. Editorial support provided by CMC (funded by Pfizer Inc).Disclosure of InterestN. Ruperto Consultant for: Abbott, AbbVie, Amgen, Astellas Pharma, Alter, AstraZeneca, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer Inc, Roche, Sanofi Aventis, Servier, Takeda, Vertex, Speakers bureau: Abbott, AbbVie, Amgen, Astellas Pharma, Alter, AstraZeneca, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, CD-Pharma, Celgene, Crescendo Bioscience, EMD Serono, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer Inc, Roche, Sanofi Aventis, Servier, Takeda, Vertex, H. Brunner Consultant for: Novartis, Roche, Pfizer Inc, UCB, Celgene, Regeneron, Amgen, AstraZeneca, GlaxoSmithKline, Speakers bureau: Novartis, Roche, A. Hazra Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Mebus Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Alvey Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Lamba Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, U. Conte Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Tzaribachev Grant/research support from: Pfizer Inc, UCB, Roche, I. Foeldvari: None declared, G. Horneff Grant/research support from: AbbVie, Chuigai, Pfizer Inc, Roche, D. Kingsbury Grant/research support from: Pfizer Inc, E. Koskova: None declared, E. Smolewska: None declared, R. Vehe Grant/research support from: Bristol-Myers Squibb, Z. Zuber: None declared, A. Martini Consultant for: Abbott, AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, Speakers bureau: Abbott, AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, D. Lovell Consultant for: AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer Inc, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Biogen Idec, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen, Speakers bureau: Genentech, Roche, Novartis
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