Real world costs and cost-effectiveness of Rituximab for diffuse large B-cell lymphoma patients: a population-based analysis.

BackgroundCurrent treatment of diffuse-large-B-cell lymphoma (DLBCL) includes rituximab, an expensive drug, combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Economic models have predicted rituximab plus CHOP (RCHOP) to be a cost-effective alternative to CHOP alone as first-line treatment of DLBCL, but it remains unclear what its real-world costs and cost-effectiveness are in routine clinical practice.MethodsWe performed a population-based retrospective cohort study from 1997 to 2007, using linked administrative databases in Ontario, Canada, to evaluate the costs and cost-effectiveness of RCHOP compared to CHOP alone. A historical control cohort (n = 1,099) with DLBCL who received CHOP before rituximab approval was hard-matched on age and treatment intensity and then propensity-score matched on sex, comorbidity, and histology to 1,099 RCHOP patients. All costs and outcomes were adjusted for censoring using the inverse probability weighting method. The main outcome measure was incremental cost per life-year gained (LYG).ResultsRituximab was associated with a life expectancy increase of 3.2 months over 5 years at an additional cost of $16,298, corresponding to an incremental cost-effectiveness ratio of$61,984 (95% CI $34,087-$135,890) per LYG. The probability of being cost-effective was 90% if the willingness-to-pay threshold was $100,000/LYG. The cost-effectiveness ratio was most favourable for patients less than 60 years old ($31,800/LYG) but increased to $80,600/LYG for patients 60-79 years old and$110,100/LYG for patients ≥ 80 years old. We found that post-market survival benefits of rituximab are similar to or lower than those reported in clinical trials, while the costs, incremental costs and cost-effectiveness ratios are higher than in published economic models and differ by age.ConclusionsOur results showed that the addition of rituximab to standard CHOP chemotherapy was associated with improvement in survival but at a higher cost, and was potentially cost-effective by standard thresholds for patients <60 years old. However, cost-effectiveness decreased significantly with age, suggesting that rituximab may be not as economically attractive in the very elderly on average. This has important clinical implications regarding age-related use and funding decisions on this drug

Factors affecting the bacterial community composition and heterotrophic production of Columbia River estuarine turbidity maxima

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in MicrobiologyOpen 6 (2017): e00522, doi:10.1002/mbo3.522.Estuarine turbidity maxima (ETM) function as hotspots of microbial activity and diversity in estuaries, yet, little is known about the temporal and spatial variability in ETM bacterial community composition. To determine which environmental factors affect ETM bacterial populations in the Columbia River estuary, we analyzed ETM bacterial community composition (Sanger sequencing and amplicon pyrosequencing of 16S rRNA gene) and bulk heterotrophic production (3H-leucine incorporation rates). We collected water 20 times to cover five ETM events and obtained 42 samples characterized by different salinities, turbidities, seasons, coastal regimes (upwelling vs. downwelling), locations, and particle size. Spring and summer populations were distinct. All May samples had similar bacterial community composition despite having different salinities (1–24 PSU), but summer non-ETM bacteria separated into marine, freshwater, and brackish assemblages. Summer ETM bacterial communities varied depending on coastal upwelling or downwelling conditions and on the sampling site location with respect to tidal intrusion during the previous neap tide. In contrast to ETM, whole (>0.2 μm) and free-living (0.2–3 μm) assemblages of non-ETM waters were similar to each other, indicating that particle-attached (>3 μm) non-ETM bacteria do not develop a distinct community. Brackish water type (ETM or non-ETM) is thus a major factor affecting particle-attached bacterial communities. Heterotrophic production was higher in particle-attached than free-living fractions in all brackish waters collected throughout the water column during the rise to decline of turbidity through an ETM event (i.e., ETM-impacted waters). However, free-living communities showed higher productivity prior to or after an ETM event (i.e., non-ETM-impacted waters). This study has thus found that Columbia River ETM bacterial communities vary based on seasons, salinity, sampling location, and particle size, with the existence of three particle types characterized by different bacterial communities in ETM, ETM-impacted, and non-ETM-impacted brackish waters. Taxonomic analysis suggests that ETM key biological function is to remineralize organic matter.National Science Foundation Grant Number: OCE-042460

Prediction of preterm birth with and without preeclampsia using mid-pregnancy immune and growth-related molecular factors and maternal characteristics.

OBJECTIVE:To evaluate if mid-pregnancy immune and growth-related molecular factors predict preterm birth (PTB) with and without (±) preeclampsia. STUDY DESIGN:Included were 400 women with singleton deliveries in California in 2009-2010 (200 PTB and 200 term) divided into training and testing samples at a 2:1 ratio. Sixty-three markers were tested in 15-20 serum samples using multiplex technology. Linear discriminate analysis was used to create a discriminate function. Model performance was assessed using area under the receiver operating characteristic curve (AUC). RESULTS:Twenty-five serum biomarkers along with maternal age <34 years and poverty status identified >80% of women with PTB ± preeclampsia with best performance in women with preterm preeclampsia (AUC = 0.889, 95% confidence interval (0.822-0.959) training; 0.883 (0.804-0.963) testing). CONCLUSION:Together with maternal age and poverty status, mid-pregnancy immune and growth factors reliably identified most women who went on to have a PTB ± preeclampsia

Sunitinib in relapsed or refractory diffuse large B-cell lymphoma: a clinical and pharmacodynamic phase II multicenter study of the NCIC Clinical Trials Group

There are limited effective therapies for most patients with relapsed diffuse large B-cell lymphoma (DLBCL). We conducted a phase II trial of the multi-targeted vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, sunitinib, 37.5 mg given orally once daily in adult patients with relapsed or refractory DLBCL. Of 19 enrolled patients, 17 eligible patients were evaluable for toxicity and 15 for response. No objective responses were seen and nine patients achieved stable disease (median duration 3.4 months). As a result, the study was closed at the end of the first stage. Grades 3—4 neutropenia and thrombocytopenia were observed in 29% and 35%, respectively. There was no relationship between change in circulating endothelial cell numbers (CECs) and bidimensional tumor burden over time. Despite some activity in solid tumors, sunitinib showed no evidence of response in relapsed/refractory DLBCL and had greater than expected hematologic toxicity

Heterogeneity of Multifunctional IL-17A Producing S. Typhi-Specific CD8+ T Cells in Volunteers following Ty21a Typhoid Immunization

Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, continues to cause significant morbidity and mortality world-wide. CD8+ T cells are an important component of the cell mediated immune (CMI) response against S. Typhi. Recently, interleukin (IL)-17A has been shown to contribute to mucosal immunity and protection against intracellular pathogens. To investigate multifunctional IL-17A responses against S. Typhi antigens in T memory subsets, we developed multiparametric flow cytometry methods to detect up to 6 cytokines/chemokines (IL-10, IL-17A, IL-2, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1β (MIP-1β)) simultaneously. Five volunteers were immunized with a 4 dose regimen of live-attenuated S. Typhi vaccine (Ty21a), peripheral blood mononuclear cells (PBMC) were isolated before and at 11 time points after immunization, and CMI responses were evaluated. Of the 5 immunized volunteers studied, 3 produced detectable CD8+ T cell responses following stimulation with S. Typhi-infected autologous B lymphoblastoid cell lines (B-LCL). Additionally, 2 volunteers had detectable levels of intracellular cytokines in response to stimulation with S. Typhi-infected HLA-E restricted cells. Although the kinetics of the responses differed among volunteers, all of the responses were bi- or tri-phasic and included multifunctional CD8+ T cells. Virtually all of the IL-17A detected was derived from multifunctional CD8+ T cells. The presence of these multifunctional IL-17A+ CD8+ T cells was confirmed using an unsupervised analysis program, flow cytometry clustering without K (FLOCK). This is the first report of IL-17A production in response to S. Typhi in humans, indicating the presence of a Tc17 response which may be important in protection. The presence of IL-17A in multifunctional cells co-producing Tc1 cytokines (IL-2, IFN-γ and TNF-α) may also indicate that the distinction between Tc17 and Tc1 responses in humans is not as clearly delineated as suggested by in vitro experiments and animal models

Sex differences in the Simon task help to interpret sex differences in selective attention.

In the last decade, a number of studies have reported sex differences in selective attention, but a unified explanation for these effects is still missing. This study aims to better understand these differences and put them in an evolutionary psychological context. 418 adult participants performed a computer-based Simon task, in which they responded to the direction of a left or right pointing arrow appearing left or right from a fixation point. Women were more strongly influenced by task-irrelevant spatial information than men (i.e., the Simon effect was larger in women, Cohen's d = 0.39). Further, the analysis of sex differences in behavioral adjustment to errors revealed that women slow down more than men following mistakes (d = 0.53). Based on the combined results of previous studies and the current data, it is proposed that sex differences in selective attention are caused by underlying sex differences in core abilities, such as spatial or verbal cognition

Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases

Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination ‘as a public health problem’ when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models’ predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020

Sampling strategies to measure the prevalence of common recurrent infections in longitudinal studies

<p>Abstract</p> <p>Background</p> <p>Measuring recurrent infections such as diarrhoea or respiratory infections in epidemiological studies is a methodological challenge. Problems in measuring the incidence of recurrent infections include the episode definition, recall error, and the logistics of close follow up. Longitudinal prevalence (LP), the proportion-of-time-ill estimated by repeated prevalence measurements, is an alternative measure to incidence of recurrent infections. In contrast to incidence which usually requires continuous sampling, LP can be measured at intervals. This study explored how many more participants are needed for infrequent sampling to achieve the same study power as frequent sampling.</p> <p>Methods</p> <p>We developed a set of four empirical simulation models representing low and high risk settings with short or long episode durations. The model was used to evaluate different sampling strategies with different assumptions on recall period and recall error.</p> <p>Results</p> <p>The model identified three major factors that influence sampling strategies: (1) the clustering of episodes in individuals; (2) the duration of episodes; (3) the positive correlation between an individual's disease incidence and episode duration. Intermittent sampling (e.g. 12 times per year) often requires only a slightly larger sample size compared to continuous sampling, especially in cluster-randomized trials. The collection of period prevalence data can lead to highly biased effect estimates if the exposure variable is associated with episode duration. To maximize study power, recall periods of 3 to 7 days may be preferable over shorter periods, even if this leads to inaccuracy in the prevalence estimates.</p> <p>Conclusion</p> <p>Choosing the optimal approach to measure recurrent infections in epidemiological studies depends on the setting, the study objectives, study design and budget constraints. Sampling at intervals can contribute to making epidemiological studies and trials more efficient, valid and cost-effective.</p