Purpose
Omacetaxine mepesuccinate (“omacetaxine”) is approved by the US Food and Drug Administration for the treatment of adult patients with chronic- or accelerated-phase chronic myeloid leukemia ...with resistance and/or intolerance to two or more tyrosine kinase inhibitors. In May 2014, the US Food and Drug Administration approved revisions to the packaging information that included directions for home administration of reconstituted omacetaxine by patients or caregivers using syringes filled at a healthcare facility. We developed recommendations for the transport, storage, and spill-clean procedure of reconstituted omacetaxine for home and clinic administration.
Methods
We conducted chemical stability and microbial growth studies of reconstituted omacetaxine solution stored in vials and syringes at room temperature or refrigerated for various durations. Several shipping configurations were tested in simulated transport conditions to evaluate their ability to contain solution leakage and maintain product quality during distribution. In addition, we evaluated cleaning products and procedures for their effectiveness in removing residual omacetaxine from household surfaces after mock spills.
Results
Reconstituted omacetaxine showed limited degradation when refrigerated for 14 days in vials and syringes, and no microbial growth was observed for 12 days after intentional inoculation. In shipping studies, the configurations maintained prepared syringes within the recommended storage temperature range throughout transport and could contain leaks if spills occurred. In the event of an accidental spill in a home environment, effective cleaning can be achieved using household cleaning products and defined procedures.
Conclusion
These data provide important information regarding the safe transportation and administration of reconstituted omacetaxine in the home and clinic.
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•Orphan drug approval strategies require specific ways to generate clinical evidence.•Real-world data today may well support regulatory submissions of novel cancer drugs.•Learn how ...individual patient data was used for hematological cancer drug approvals.•Consider carefully the multiple methodological concerns and pitfalls when using RWD.
Tafasitamab (TAF) plus lenalidomide (LEN) is a novel treatment option for patients with relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) who are not eligible for autologous stem cell transplantation. The initial US/EU approvals for TAF represent precedents because this is the first time that approval of a novel combination therapy was granted based on a pivotal single-arm trial (SAT). Matching real-world data (RWD) helped to disentangle the contribution of individual agents. In this review, we present the TAF development strategy, the prospective incorporation of RWD within the clinical development plan, the corresponding regulatory hurdles of this strategy, and the prior regulatory actions for other cancer drugs that previously incorporated RWD and propensity score matching in EU and US regulatory submissions. We also outline how RWD could further advance and impact orphan drug development.
•Heterogeneity in perception and non-repeatability can result in temporal imprecision.•Imprecision can make the interpretation of TDS/CATA curves/difference curves tricky.•Temporal differences within ...and between products were tested using bootstrap.•Time-variability plots enable to visualize uncertainty in periods of perception.•Differences lasting for less than 10% of total duration can be uncertain/spurious.
Temporal Dominance of Sensations (TDS) and Temporal Check-All-That-Apply (TCATA) make it possible to capture temporal changes in the perception of sensory attributes within a product. However, temporal measurements bring new sources of uncontrolled variability that can make them imprecise, particularly with consumer panels. This article aims to demonstrate the importance of considering this imprecision when interpreting temporal data. First, the levels of imprecision due to non-repeatability or disagreement were assessed. The precision of TDS and TCATA was shown to be low, mainly due to disagreement caused by high heterogeneity in total durations of perception. Then, a new framework of analysis has been introduced. It allowed testing of differences in the median times of selection or unselection of attributes. A new representation of TDS and TCATA data has been proposed to visualize and objectify uncertainty in periods of perception. The conclusions obtained with the new framework were compared to those obtained with the usual analyses based on the evolution of citation rates over time. It was shown that the interpretation of TDS/TCATA curves and difference curves can be tricky without guidelines regarding the minimum size of differences that can be considered significant and interpretable. Finally, it was shown that the temporal resolution of the methods was about 10% of the total duration of the perception. These findings question the ability of TDS and TCATA to capture subtle temporal differences. Therefore, recommendations were made for interpreting temporal data in a way that robust conclusions can be drawn.
This paper deals with the homology computation of a subdivided object during its construction. In this paper, we focus on the construction operation consisting of merging cells. For each step of the ...construction, a homological equivalence is maintained. This algebraic structure connects the chain complex associated with the object to a smaller object (i.e. containing less cells) having the same homology. So, homology computation is achieved on this smaller object more efficiently than on the constructed object, due to their respective sizes. We prove that, at each step, maintaining the homological equivalence has a complexity depending only on the size of the part of the object impacted by the operation. We define a convenient data structure based on sparse matrices that guarantees this result in practice, and show some experimental results obtained with its implementation. Moreover, the method may also be used to compute homology groups generators of any dimension at the cost of an increased complexity.
•Application of the Short Exact Sequence theorem in the case of an identification.•Tracking the variations of homology of an object evolving over a construction process.•Homology groups computation, including torsion and generators of any dimension.•Computation with a theoretical complexity depending on the number of identified cells.•Conception and implementation of a data structure ensuring the theoretical complexity.
•Using only one evaluation (no replicate) is sufficient to obtain a good picture of the data.•A second evaluation (1 replicate) allows the discrimination to be slightly improved.•Adding a third ...evaluation (2 replicates) seems not to bring much more information than the second one.
Several evaluations are necessary to test individual repeatability in sensory profiling. But do additional replicates really provide more information than the first evaluation? Statistical analysis of 339 studies with at least two evaluations showed that when using the first evaluation alone:•Significance of product discrimination was identical for 6 out of 7 attributes,•85% of the significant attributes had a similar vector of mean scores ie a correlation coefficient higher than 0.9,•Significance of multivariate product discrimination assessed by MANOVA was identical for 97% of the datasets,•93% of the datasets had a similar product configuration (RV>0.9),•the CVA product maps were similar (according to several criteria including product configurations, attribute positions…).Further, the second evaluation was found less relevant in studies including a small number of products (<5). Finally, a third evaluation seemed irrelevant for the improvement of the statistical analysis.
Proton Transfer Reaction-Time-of-Flight- Mass Spectrometry (PTR-ToF-MS) is an analytical chemistry technique that can be used for measuring the concentration of volatile organic compounds directly in ...the subjects’ noses (nosespace, in vivo analysis) during a tasting and over time. It can be combined with temporal sensory methods such as Temporal Dominance of Sensations (TDS) or Temporal Check All That Apply (TCATA) in order to obtain simultaneous sensory and physico-chemical signals. This paper aims to provide a methodology to analyze in vivo PTR-MS and temporal sensory data and illustrate it on a real dataset. First, relevant pretreatments of PTR-MS data were established, including breathing correction, blank periods removal and standardization. Then, a statistical multiblock analysis was presented: the Regularized Generalized Canonical Correlation Analysis (RGCCA). The versality of the approach was demonstrated, as it can be used to answer most of problematics (exploratory or supervised). Finally, this methodology is illustrated on a dataset of PTR-MS and TDS or TCATA data collected simultaneously. In this study, 16 semi-trained subjects evaluated 3 chocolates in TDS and TCATA on six flavor attributes (Spicy, Cocoa, Woody, Fruity, Roasty and Dry Fruits) with 2 replicates for each sensory method. Results showed that TCATA and TDS gave similar results, but TDS was shown to slightly better preserve the PTR-MS observed product configuration than TCATA. All computing tools developed in this work are freely available.
Proton transfer reaction‐time‐of‐flight‐mass spectrometry (PTR‐ToF‐MS or PTR‐MS) is an analytical chemistry technique that can be used for measuring the concentration of volatile organic compounds ...directly in the subjects' noses (nosespace, in vivo analysis) during a tasting and over time. It can be combined with temporal sensory methods such as temporal dominance of sensations (TDS) or temporal check all that apply (TCATA) in order to obtain simultaneous sensory and physico‐chemical signals. This paper aims to provide a methodology to analyze in vivo PTR‐MS and temporal sensory data and illustrate it on a real dataset. First, relevant pretreatments of PTR‐MS data were established, including breathing correction, blank periods removal, and standardization. Then, a statistical multiblock analysis was presented: the regularized generalized canonical correlation analysis (RGCCA). The versality of the approach was demonstrated, as it can be used to answer most of problematics (exploratory or supervised). Finally, this methodology is illustrated on a dataset of PTR‐MS and TDS or TCATA data collected simultaneously. In this study, 16 semitrained subjects evaluated three chocolates in TDS and TCATA on six flavor attributes (Spicy, Cocoa, Woody, Fruity, Roasty, and Dry Fruits) with two replicates for each sensory method. Results showed that TCATA and TDS gave similar results, but TDS was shown to slightly better preserve the PTR‐MS observed product configuration than TCATA. All computing tools developed in this work are freely available.
Associations between HIV-related stigma and reduced antiretroviral therapy (ART) adherence are widely established, yet the mechanisms accounting for this relationship are underexplored. There has ...been less attention to HIV-related stigma and its associations with ART initiation and current ART use. We examined pathways from HIV-related stigma to ART initiation, current ART use, and ART adherence among women living with HIV in Canada.
We used baseline survey data from a national cohort of women living with HIV in Canada (n = 1425). Structural equation modeling using weighted least squares estimation methods was conducted to test the direct effects of HIV-related stigma dimensions (personalized, negative self-image, and public attitudes) on ART initiation, current ART use, and 90% ART adherence, and indirect effects through depression and HIV disclosure concerns, adjusting for sociodemographic factors.
In the final model, the direct paths from personalized stigma to ART initiation (β = -0.104, P < 0.05) and current ART use (β = -0.142, P < 0.01), and negative self-image to ART initiation (β = -0.113, P < 0.01) were significant, accounting for the mediation effects of depression and HIV disclosure concerns. Depression mediated the pathways from personalized stigma to ART adherence, and negative self-image to current ART use and ART adherence. Final model fit indices suggest that the model fit the data well χ(25) = 90.251, P < 0.001; comparative fit index = 0.945; root-mean-square error of approximation = 0.044.
HIV-related stigma is associated with reduced likelihood of ART initiation and current ART use, and suboptimal ART adherence. To optimize the benefit of ART among women living with HIV, interventions should reduce HIV-related stigma and address depression.
•Carrot represents one of the most important carotenoid intakes and is a very interesting model to study carotenoid metabolism.•Abiotic and biotic stresses applied separately or in combination may ...have an impact on carotenoid accumulation.•In carrot roots, the decrease in carotenoid content could be mostly associated with A. dauci infection.•Stresses impact carotenoid content in leaves depending on the genotype and the year.•Stresses affect plant metabolism and subsequently the carotenoid accumulation.
Carotenoids are important secondary metabolites involved in plant photosynthesis, vegetable nutritional quality but also in metabolic prevention in human health. Carrot represents one of the most important carotenoid intakes and is a very interesting model to study carotenoid metabolism. Till now, the knowledge about the impact of stress on carotenoid accumulation is limited. The purpose of this work was to investigate the impact of abiotic and biotic stresses applied separately or in combination on carotenoid accumulation in carrot leaves and roots. Results showed that combined stress decreased dramatically carotenoid content in both organs. In roots, the decrease in carotenoid content could be mostly associated in carrot response to A. dauci infection. Moreover, carotenoid and sugar contents were highly correlated, which suggests that stored metabolites are directly or indirectly involved in plant response to pathogen infection. In leaves, in contrast to results observed in roots, stresses impact carotenoid content depending on the genotype and the year. Moreover, carotenoid content variations were correlated to chlorophyll contents suggesting that a common mechanism of regulation for photosynthetic biosynthesis pigment exists.
Background and Aims
Identifying typologies of social determinants of health (SDoH) vulnerability influencing drug use practices among women living with HIV (WLWH) can help to address associated ...harms. This research aimed to explore the association of SDoH clusters with drug use among WLWH.
Design
Latent class analysis (LCA) was used to identify the distinct clusters of SDoH. Inverse probability weighting (IPW) was employed to account for confounding and potential selection bias. Associations were analyzed using generalized linear model with log link and Poisson distribution, and then weighted risk ratio (RR) and 95% confidence intervals (CI) were reported.
Setting and Participants
Data from 1422 WLWH recruited at time‐point 1 of the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS, 2013–15), with 1252 participants at 18 months follow‐up (time‐point 2).
Measurements
Drug use was defined as use of illicit/non‐prescribed opioids/stimulants in the past 6 months. SDoH indicators included: race discrimination, gender discrimination, HIV stigma, social support, access to care, food security, income level, employment status, education, housing status and histories of recent sex work and incarceration.
Findings
LCA identified four SDoH classes: no/least SDoH adversities (6.6%), discrimination/stigma (17.7%), economic hardship (30.8%) and most SDoH adversities (45.0%). Drug use was reported by 17.5% and 17.2% at time‐points 1 and 2, respectively. WLWH with no/least SDoH adversities were less likely to report drug use than those in economic hardship class (weighted RR = 0.13; 95% CIs = 0.03, 0.63), discrimination/stigma class (weighted RR = 0.15; 95% CIs = 0.03, 0.78), and most SDoH adversities class (weighted RR = 0.13; 95% CIs = 0.03, 0.58).
Conclusions
Social determinants of health vulnerabilities are associated with greater likelihood of drug use, underscoring the significance of addressing interlinked social determinants and drug use through the course of HIV care and treatment.
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